TW202417441A - Autotaxin inhibiting compound, autotaxin inhibitor composition and pharmaceutical composition containing the same - Google Patents

Abstract

The present disclosure relates to a novel compound for inhibiting autotaxin, a stereoisomer thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, an autotaxin inhibitor composition and a pharmaceutical composition containing the same.

Description

Compounds as inhibitors of phosphatidic acid hydrolysis synthase and pharmaceutical compositions containing the same

This application claims priority to and benefits of Korean Patent Application No. 10-2022-0106558 filed with the Korean Intellectual Property Office on August 25, 2022, and all contents of the said Korean patent application are incorporated herein by reference.

The present disclosure relates to a novel compound as a phosphatidic acid synthase inhibitor and a pharmaceutical composition containing the same for treating and preventing pathological conditions or diseases caused by activation of phosphatidic acid synthase or increased lysophosphatidic acid concentration.

Autotaxin (ATX) is an enzyme that causes an increase in lysophosphatidic acid (LPA) in ascites and plasma and is an important secreted enzyme in the conversion of lisophosphatidylcholine (LPC) to lysophosphatidic acid, a biologically active signaling molecule. Autotaxin is also known as ectonucleotide pyrophosphatase/phosphodiesterase-2 (ENPP-2) or lysophospholipase D (lysoPLD) and plays a role in the pathological conditions that include fibrosis, arthritis, neurodegeneration, neuropathic pain, and cancer.

Lysophosphatidic acid is a physiologically active lipid that affects the migration, proliferation, and survival of various cell types. Since the activity of lysophosphatidic acid in plasma is highly correlated with the activity of phosphatidic acid synthase, phosphatidic acid synthase is considered to be an important source of extracellular lysophosphatidic acid.

Inhibition of phosphatidic acid synthase pathologically reduces lysophosphatidic acid and is known to be effective in treating diseases such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrodegenerative diseases (e.g., idiopathic pulmonary fibrosis (IPF)), thrombosis, and cholestatic pruritus that are caused or involved in the activation of lysophosphatidic acid or phosphatidic acid synthase.

For the treatment of cancer patients, it is preferred to reduce the level of lysophosphatidic acid, and this can be achieved, for example, by inhibiting enzymes involved in the biosynthesis of lysophosphatidic acid, such as hydrophosphatidic acid synthase. Hydrophosphatidic acid synthase belongs to the enzyme family of nucleotide pyrophosphatases and phosphodiesterases and provides an important starting point for anti-tumor therapy. This is due to the fact that hydrophosphatidic acid synthase is expressed at increased levels in tumors, thereby allowing tumor cells to proliferate and invade into neighboring tissues, and this may lead to metastasis formation.

In other words, since phosphatidic acid synthase is expressed in tumors and allows tumor cells to proliferate and invade surrounding tissues (both of which may lead to metastasis formation), phosphatidic acid synthase is a target for anti-tumor therapy. In addition, during the angiogenesis process, phosphatidic acid synthase, together with other angiogenic factors, leads to blood vessel formation. During tumor growth, angiogenesis supplies nutrients to the tumor. Therefore, inhibiting angiogenesis can be considered an important starting point for cancer and tumor treatment.

Based on the above principle, there is an increasing need for a class of anti-tumor compounds that can inhibit the hydrolysis of phosphatidic acid synthase and treat various types of cancer. Prior art documents Patent documents (Patent document 1) U.S. Patent Application Publication No. 2021-0009589 (January 14, 2021) (Patent document 2) International Patent Publication No. WO2018-212534 (November 22, 2018)

[Technical issues]

Therefore, the inventors of the present disclosure have identified compounds with novel structures that exhibit excellent inhibitory activity against phosphatidic acid synthase, and have completed the present disclosure.

The present disclosure relates to providing a novel compound as a phosphatidic acid synthase inhibitor for treating and preventing pathological conditions or diseases caused by the activation of phosphatidic acid synthase, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound or a pharmaceutically acceptable salt of the compound.

The present disclosure also relates to providing a phosphatidic acid synthase inhibitor composition, which comprises a phosphatidic acid synthase inhibitor compound, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound as an active substance.

The present disclosure also relates to providing a pharmaceutical composition for preventing or treating a disease associated with the activity of phosphatidic acid synthase, wherein the pharmaceutical composition comprises as an active substance a compound that is a phosphatidic acid synthase inhibitor, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound. [Technical Solution]

In view of the above, an embodiment of the present disclosure provides a novel compound represented by the following chemical formula 1, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound, which can effectively inhibit the activity of hydrolyzing phosphatidic acid synthase. [Chemical formula 1]

In Chemical Formula 1, A is a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, L is a single bond, -C(=O)-, -C(=O)-NR ₁ -, -C(=O)-NR ₂ -(CR ₃ R ₄ ) _a - or -S(=O) ₂ -NR ₅ -, B is a substituted or unsubstituted carbocyclic ring; or a substituted or unsubstituted heterocyclic ring, R ₁ to R ₅ are each independently hydrogen or a substituted or unsubstituted C1-C10 alkyl group, and a is an integer from 1 to 5.

A may be a substituted or unsubstituted 5- to 6-membered heteroaryl ring having 1 to 4 hetero atoms independently selected from nitrogen, oxygen and sulfur; a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing a triazole group; or a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing an oxazolidinone group.

A may be a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted benzoxazolonyl group, a substituted or unsubstituted benzotriazolyl group, a substituted or unsubstituted tetrahydrobenzotriazolyl group, a substituted or unsubstituted triazolopyridyl group or a substituted or unsubstituted tetrahydrotriazolopyridine group.

A can be selected from the following structures.

Ra is hydrogen, _R6 -S(=O) ₂ -NH-, _R6 -S(=O) ₂ - _CH2- or tetrazolyl, Rb is halogen or substituted or unsubstituted C1-C10 alkoxy, _R6 is hydroxyl or substituted or unsubstituted C1-C10 alkyl, d is an integer from 0 to 6, and e is an integer from 0 to 3.

A can be selected from the following structures.

Rb is a halogen or a substituted or unsubstituted C1-C10 alkoxy group, and e is an integer from 0 to 1.

L can be selected from the following structures.

_R3 and _R4 are each independently hydrogen or substituted or unsubstituted C1-C5 alkyl.

B may be a substituted or unsubstituted C6-C10 carbon ring; or a substituted or unsubstituted 5- to 11-membered mono- or di-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

B may be a substituted or unsubstituted C6-C10 aryl group; a substituted or unsubstituted 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a substituted or unsubstituted 8- to 11-membered spiro ring including an isoxazolyl group.

B may be a substituted or unsubstituted phenylene group, a substituted or unsubstituted pyridone group, a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted thiazolyl group, or a substituted or unsubstituted thiadiazolyl group.

B can be selected from the following structures.

Rc and Rc1 to Rc6 are each independently hydrogen, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, -NR ₇ R ₈ or -C(=O)OR ₉ , wherein R ₇ and R ₈ may be linked to each other to form a saturated monocyclic ring, and the formed ring may include one or more heteroatoms selected from nitrogen or oxygen, and may be further substituted by one or more substituents selected from hydroxyl and substituted or unsubstituted C1-C10 alkyl, R ₉ is hydrogen, substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C3-C10 cycloalkyl, and f is an integer from 0 to 4, g is an integer from 0 to 2, h is an integer from 0 to 3, s and t are the same as or different from each other and are each independently an integer from 0 to 4, and herein, the sum of s and t is 2 to 5.

B can be selected from the following structures.

Rc is hydrogen, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy _{, -NR7R8} or -C(=O) _OR9 , wherein _R7 and _R8 may be bonded to each other to form a saturated monocyclic ring, and the formed ring may include one or more heteroatoms selected from nitrogen or oxygen, _R9 is hydrogen or substituted or unsubstituted C1-C10 alkyl, and f is an integer from 0 to 4.

In addition, one embodiment of the present disclosure provides a phosphatidic acid synthase inhibitor composition, which comprises the compound, the stereoisomer of the compound, the hydrate of the compound, the solvate of the compound or the pharmaceutically acceptable salt of the compound as an active substance.

In addition, an embodiment of the present disclosure provides a pharmaceutical composition for preventing or treating diseases related to the activity of hydrolyzed phosphatidic acid synthase by identifying the excellent hydrolyzed phosphatidic acid synthase inhibitory activity of the compound represented by Chemical Formula 1, the pharmaceutical composition comprising as an active substance a compound represented by Chemical Formula 1, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound. [Beneficial Effects]

The compound according to the present disclosure is a novel compound and can be usefully used for treating, preventing and alleviating diseases mediated and caused by phosphatidic acid synthase without side effects by showing very high inhibitory activity against phosphatidic acid synthase.

Hereinafter, the present disclosure will be described in more detail.

The following description needs to be understood as describing specific embodiments of the present disclosure, and the present disclosure is not necessarily limited thereto. The embodiments of the present disclosure may undergo various changes and may be implemented in various forms. Therefore, the following description needs to be understood as including all changes, equivalent forms, and substituted forms within the scope of recognizing the sameness of the concepts and technical features of the present disclosure.

Even when not otherwise indicated, it is to be understood that in each instance, all numbers used in the present disclosure are modified by the term "about". The modifier "about" is intended to have the commonly recognized meaning of "approximately", and this may be more accurately interpreted as having the meaning of being within a particular percentage of the modified value, and more specifically may mean ±20%, ±10%, ±5%, ±2%, ±1% or less than ±1%.

The definition of each substituent used in this specification will be explained in detail. Unless otherwise specified, each substituent has the following definition.

The term "alkyl" as used herein refers to a monovalent straight or branched saturated alkyl group formed only of carbon and hydrogen atoms, and the alkyl group may have 1 to 10 carbon atoms, and preferably has 1 to 7 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like, but are not limited thereto.

The term "aryl" in the present disclosure refers to a carbocyclic organic group derived from an aromatic hydrocarbon by removing one hydrogen, and the aryl group includes a monocyclic system or a condensed ring system containing 4 to 7 and preferably 5 or 6 ring atoms in each ring, and also includes a form in which multiple aryl groups are linked by a single bond. Specific examples of aryl groups include phenyl, naphthyl, biphenyl, anthracenyl, indenyl, fluorenyl and similar groups, but are not limited thereto. The aryl group may be linked to other groups at appropriate positions on the aromatic ring.

The term "heteroaryl" disclosed herein refers to an aryl group containing 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeleton atoms and having carbon as the remaining aromatic ring skeleton atoms. The heteroaryl group may be a 5-6 membered monocyclic heteroaryl group and a polycyclic heteroaryl group fused to one or more benzene rings, and may be partially saturated. In addition, the heteroaryl group in the present disclosure also includes a form in which one or more heteroaryl groups are linked by a single bond. Examples of heteroaryl groups include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzimidazole, isoxazole, benzoisoxazole, thiophene, benzothiophene, furan, benzofuran and similar groups, but are not limited thereto.

The term “halogen” or “halogen” used in the present disclosure refers to a halogen-based element, and examples of the halogen or halogen include fluorine, chlorine, bromine and iodine.

The term "cycloalkyl" used in the present disclosure refers to a monovalent saturated carbocyclic organic group formed by one or more rings, and the cycloalkyl group may have 3 to 10 carbon atoms and preferably has 3 to 7 carbon atoms. Specific examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, but are not limited thereto.

The term "alkoxy" in the present disclosure refers to an -O-alkyl organic group, and the alkoxy group may have 1 to 10 carbon atoms and preferably 1 to 7 carbon atoms. In this document, "alkyl" has the same definition as above. Specific examples of alkoxy include methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and similar groups, but are not limited thereto.

The term "heterocyclic ring" used in the present disclosure refers to an aromatic ring or non-aromatic ring containing a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring-forming atom in addition to a carbon atom, and the heterocyclic ring preferably includes a 4- to 10-membered, more preferably a 5- to 9-membered aromatic ring or non-aromatic ring containing 1 to 4 of the heteroatom. Examples of such aromatic rings include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and benzothiazolyl. In addition, examples of such non-aromatic rings include tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrooxazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxolinyl, thiooxolinyl, azacycloheptanyl, diazacycloheptanyl and azapentyl.

The terms "arylene" and "heteroarylene" used herein refer to divalent organic groups of aromatic rings and heteroaryl rings.

The terms "heterocycloalkyl" and "heterocycloalkenyl" used herein refer to saturated heterocyclic and unsaturated heterocyclic divalent organic groups.

One embodiment of the present disclosure provides a compound represented by the following Chemical Formula 1, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound. [Chemical Formula 1]

In Chemical Formula 1, A is a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, L is a single bond, -C(=O)-, -C(=O)-NR ₁ -, -C(=O)-NR ₂ -(CR ₃ R ₄ ) _a - or -S(=O) ₂ -NR ₅ -, B is a substituted or unsubstituted carbocyclic ring; or a substituted or unsubstituted heterocyclic ring, R ₁ to R ₅ are each independently hydrogen or a substituted or unsubstituted C1-C10 alkyl group, and a is an integer from 1 to 5.

The compound of Chemical Formula 1 according to the present disclosure is a novel compound and inhibits the production of lysophosphatidic acid due to its very high inhibitory activity against phosphatidic acid synthase, and thus can be used as a therapeutic agent and a prophylactic agent for diseases in which phosphatidic acid synthase is involved (particularly kidney disease, liver disease, inflammatory disease, neurological disease, fibrodegenerative disease, and acute or chronic organ transplant rejection).

In the compound according to one embodiment of the present disclosure, A may be a substituted or unsubstituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing a triazole group; or a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing an oxazolidinone group.

In the compound according to one embodiment of the present disclosure, A may be a substituted or unsubstituted pyridyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted benzoxazolone group, a substituted or unsubstituted benzotriazolyl group, a substituted or unsubstituted tetrahydrobenzotriazolyl group, a substituted or unsubstituted triazolopyridyl group, or a substituted or unsubstituted tetrahydrotriazolopyridyl group.

In the compound according to one embodiment of the present disclosure, A can be selected from the following structures.

In the structure, Ra is hydrogen, R ₆ -S(=O) ₂ -NH-, R ₆ -S(=O) ₂ -CH ₂ - or tetrazolyl ( ), Rb is halogen or substituted or unsubstituted C1-C10 alkoxy, _R6 is hydroxyl or substituted or unsubstituted C1-C10 alkyl, d is an integer from 0 to 6, and e is an integer from 0 to 3.

In the compound according to one embodiment of the present disclosure, A can be selected from the following structures.

In the structure, Rb is halogen or substituted or unsubstituted C1-C10 alkoxy, and e is an integer from 0 to 1.

In the compound according to one embodiment of the present disclosure, L can be selected from the following structures.

In the structure, _R3 and _R4 are each independently hydrogen or a substituted or unsubstituted C1-C5 alkyl group.

In the compound according to one embodiment of the present disclosure, B may be a substituted or unsubstituted C6-C10 carbon ring; or a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In the compound according to one embodiment of the present disclosure, B may be a substituted or unsubstituted C6-C10 aryl group; a substituted or unsubstituted 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a substituted or unsubstituted 8- to 11-membered spiro ring containing an isoxazolyl group.

In the compound according to one embodiment of the present disclosure, B may be a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridonyl group, a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted thiazolyl group, or a substituted or unsubstituted thiadiazolyl group.

In the compound according to one embodiment of the present disclosure, B can be selected from the following structures.

In the structure, Rc and Rc1 to Rc6 are each independently hydrogen, a halogen group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C10 alkoxy group, -NR ₇ R ₈ or -C(=O)OR ₉ , wherein R ₇ and R ₈ may be linked to each other to form a saturated monocyclic ring, and the formed ring may include one or more heteroatoms selected from nitrogen or oxygen, and may be further substituted with one or more substituents selected from a hydroxyl group and a substituted or unsubstituted C1-C10 alkyl group, R ₉ is hydrogen, substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C3-C10 cycloalkyl, f is an integer from 0 to 4, g is an integer from 0 to 2, h is an integer from 0 to 3, and s and t are the same as or different from each other and are each independently an integer from 0 to 4, and herein, the sum of s and t is 2 to 5.

In the compound according to one embodiment of the present disclosure, B can be selected from the following structures.

In the structure, Rc is hydrogen, a halogen group, a hydroxyl group, a carboxyl group, _a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C10 alkoxy group, _-NR7R8 or -C(=O) _OR9 , wherein _R7 and _R8 may be bonded to each other to form a saturated monocyclic ring, and the formed ring may include one or more heteroatoms selected from nitrogen or oxygen, _R9 is hydrogen or a substituted or unsubstituted C1-C10 alkyl group, and f is an integer from 0 to 4.

In the compound according to one embodiment of the present disclosure, the compound can be specifically selected from the structures in Table 1 below, but is not limited thereto. [Table 1] 1 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 2 ( S ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 3 ( R ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 4 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)benzyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 5 ( R ) -N- (1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 6 N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-2-fluorobenzyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 7 3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro- 1H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamido)methyl)benzoic acid methyl ester 8 N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide 9 (7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridin-5-yl)methanone 10 (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone 11 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamido)methyl)benzoic acid 12 ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 13 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-fluoro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 14 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 15 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonamido)isosonicotinamide 16 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(methylsulfonamido)nicotinamide 17 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonamido)thiazole-4-carboxamide 18 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-((methylsulfonyl)methyl)nicotinamide 19 (5-((3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)aminoformyl)pyridin-2-yl)methanesulfonic acid 20 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-((methylsulfonyl)methyl)isonicotinamide twenty one N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-( 1H -tetrazol-5-yl)nicotinamide twenty two ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide twenty three N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-6-fluoro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide twenty four 6-(2,2-Difluoroethoxy) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl) -1H -benzo[ d ][1,2,3]triazole-5-carboxamide 25 ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-isopropoxyphenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 26 ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-(dimethylamino)phenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 27 ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxolinylphenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 28 ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylphenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 29 ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 30 6-(2,2-Difluoroethoxy) -N- (1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-6 - oxo-1,6-dihydropyridin-3-yl) -1H -benzo[ d ][1,2,3]triazole-5-carboxamide 31 ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 32 N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 33 ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 34 ( R ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 35 N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 36 6-(2,2-Difluoroethoxy) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl) -1H -benzo[ d ][1,2,3]triazole-5-carboxamide 37 ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-4-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 38 ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 39 ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 40 (S)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide 41 (S)-N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide 42 ( S )- N -(( S )-1-(4-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide 43 ( S ) -N -(( R )-1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide 44 ( R ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxamide 45 (5S)-N-(1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide 46 ( R )- N -(( R )-1-(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide 47 ( R ) -N- (1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxamide 48 ( S )-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazol-5-yl)methanone 49 ( R )-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazol-5-yl)methanone 50 6-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)benzo[ d ]oxazol-2( 3H )-one 51 N- (4-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide 52 N- (5-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide 53 (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl)((S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone 54 ( S )-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)(4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazol-5-yl)methanone 55 N- (4-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carbonyl)pyridin-2-yl)methanesulfonamide 56 N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl) -1H -benzo[ d ][1,2,3]triazole-5-sulfonamide 57 N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl) -1H -benzo[ d ][1,2,3]triazole-5-sulfonamide

As a result of biochemical and pharmacological tests, the compound of Chemical Formula 1 according to the present disclosure exhibits excellent inhibitory activity against phosphatidic acid synthase and simultaneously reduces the concentration of lysophosphatidic acid, and thus can exhibit the effect of treating and preventing pathological conditions or diseases caused by activation of phosphatidic acid synthase or increased lysophosphatidic acid concentration.

In order to improve in vivo absorption or increase solubility, the compound represented by Chemical Formula 1 according to the present disclosure can be prepared and used in the form of a hydrate, a solvent complex and a pharmaceutically acceptable salt, and therefore, the hydrate, the solvent complex and the pharmaceutically acceptable salt also fall within the scope of the present disclosure. In addition, since the compound represented by Chemical Formula 1 has a chiral carbon, stereoisomers of the compound exist, and such stereoisomers also fall within the scope of the present disclosure.

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause severe irritation to an organism to which the compound is administered and does not impair the biological activity and properties of the compound. The terms "hydrate", "solvate" and "isomer" also have the same meaning as above. Pharmaceutical salts include pharmaceutically acceptable anion-containing non-toxic acid addition salts formed from acids, such as: inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid or hydroiodic acid; organic carbonic acid, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or salicylic acid; and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. For example, pharmaceutically acceptable carboxylates include metal salts or alkali earth metal salts formed from lithium, sodium, potassium, calcium, magnesium or similar materials; amino acid salts, such as lysine, arginine or guanidine; and organic salts, such as dicyclohexylamine, N-methyl-D-reduced glucosamine, tri(hydroxymethyl)methylamine, diethanolamine, choline or triethylamine and similar salts. The compound of Formula 1 according to the present disclosure can be converted into a salt of the compound using common methods.

The term "hydrate" refers to a compound of the present disclosure or a salt of the compound that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "solvate" refers to a compound of the present disclosure or a salt of the compound that contains a stoichiometric or non-stoichiometric amount of a solvent that is bound by non-covalent intermolecular forces. Preferred solvents in this regard may include solvents that are volatile, non-toxic, and/or suitable for administration to humans.

The term "isomer" refers to a compound of the present disclosure or a salt of the compound that has the same chemical formula or molecular formula but is structurally or spatially different. Such isomers include all of structural isomers (e.g., tautomers) and stereoisomers (e.g., R or S isomers or geometric isomers (trans, cis) with asymmetric carbon centers). All such isomers and mixtures of the isomers also fall within the scope of the present disclosure.

Other terms may be construed as having meanings commonly understood in the art to which this disclosure belongs.

In addition, one embodiment of the present disclosure provides a phosphatidic acid synthase inhibitor composition, which comprises a compound of Chemical Formula 1 as an active substance, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound.

In addition, one embodiment of the present disclosure provides a pharmaceutical composition for preventing or treating a disease associated with the activity of hydrolyzing phosphatidic acid synthase, the pharmaceutical composition comprising as an active substance a compound of Chemical Formula 1, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharmaceutically acceptable salt of the compound.

As described above, the compound of Chemical Formula 1, the stereoisomer of the compound, the hydrate of the compound, the solvate of the compound or the pharmaceutically acceptable salt of the compound exhibits high inhibitory activity against hydrolyzed phosphatidic acid synthase and simultaneously inhibits the production of lysophosphatidic acid. Therefore, the pharmaceutical composition comprising these materials as active substances can be usefully used as an effective preventive or therapeutic agent without side effects for diseases mediated by hydrolyzed phosphatidic acid synthase, such as cardiovascular disease, cancer, obesity, diabetes, acute renal failure, chronic kidney disease, diabetic nephropathy, acute renal transplant rejection, chronic allograft nephropathy, cirrhosis, liver hemorrhage, pruritus, non-alcoholic fatty hepatitis, Acute and chronic liver transplant rejection, arthritis, atopic dermatitis, asthma, neuropathic pain, schizophrenia, neuroinflammation, peripheral neuropathy, autonomic neuropathy, systemic disease, vasculitis, sarcoidosis, allergic pneumonia, pulmonary alveolar proteinosis, Langerhan cell granulomatosis, lymphangioleiomyomatosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS) respiratory distress syndrome (ARDS), myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, cystic peritonitis, renal interstitial fibrosis, glomerulosclerosis, nonalcoholic hepatic steatosis, spontaneous pulmonary fibrosis, proliferative and nonproliferative retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous embolism, traumatic injury, glaucoma, chronic pruritus of cholestatic type, and acute or chronic organ transplant rejection.

Cardiovascular diseases include but are not limited to acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, pulsatile disorders (e.g. atrial fibrillation), stroke and other vascular injuries.

Cancers include but are not limited to breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, stomach cancer and similar cancers.

Metabolic diseases include but are not limited to obesity and diabetes.

Kidney diseases include, but are not limited to, acute renal failure and chronic kidney diseases with or without proteinuria (including end-stage renal disease (ESRD)). More specifically, kidney diseases include decreased creatine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with reticuloglomerular intercellular matrix dilation with or without marked hypercellularity (especially diabetic nephropathy and amyloid degeneration), localized thrombosis of the glomerular capillaries (especially thrombotic microangiopathy), global Systemic fibronecrosis, ischemic lesions, malignant nephrosclerosis (e.g., ischemic retractions, decreased renal blood flow, and nephrotic arteriopathies), swelling and proliferation of endocapillary cells (endothelium and interglomerular membrane) and/or extracapillary cells (crescents) (e.g., glomerulonephritis solids), localized segmental glomerulosclerosis, immunoglobulin A (IgA) nephropathy, vasculitis/systemic disease, and acute and chronic renal transplant rejection.

In one embodiment of the present disclosure, the kidney disease is selected from the group consisting of acute renal failure, chronic kidney disease, diabetic nephropathy, acute renal transplant rejection and chronic allograft nephropathy.

Liver diseases include but are not limited to cirrhosis, hepatic bleeding, cholestatic liver disease (e.g. pruritus), non-alcoholic steatohepatitis, and acute and chronic liver transplant rejection.

In one embodiment of the present disclosure, the liver disease is acute and chronic liver transplant rejection.

Inflammatory diseases include, but are not limited to, atopic dermatitis, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, and inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or chronic bronchial asthma.

In one embodiment of the present disclosure, the inflammatory disease is selected from arthritis, idiopathic dermatitis and asthma.

Neurological diseases include, but are not limited to, neuropathic pain, schizophrenia, neuroinflammation (e.g., astrogliosis), peripheral and/or autonomic (diabetic) neuropathy, and the like.

In one embodiment of the present disclosure, the neurological disease is neuropathic pain.

Respiratory diseases include but are not limited to other diffuse parenchymal lung diseases of varying etiologies, such as iatrogenic drug-induced fibrosis, occupational and/or environmentally induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, allergic pneumonitis), collagen vascular disease, pulmonary alveolar proteinosis, Langerhan cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disease, familial interstitial lung disease), radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, or acute respiratory distress syndrome (ARDS).

Fibrotic diseases include but are not limited to myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and cystic peritonitis. In addition, fibrotic diseases are renal interstitial fibrosis or glomerular sclerosis, or non-alcoholic hepatic steatosis, hepatic fibrosis or cirrhosis, or spontaneous pulmonary fibrosis.

In one embodiment of the present disclosure, the fibrotic disease is selected from cystic peritonitis, idiopathic pulmonary fibrosis, non-alcoholic hepatic steatosis, liver fibrosis and cirrhosis.

Diseases of the eye include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous embolism, traumatic injury, glaucoma, and similar diseases.

The term "pharmaceutical composition" refers to a mixture of the compound of the present disclosure and other chemical substances (such as diluents or carriers). The pharmaceutical composition helps to administer the compound to a living body. There are various techniques for administering the compound, and examples of the techniques include oral administration, injection, aerosol administration, parenteral administration, topical administration, and the like, however, the techniques are not limited thereto. The pharmaceutical composition can also be obtained by reacting acidic compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

The term "therapeutically effective amount" refers to an amount of active substance that is effective to reduce or diminish to some extent one or more symptoms of the disorder being treated by the amount of compound administered, or that is effective to delay the onset of clinical markers or symptoms of the disease to be prevented. Thus, a therapeutically effective amount refers to an amount that has the effect of (1) reversing the rate of progression of the disease, (2) inhibiting to some extent the further progression of the disease, and/or (3) reducing to some extent (preferably, eliminating) one or more symptoms associated with the disease. Therapeutically effective amounts can be determined empirically by testing the compound in known in vivo and in vitro model systems for the disease known to be treated.

The term "carrier" is defined as a compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into living cells or tissues.

The term "diluent" is defined as a compound that stabilizes the biologically active form of the target compound and is otherwise diluted in the water used to dissolve the compound. In this technology, a salt dissolved in a buffer solution is used as a diluent. A commonly used buffer solution is phosphate buffered saline due to the fact that phosphate buffered saline simulates the saline state of human fluids. Buffer diluents rarely modify the biological activity of a compound due to their ability to control the pH of a solution at low concentrations.

The compounds used herein can be administered alone to human patients, or as a pharmaceutical composition in combination therapy, in which the compound is mixed with other active substances or with appropriate carriers or excipients. The formulation and administration techniques of the compounds in this application can be found in "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, Pennsylvania, 18th edition, 1990.

The pharmaceutical composition disclosed herein can be prepared in a known manner by means of a common mixing process, dissolving process, granulating process, dragee-making process, powdering process, emulsifying process, encapsulating process, trapping process or lyophilizing process.

Therefore, the pharmaceutical composition used according to the present disclosure can also be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, which are formed to include excipients or adjuvants that promote the processing of active compounds into formulations that can be used in medicine. The appropriate formulation depends on the selected route of administration. Any known technology, carriers and excipients can be appropriately used and understood in this technology (such as the above-mentioned Remington's Medical Science). In the present disclosure, depending on the purpose, the compound of Chemical Formula 1 can be formulated into a preparation for injection and a preparation for oral administration and the like.

For injection, the disclosed substances can be formulated using liquid solutions, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, or saline buffer. For transmucosal administration, non-invasive agents suitable for the barrier to be passed are used in the formulation. Such non-invasive agents are well known in the art.

For oral administration, the compounds can be readily formulated by combining the active compound with a therapeutically acceptable carrier known in the art. Such carriers enable the compounds of the present disclosure to be formulated as tablets, pills, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Preferably, capsules, tablets, pills, powders, and granules are used, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric coatings. Pharmaceutical preparations for oral administration can be obtained by mixing one or two or more excipients with one or two or more compounds of the present disclosure, optionally grinding the mixture, and, when necessary, processing the granule mixture after dosing with suitable auxiliary agents to obtain tablets or dragee cores. Suitable excipients include fillers such as lactose, sucrose, mannitol or sorbitol; cellulose-based materials such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl pyrrolidone (PVP). When necessary, a disintegrator (e.g., cross-linked polyvinyl pyrrolidone, agar or alginic acid) or a salt thereof (e.g., sodium alginate), a lubricant (e.g., magnesium stearate) and a carrier (e.g., a binder) may also be added.

Pharmaceutical preparation materials that can be used for oral administration may also include push-fit capsules made of gelatin and soft-sealed capsules made of gelatin and plasticizers (e.g., ethylene glycol or sorbitol). Push-fit capsules are mixtures with fillers (e.g., lactose), binders (e.g., starch) and/or lubricants (e.g., talc or magnesium stearate), and may also include active substances. In soft capsules, active compounds may be dissolved or dispersed in suitable liquids such as fatty acids, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers may also be included. All preparations for oral administration need to be in a dosage suitable for such administration.

The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage form, for example, in ampoules or multi-dose containers with added preservatives. The compositions may take the form of, for example, suspensions, solutions or emulsions in oily or liquid vehicles, and may contain substances useful for formulation, such as suspending agents, stabilizers and/or dispersants.

Alternatively, the compound may be in the form of a dried powder for use after dissolving in sterile pyrogen-free water.

The compounds may also be formulated as suppositories containing conventional suppository bases such as cocoa butter or other glycerides, or in rectal compositions such as retention enema.

The pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active substance is contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound that effectively prolongs the survival time of a subject to be treated or effectively prevents, alleviates or relieves symptoms of a disease. The determination of a therapeutically effective amount may be within the capabilities of those skilled in the art, especially in light of the detailed description provided herein.

When formulated into a unit dosage form, it is preferred that the compound of Formula 1 as the active substance is contained in a unit dose of about 0.1 mg to 1,000 mg. The dosage of the compound of Formula 1 is determined according to the prescription prescribed by the doctor based on factors such as the patient's weight and age and the specific nature and severity of the disease. However, depending on the frequency and strength of administration, the dosage required for adult treatment may be one to three times a day, and the single dose is generally in the range of about 1 mg to 1,000 mg. When administered intramuscularly or intravenously to adults, it can be administered once to three times a day after being divided into single doses, and a single dose of about 1 mg to 1,000 mg is generally sufficient, however, for some patients, a higher daily dose may be preferred.

The pharmaceutical composition disclosed herein inhibits the activity of phosphatidic acid synthase. According to the disclosure, the compound of Chemical Formula 1 efficiently inhibits the activity of phosphatidic acid synthase, which is a basic regulator for converting lysophosphatidylcholine to lysophosphatidic acid. In the disclosure, the term "inhibit" refers to reducing the in vivo expression or biological activity of the target substance to a significant level.

Hereinafter, the present disclosure will be described in more detail with reference to preferred examples. However, these examples are provided only to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto in any sense, and the scope of the present disclosure is defined only by the claims to be described later. Preparation Example [ Preparation Example 1] Preparation of Intermediate A (Preparation Example A-1 ) Preparation of 5-bromo- N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate A-1)

5-Bromo-2-chloropyrimidine (5.0 g, 25.8 mmol), 2-aminoindane (4.0 ml, 31.0 mmol) and N,N-diisopropylethylamine (11.3 ml, 64.6 mmol) were dissolved in ethanol (15 ml), and the mixture was stirred at 80° C. for 4 hours. After completion of the reaction, the resultant was cooled to room temperature, and the resulting solid was filtered, washed with ethanol (40 ml), and then dried to obtain the title compound (6.76 g, 90%) as a beige solid. MS m/z: 290 [M+1] ⁺ 1H nuclear magnetic resonance (NMR) (CDCl ₃ , 400 MHz), δ ppm: 8.27 (s, 2H), 7.24-7.18 (m, 4H), 5.45 (d, 1H), 4.77-4.70 (m, 1H), 3.38 (dd, 2H), 2.87 (dd, 2H). (Preparation Example A-2 ) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-iodopyrimidin-2-amine (Intermediate A-2)

Using 2-chloro-5-iodopyrimidine (5.0 g, 20.8 mmol) instead of 5-bromo-2-chloropyrimidine, the title compound (6.6 g, 95%) was obtained as a gray-brown solid in the same manner as in Preparation Example A-1. MS m/z: 338 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.45 (s, 2H), 7.73 (m, 1H), 7.21-7.15 (m, 4H), 4.54 (m, 1H), 3.25-3.22 (m, 2H), 2.90-2.86 (m, 2H). (Preparation Example A-3 ) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate A-3)

To a mixture of intermediate A-1 (6.72 g, 23.16 mmol), bis(pinacolato)diboron (7.65 g, 30.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.89 g, 2.32 mmol) and potassium acetate (6.82 g, 69.48 mmol) was added 1,4-dioxane (55 ml), and the reaction mixture was stirred at 100° C. for 18 hours under a nitrogen atmosphere. After completion of the reaction, the resultant was cooled to room temperature, and after removing insoluble matter by diatomaceous earth, distilled water (150 ml) was added to the filtrate washed with ethyl acetate, and the resultant was extracted 3 times with ethyl acetate (50 ml). The organic layers were collected, washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=15:85) to obtain the title compound as a white solid (5.38 g, 69%). MS m/z: 338 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.44 (s, 2H), 7.90 (d, 1H), 7.21-7.12 (m, 4H), 4.68-4.63 (m, 1H), 3.24 (dd, 2H), 2.88 (dd, 2H), 1.27 (s, 12H). (Preparation Example A-4 ) Preparation of ethyl 2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidine-5-carboxylate (Intermediate A-4)

Ethyl 2-chloropyrimidine-5-carboxylate (2.0 g, 10.7 mmol), 2-aminoindane (1.7 ml, 12.9 mmol) and N,N-diisopropylethylamine (4.7 ml, 26.8 mmol) were dissolved in ethanol (6 ml), and the mixture was stirred at 80° C. for 18 hours. After the reaction was completed, the resultant was cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the title compound (2.54 g, 84%) as a white solid. MS m/z: 284 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.76 (d, 2H), 8.46 (s, 1H), 7.22-7.15 (m, 4H), 4.70 (m, 1H), 4.27 (q, 2H), 3.29-3.25 (m, 2H), 2.95-2.91 (m, 2H), 1.29 (t, 3H). (Preparation Example A-5 ) Preparation of 3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-3-oxopropionitrile (Intermediate A-5)

After anhydrous acetonitrile (0.74 ml, 13.12 mmol) was added to anhydrous toluene (15 ml), the resultant was cooled to -78°C. A 2 mol/L (M) hexane solution of n-butyl lithium (5.6 ml, 14.1 mmol) was slowly added dropwise thereto, and the resultant was stirred for 20 minutes. Intermediate A-4 (1.00 g, 3.53 mmol) dissolved in anhydrous toluene (15 ml) was added dropwise to the reaction mixture, and after the temperature was slowly raised, the resultant was stirred at room temperature for 2 hours. The reaction was terminated by adding a 1 N aqueous solution of hydrogen chloride thereto, and the resultant was extracted 3 times with ethyl acetate (10 ml). The organic layers were collected, washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to 2:3) to obtain the title compound (0.67 g, 68%) as a yellow solid. MS m/z: 279 [M+1] ⁺ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.87 (s, 1H), 8.76 (s, 1H), 7.27–7.21 (m, 4H), 6.03 (s, 1H), 4.93 (s, 1H), 3.90 (s, 2H), 3.43 (d, 2H), 2.93 (d, 2H). (Preparation Example A-6 ) Preparation of 2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidine-5-carbonitrile (Intermediate A-6)

Intermediate A-1 (2.5 g, 8.6 mmol) was dissolved in N,N-dimethylformamide (41 ml), and after copper cyanide (1.0 g, 11.20 mmol) was added thereto, the mixture was stirred at 180°C for 18 hours. After the reaction was completed, the resultant was diluted by adding ethyl acetate (40 ml) thereto, and then washed twice with a 10% aqueous sodium cyanide solution (50 ml). The organic layer was collected, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2:8) to obtain the title compound (1.5 g, 74%) as a white solid. MS m/z: 237 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.56 (s, 1H), 8.25 (s, 1H), 7.26-7.18 (m, 4H), 6.19 (d, 1H), 4.90-4.82 (m, 1H), 3.43-3.38 (m, 2H), 2.92-2.85 (m, 2H). [ Preparation Example 2] Preparation of Intermediate B (Preparation Example B-1 ) Preparation of 4,5,6,7-tetrahydro- 1H- [1,2,3]triazolo[4,5- c ]pyridine hydrochloride (Intermediate B-1) (Step 1) Preparation of 1H- [1,2,3]triazolo[4,5- c ]pyridine

3,4-Diaminopyridine (2.0 g, 48 mmol) was dissolved in 2N aqueous hydrogen chloride solution (25 ml), and the mixture was then cooled to 0°C. Sodium nitrite (1.9 g, 27 mmol) dissolved in distilled water (3 ml) was slowly added thereto, and the resultant was stirred for 1 hour. The resulting solid was filtered and washed with distilled water to obtain the title compound (1.96 g, 89%) as a yellow solid. MS m/z: 121 [M+1] ⁺ . ¹ H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 9.47 (s, 1H), 8.49 (d, 1H), 7.89 (d, 1H). (Step 2) Preparation of 4,5,6,7-tetrahydro- 1H- [1,2,3]triazolo[4,5- c ]pyridine hydrochloride

The compound prepared in (Step 1) (1.0 g, 8.3 mmol) was dissolved in methanol (60 ml), and after adding Pd/C (10 wt %, 2.0 g) and concentrated hydrochloric acid (1 ml), the mixture was reacted under hydrogen pressure (75 pounds per square inch, psi) for 7 hours. Insoluble matter was removed by celite, and the filtrate washed with methanol was concentrated under reduced pressure to quantitatively obtain the title compound (1.38 g) as a yellow solid. MS m/z: 125 [M+1] ⁺ . ¹ H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 9.54 (s, 2H), 4.34 (s, 2H), 2.98 (t, 2H). (Preparation Example B-2 ) Preparation of ( S )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-2) (Step 1) Preparation of 1-azido-4-nitrobenzene

p-Toluenesulfonic acid (124 g, 651 mmol) and 4-nitroaniline (10.0 g, 72.4 mmol) were dissolved in distilled water (800 ml), and the mixture was stirred at room temperature for 30 minutes, and sodium nitrite (45.0 g, 651 mmol) was slowly added thereto over 1 hour. After all the starting materials disappeared by thin layer chromatography (TLC), sodium azide (7.53 g, 115 mmol) was slowly added to the reaction mixture over 1 hour, and the resultant was stirred at room temperature. After the reaction, the resulting solid was filtered and washed with distilled water (500 mL) to obtain the title compound (13.0 g, 90%) as a yellow solid. MS m/z: 165 [M+1] ⁺ (Step 2) Preparation of ( S )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid ethyl ester, ( R )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid ethyl ester

The compound prepared in (Step 1) (11.9 g, 72.4 mmol) was dissolved in N,N-dimethylformamide (100 ml), and after ethyl 4-oxocyclic-1-carboxylate (9.5 g, 55.7 mmol) and ammonium acetate (21.5 g, 278 mmol) were sequentially added thereto, the mixture was stirred at 80° C. for 16 hours. After the resultant was cooled to room temperature, the reaction was terminated by adding distilled water (200 ml) thereto, and the resultant was extracted twice with ethyl acetate (150 ml). The organic layer was washed with saturated saline (100 ml), dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5:95 to 10:90) to obtain a racemic mixture of the title compound (7.50 g, 71%) as a red oil.

The racemic mixture (17.0 g) was purified by supercritical fluid chromatography (SFC) to obtain the ( S )-isomer (peak 1, R _t =4.122, 8.0 g, enantiomeric excess (ee) >99%) and the ( R )-isomer (peak 2, R _t =4.347, 8.1 g, ee >99%) (ChiralPak IC, 250 mm × 50 mm, i.d. 10 μm); mobile phase A: CO ₂ , B: 0.1% NH ₄ OH/EtOH; gradient: 5%-40% B; flow rate: 2.5 mL/min). MS m/z: 196 [M+1] ⁺ ( S )-isomer ¹ H NMR (CDCl ₃ , 500 MHz), δ ppm: 4.27-4.11 (m, 2H), 3.13-3.06 (m, 1H), 3.02-2.89 (m, 2H), 2.85-2.72 (m, 2H), 2.33-2.24 (m, 1H), 1.97 (dtd, 1H), 1.28 (t, 3H). ( R )-isomer ¹ H NMR (CDCl ₃ , 500 MHz), δ ppm: 4.20 (q, 2H), 3.13-3.06 (m, 1H), 3.02-2.89 (m, 2H), 2.86-2.71 (m, 2H), 2.36-2.24 (m, 1H), 1.98 (dtd, 1H), 1.28 (t, 3H). (Step 3) Preparation of ( S )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid

The ( S )-isomer (8.0 g, 40.9 mmol) prepared in (Step 3) was dissolved in a mixed solvent of methanol (50 ml) and distilled water (50 ml), and after sodium hydroxide (3.28 g, 81.9 mmol) was added thereto, the mixture was stirred at 45°C for 6 hours. The yellow suspension was concentrated under reduced pressure, and a 1 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 5, and then the resultant was concentrated again. Dichloromethane/methanol (1/1, 40 ml) was added to the residue to obtain the title compound (6.0 g, 87%, ee = 98.96%) as a white solid. MS m/z: 169 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 2.86-2.64 (m, 3H), 2.62-2.52 (m, 2H), 2.14-2.04 (m, 1H), 1.81-1.67 (m, 1H). (Preparation Example B-3 ) Preparation of ( R )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-3)

The title compound (6.8 g, 98%, ee = 97.98%) was obtained as a white solid in the same manner as in Preparation Example B-2 (Step 3) using the ( R )-isomer prepared in Preparation Example B-2 (Step 2) (8.1 g, 41.2 mmol). MS m/z: 169 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 2.82-2.65 (m, 3H), 2.59-2.52 (m, 1H), 2.47-2.39 (m, 1H), 2.13-2.02 (m, 1H), 1.77-1.65 (m, 1H). (Preparation Example B-4 ) Preparation of 6-fluoro- 1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-4) (Step 1) Preparation of methyl 4-amino-2-fluoro-5-nitrobenzoate

Methyl 2,4-difluoro-5-nitrobenzoate (1.0 g, 4.6 mmol) was dissolved in tetrahydrofuran (9 ml), and after adding 28% aqueous ammonia (0.9 ml, 12.9 mmol) thereto at 0°C, the mixture was stirred at room temperature for 40 hours. After completion of the reaction, the solvent was concentrated under reduced pressure. A yellow solid produced by adding distilled water (30 ml) to the residue was filtered and dried under reduced pressure to obtain the title compound (0.96 g, 97%). MS m/z: 215 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.59 (d, 1H), 8.08 (s, 1H), 6.78 (d, 1H), 3.81 (s, 3H). (Step 2) Preparation of methyl 4,5-diamino-2-fluorobenzoate

The compound prepared in (Step 1) (0.96 g, 4.46 mmol) was dissolved in a mixed solvent of methanol (30 ml) and ethyl acetate (30 ml), and after Pd/C (10 wt %, 186 mg) was added thereto, the mixture was stirred under 1 atmosphere of hydrogen at room temperature for 16 hours. Insoluble matter was removed by celite, and the filtrate washed with methanol was concentrated under reduced pressure to obtain the title compound (943 mg) as a brown solid. MS m/z: 185 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 7.30 (m, 1H), 6.40 (dd, 1H), 4.00 (brs, 2H), 3.85 (s, 3H), 3.15 (brs, 2H). (Step 3) Preparation of methyl 6-fluoro- 1H -benzo[ d ][1,2,3]triazole-5-carboxylate

After the compound prepared in (Step 2) (0.90 g, 4.89 mmol) was dissolved in acetic acid (7 ml), a solution obtained by dissolving sodium nitrite (0.37 g, 5.38 mmol) in distilled water (1.4 ml) was added thereto at 0°C, and the mixture was stirred at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 20:80) to obtain the title compound (0.72 g, 75%) as a dark brown solid. MS m/z: 196 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.54 (d, 1H), 7.85 (d, 1H), 3.90 (s, 3H). (Step 4) Preparation of 6-fluoro- 1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid

The compound prepared in (Step 3) (0.72 g, 3.69 mmol) was dissolved in a mixed solvent of tetrahydrofuran/distilled water (1/1, 7 ml), and after lithium hydroxide monohydrate (0.77 g, 18.45 mmol) was added thereto, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, a 1 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2, and the resultant was extracted twice with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then filtered. To the residue obtained by concentrating the filtrate under reduced pressure was added diethyl ether, and the resulting solid was filtered, washed with diethyl ether, and then dried to obtain the title compound (0.54 g, 81%) as a brown solid. MS m/z: 182 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.50 (d, 1H), 7.81 (d, 1H). (Preparation Example B-5 ) Preparation of 6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-5) (Step 1) Preparation of methyl 4,5-diamino-2-methoxybenzoate

Methyl 4-amino-2-methoxy-5-nitrobenzoate (0.5 g, 2.2 mmol) was dissolved in ethyl acetate (22 ml), and after Pd/C (10 wt%, 100 mg) was added thereto, the mixture was stirred at 50° C. for 18 hours under 1 atmosphere of hydrogen. Insoluble matter was removed by celite, and the filtrate washed with methanol was concentrated under reduced pressure to obtain the title compound (0.43 g, 99%) as a brown solid. MS m/z: 197 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 7.02 (s, 1H), 6.24 (s, 1H), 5.35 (s, 2H), 4.24 (brs, 2H), 3.64 (s, 6H). (Step 2) Preparation of methyl 6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxylate

After the compound prepared in (Step 1) (0.43 g, 2.18 mmol) was dissolved in acetic acid (3 ml), a solution obtained by dissolving sodium nitrite (0.16 g, 2.40 mmol) in distilled water (0.6 ml) at 0°C was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (methanol: dichloromethane = 5:95) to obtain the title compound (0.39 g, 86%) as a light brown solid. MS m/z: 208 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.24 (s, 1H), 7.33 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H). (Step 3) Preparation of 6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid

The compound prepared in (Step 2) (0.39 g, 1.89 mmol) was dissolved in a mixed solvent of tetrahydrofuran/methanol/distilled water (3/2/1, 6 ml), and after adding lithium hydroxide monohydrate (0.55 g, 13.2 mmol), the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, a 1 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2, and the resultant was extracted twice with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated brine, dried with anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether and then dried to obtain the title compound (0.32 g, 88%) as a brown solid. MS m/z: 194 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 12.88 (brs, 1H), 8.19 (s, 1H), 7.30 (s, 1H), 3.90 (s, 3H). (Preparation Example B-6 ) Preparation of 6-(2,2-difluoroethoxy) -1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-6) (Step 1) Preparation of methyl 4-amino-2-fluoro-5-nitrobenzoate

Methyl 2,4-difluoro-5-nitrobenzoate (1.0 g, 4.6 mmol) was dissolved in tetrahydrofuran (9 ml), and after 28% aqueous ammonia (0.9 ml) was added dropwise thereto at 0°C, the mixture was stirred at room temperature for 40 hours. After the solvent was removed by concentration under reduced pressure, distilled water (50 ml) was added thereto. The resulting solid was filtered and washed with distilled water to obtain the title compound (0.96 g, 97%) as a yellow solid. MS m/z: 215 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.59 (d, 1H), 8.08 (s, 1H), 6.78 (d, 1H), 3.81 (s, 3H). (Step 2) Preparation of methyl 4-amino-2-(2,2-difluoroethoxy)-5-nitrobenzoate

2,2-Difluoroethanol (0.14 ml, 2.24 mmol) was dissolved in tetrahydrofuran (9 ml), and after potassium tert-butoxide (0.25 g, 2.24 mmol) was added thereto, the mixture was stirred at room temperature for 30 minutes. The compound prepared in (Step 1) (0.40 g, 1.87 mmol) was slowly added to the reaction mixture, and the resultant was stirred at room temperature for 18 hours. After the reaction was terminated by adding distilled water (30 ml), the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 40:60) to obtain the title compound (0.44 g, 86%) as a yellow solid. MS m/z: 277 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.52 (s, 1H), 7.89 (s, 2H), 6.56 (s, 1H), 6.54-6.27 (t, 1H), 4.38-4.32 (m, 2H), 3.75 (s, 3H). (Step 3) Preparation of methyl 4,5-diamino-2-(2,2-difluoroethoxy)benzoate

The compound prepared in (Step 2) (0.44 g, 1.61 mmol) was dissolved in ethyl acetate (16 ml), and after Pd/C (10 wt%, 89 mg) was added thereto, the mixture was stirred at room temperature for 18 hours under 1 atmosphere of hydrogen. After completion of the reaction, insoluble matter was removed by celite, and the filtrate washed with ethyl acetate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=30:70 to 60:40) to obtain the title compound (0.27 g, 67%) as a brown solid. MS m/z: 247 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 7.02 (s, 1H), 6.41-6.14 (m, 2H), 5.39 (s, 2H), 4.40 (s, 2H), 4.12-4.04 (m, 2H), 3.67 (s, 3H). (Step 4) Preparation of methyl 6-(2,2-difluoroethoxy) -1H -benzo[ d ][1,2,3]triazole-5-carboxylate

After the compound prepared in (Step 3) (0.27 g, 1.08 mmol) was dissolved in acetic acid (2 ml), a solution obtained by dissolving sodium nitrite (0.082 g, 1.19 mmol) in distilled water (1 ml) was added thereto at 0°C, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the remaining residue was purified by silica gel column chromatography (methanol: dichloromethane = 5:95) to obtain the title compound (0.27 g, 97%) as a light brown solid. MS m/z: 258 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.29 (s, 1H), 7.50 (s, 1H), 6.56-6.28 (t, 1H), 4.52-4.44 (m, 2H), 3.84 (s, 3H). (Step 5) Preparation of 6-(2,2-difluoroethoxy) -1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid

The compound prepared in (Step 4) (0.27 g, 1.05 mmol) was dissolved in a mixed solvent of tetrahydrofuran/methanol/distilled water (3/2/1, 2 ml), and after adding lithium hydroxide monohydrate (0.22 g, 5.27 mmol), the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, a 1 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2, and the resultant was extracted twice with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with dichloromethane to obtain the title compound (0.21 g, 83%) as a brown solid. MS m/z: 243 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 12.99 (brs, 1H), 8.23 (s, 1H), 7.46 (s, 1H), 6.56-6.28 (t, 1H), 4.51-4.43 (m, 2H). (Preparation Example B-7 ) Preparation of 6-(methylsulfonylamino)nicotinic acid (Intermediate B-7)

Methyl 6-aminopyridine-3-carboxylate (1.0 g, 6.57 mmol) and triethylamine (1.1 ml, 7.89 mmol) were dissolved in dichloromethane (22 ml), and after methanesulfonyl chloride (0.6 ml, 7.3 mmol) was added thereto at 0°C, the mixture was stirred at room temperature for 18 hours. After checking the reaction by TLC, methanol (24 ml) and a 4 N aqueous sodium hydroxide solution (8 ml) were added thereto, and the resultant was stirred at room temperature for 1 hour. After completion of the reaction, the organic solvent was concentrated under reduced pressure. A 1 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2, and the resultant was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and filtered, and then the solvent was concentrated under reduced pressure. The residue was filtered and washed with diethyl ether to obtain the title compound (0.52 g, 37%) as a gray-brown solid. MS m/z: 217 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.72 (s, 1H), 8.18-8.15 (m, 1H), 7.04 (d, 1H), 3.31 (s, 3H). (Preparation Example B-8 ) Preparation of 2-(methylsulfonylamino)isosonicotinic acid (Intermediate B-8)

Using 2-aminopyridine-4-carboxylic acid methyl ester (2.0 g, 13.15 mmol) instead of 6-aminopyridine-3-carboxylic acid methyl ester, the title compound (1.33 g, 47%) was obtained as a gray-brown solid in the same manner as in Preparation Example B-7. MS m/z: 217 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.43 (d, 1H), 7.44-7.41 (m, 2H), 3.32 (m, 3H). (Preparation Example B-9 ) Preparation of 2-(methylsulfonylamino)thiazole-4-carboxylic acid (Intermediate B-9)

Using ethyl 2-aminothiazole-4-carboxylate (0.93 g, 5.37 mmol) instead of methyl 6-aminopyridine-3-carboxylate, the title compound (0.14 g, 48%) was obtained as a white solid in the same manner as in Preparation Example B-7. MS m/z: 223 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 7.62 (s, 1H), 2.94 (s, 3H). (Preparation Example B-10 ) Preparation of 6-((methylsulfonyl)methyl)nicotinic acid (Intermediate B-10) (Step 1) Preparation of methyl 6-(bromomethyl)nicotinate

Methyl 6-(bromomethyl)nicotinate (1.5 g, 9.0 mmol) was dissolved in chloroform (38 ml), and phosphorus bromide (1.0 ml, 10.8 mmol) was slowly added dropwise thereto at 0°C, and the mixture was stirred at room temperature for 3 hours. A saturated sodium carbonate aqueous solution (20 ml) was added thereto to terminate the reaction, and the resultant was extracted three times with chloroform (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 30:70) to obtain the title compound (1.5 g, 73%) as a white solid. MS m/z: 231 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 9.16 (s, 1H), 8.30 (dd, 1H), 7.53 (d, 1H), 4.58 (s, 2H), 3.96 (s, 3H). (Step 2) Preparation of 6-((methylsulfonyl)methyl)nicotinic acid

The compound prepared in (Step 1) (0.3 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (15 ml), and after sodium sulfinate (0.27 g, 2.6 mmol) was added thereto, the mixture was stirred at 120° C. for 2 hours. After the reaction was completed, the resultant was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in tetrahydrofuran (2 ml). A 1 N aqueous sodium hydroxide solution (4 ml) was added thereto, and the resultant was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and then a 2 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2, and the resultant was extracted three times with ethyl acetate (30 ml). The organic layer was collected, washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound as a gray-brown solid (0.20 g, 72%). MS m/z: 216 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 13.49 (s, 1H), 9.22 – 8.95 (m, 1H), 8.33 (dt, 1H), 7.65 (d, 1H), 4.77 (s, 2H), 3.05 (s, 3H). (Preparation Example B-11 ) Preparation of 2-((methylsulfonyl)methyl)isonicotinic acid (intermediate B-11) (Step 1) Preparation of methyl 2-(hydroxymethyl)isonicotinate

After dissolving methyl isonicotinate (5.0 g, 36.5 mmol) in methanol (50 ml), sulfuric acid (0.2 ml) was added thereto, and while the mixture was stirred at 50° C., an aqueous solution (25 ml) of ammonium persulfate (15 g, 65.6 mmol) was slowly added thereto, and the mixture was further stirred at 100° C. for 30 minutes. After completion of the reaction, the resultant was cooled to room temperature, neutralized with a saturated aqueous sodium carbonate solution (30 ml), and then extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 50:50) to obtain the title compound (2.26 g, 37%) as a yellow solid. MS m/z: 168 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.51 (d, 1H), 7.80 (s, 1H), 7.58 (d, 1H), 4.70 (s, 3H), 3.81 (d, 3H). (Step 2) Preparation of methyl 2-(bromomethyl)isosonicotinate

The compound prepared in (Step 1) (1.2 g, 7.18 mmol) was dissolved in chloroform (30 ml), and phosphorus bromide (0.8 ml, 8.61 mmol) was slowly added dropwise thereto at 0°C, and the mixture was stirred at room temperature for 3 hours. A saturated sodium carbonate aqueous solution (20 ml) was added thereto to terminate the reaction, and the resultant was extracted three times with chloroform (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 30:70) to obtain the title compound (1.38 g, 84%) as a white solid. MS m/z: 231 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.73 (d, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 4.61 (s, 2H), 3.97 (s, 3H). (Step 3) Preparation of 2-((methylsulfonyl)methyl)isonicotinic acid

The compound prepared in (Step 2) (0.3 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (15 ml), and after sodium sulfinate (0.27 g, 2.6 mmol) was added thereto, the mixture was stirred at 120° C. for 2 hours. After the reaction was completed, the solvent was distilled under reduced pressure, and after the resultant was dissolved in a 1 N aqueous sodium hydroxide solution (3.9 ml) and tetrahydrofuran (1.3 ml), the resultant was stirred at 70° C. for 3 hours. After the reaction was completed, a 2 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2 or less to produce a solid. The resulting solid was filtered, washed with distilled water, and then dried to obtain the title compound (0.22 g, 79%) as a brown solid. MS m/z: 216 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.78 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 4.78 (s, 2H), 3.03 (s, 3H). (Preparation Example B-12 ) Preparation of 6-(sulfomethyl)nicotinic acid (Intermediate B-12)

The compound prepared in (step 1) of Intermediate B-10 (0.40 g, 1.74 mmol) was dissolved in distilled water (20 ml), and after sodium sulfite (0.22 g, 1.74 mmol) was added thereto, the mixture was stirred at 100° C. for 16 hours. After the reaction was completed, the solvent was distilled under reduced pressure, and after the resultant was dissolved in a 4 mol/L hydrogen chloride aqueous solution (20 ml), the resultant was stirred at 100° C. for 16 hours. After the reaction was completed, the resultant was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was washed with methanol and distilled water to obtain the title compound (0.21 g, 56%) as a white solid. MS m/z: 218 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 9.07 (s, 1H), 8.52 (s, 1H), 7.86 (d, 1H), 4.12 (s, 2H). (Preparation Example B-13 ) Preparation of 6-(1 H -tetrazolyl-5-yl)nicotinic acid (Intermediate B-13) (Step 1) Preparation of methyl 6-cyanonicotinate

Methyl 6-bromonicotinate (1.0 g, 4.6 mmol) was dissolved in N,N-dimethylformamide (6.5 ml), and after adding tetrakis(triphenylphosphine)palladium(0) (267 mg, 0.23 mmol) and zinc cyanide (326 mg, 2.78 mmol), the mixture was stirred at 100° C. for 18 hours under a nitrogen atmosphere. Distilled water (30 ml) was added thereto to terminate the reaction, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline water, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 20:80) to obtain the title compound (0.57 g, 72%) as a white solid. MS m/z: 163 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 9.29 (d, 1H), 8.44 (dd, 1H), 7.80 (d, 1H), 4.00 (s, 3H). (Step 2) Preparation of methyl 6-( 1H -tetrazol-5-yl)nicotinate

The compound prepared in (Step 1) (0.57 g, 3.53 mmol) was dissolved in N,N-dimethylformamide (36 ml), and sodium azide (0.25 g, 3.88 mmol), ammonium chloride (0.20 g, 3.88 mmol) and lithium chloride (0.075 g, 1.76 mmol) were added thereto, and the mixture was stirred at 110° C. for 18 hours under a nitrogen atmosphere. After completion of the reaction, the resultant was cooled to room temperature, insoluble matter was removed by diatomaceous earth, and the filtrate washed with ethyl acetate was concentrated under reduced pressure. The residue was recrystallized by adding distilled water and 1N aqueous hydrogen chloride solution to the residue, and the title compound (0.65 g, 90%) was obtained as a gray-brown solid. MS m/z: 206 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 9.34 (s, 1H), 8.57-8.47 (m, 2H), 4.02 (s, 3H). (Step 3) Preparation of 6-( 1H -tetrazol-5-yl)nicotinic acid

The compound prepared in (Step 2) (0.65 g, 3.18 mmol) was dissolved in tetrahydrofuran (32 ml), and after adding a 1 N aqueous lithium hydroxide solution (32 ml), the mixture was stirred at room temperature for 3 hours. After the reaction was completed, a 2 N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2 and produce a solid. The produced solid was filtered, washed with distilled water, and then dried to obtain the title compound (0.43 g, 70%) as a gray-brown solid. MS m/z: 192 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 9.23 (d, 1H), 8.53 (m, 1H), 8.36 (m, 1H). (Preparation Example B-14 ) Preparation of 1 H -benzo[ d ][1,2,3]triazole-5-sulfonyl chloride (Intermediate B-14) (Step 1) Preparation of 4-chloro-3-nitrobenzenesulfonyl chloride

1-Chloro-2-nitrobenzene (1.0 g, 6.3 mmol) was dissolved in chlorosulfonic acid (5 ml), and the mixture was stirred at 120° C. for 18 hours. The reaction mixture was slowly added to ice water to terminate the reaction, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to quantitatively obtain the title compound (1.73 g) as a brown liquid. MS m/z: 257 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.54 (d, 1H), 8.19-8.17 (m, 1H), 7.88-7.86 (m, 1H). (Step 2) Preparation of 4-amino-3-nitrobenzenesulfonamide

The compound prepared in (Step 1) (1.73 g, 6.76 mmol) was dissolved in 1,4-dioxane (6 ml), and after adding 28% aqueous ammonia (25 ml), the mixture was stirred at 120° C. for 30 hours. Distilled water (30 ml) was added thereto to terminate the reaction, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 30:70 to 80:20) to obtain the title compound (0.87 g, 59%) as a yellow solid. MS m/z: 218 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.40 (d, 1H), 7.94 (s, 2H), 7.73-7.70 (m, 1H), 7.29 (s, 2H), 7.13-7.11 (m, 1H). (Step 3) Preparation of 3,4-diaminobenzenesulfonamide

The compound prepared in (Step 3) (0.87 g, 4.01 mmol) was dissolved in ethanol (20 ml), and after tin (II) chloride dihydrate (4.52 g, 20.05 mmol) was added thereto, the mixture was stirred at 70°C for 18 hours. After the reaction was completed, a saturated sodium carbonate aqueous solution was added thereto to adjust the pH of the liquid to 7, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 10:90) to obtain the title compound (0.70 g, 93%) as a reddish brown solid. MS m/z: 188 [M+1] ⁺ (Step 4) Preparation of 1 H -benzo[ d ][1,2,3]triazole-5-sulfonamide

After the compound prepared in (Step 3) (0.70 g, 3.72 mmol) was dissolved in acetic acid (5.5 ml), a solution obtained by dissolving sodium nitrite (0.28 g, 4.1 mmol) in distilled water (1 ml) was added thereto at 0°C, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the resultant was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol: dichloromethane = 10:90 to 20:80) to obtain the title compound (0.52 g, 71%) as a reddish brown solid. MS m/z: 199 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.38 (s, 1H), 8.09 (d, 1H), 7.89 (d, 1H), 7.51 (s, 2H). (Step 5) Preparation of 1 H -benzo[ d ][1,2,3]triazole-5-sulfonyl chloride

The compound prepared in (Step 4) (0.050 g, 0.25 mmol) was dissolved in chlorosulfonic acid (1 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was slowly added to ice water to terminate the reaction, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to quantitatively obtain the title compound (0.055 g) as a brown liquid, and the title compound was directly used in the next reaction without separate purification. MS m/z: 218 [M+1] ⁺ (Preparation Example B-15 ) Preparation of 2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxylic acid (Intermediate B-15)

4-Amino-3-hydroxybenzoic acid (2.0 g, 13 mmol) and potassium carbonate (2.9 g, 20.9 mmol) were dissolved in distilled water (16 ml), and after methyl chloroformate (1.5 ml, 19.6 mmol) was added thereto at 40°C, the mixture was stirred at 80°C for 18 hours. After the reaction was completed, a 2N aqueous hydrogen chloride solution was added thereto to adjust the pH of the liquid to 2. The resulting solid was filtered, washed with distilled water, and dried to obtain the title compound (1.55 g, 66%) as a brown solid. MS m/z: 180 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 7.80 (d, 1H), 7.74 (s, 1H), 7.17 (d, 1H). [ Preparation Example 3] Preparation of Intermediate C (Preparation Example C-1 ) Preparation of 3-(aminomethyl)-5-bromobenzoic acid methyl ester

Methyl 3-bromo-5-(bromomethyl)benzoate (1.80 g, 5.84 mmol) was dissolved in dimethyl sulfoxide (15 ml), and after (dimethylamino) sodium (0.93 g, 8.77 mmol) was added thereto, the mixture was stirred at 80° C. for 16 hours. After TLC checked that the starting material had disappeared, a 6 N aqueous solution of hydrogen chloride (3 ml) and ethanol (20 ml) were added thereto, and the resultant was stirred at 75° C. for 16 hours. After completion of the reaction, the pH of the liquid was adjusted to 8 using a saturated aqueous sodium bicarbonate solution, and the resultant was extracted three times with a mixed solvent of dichloromethane/methanol (9/1) (50 ml). The organic layer was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase high performance liquid chromatography (HPLC) (preparative HPLC, column: Boston Uni C18 40×150×5 μm; mobile phase: 0.1% trifluoroacetic acid (TFA) acetonitrile: distilled water = 5:95 to 35:45) and lyophilized to obtain the title compound (0.70 g, 38%) as a white solid. MS m/z: 245 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.29 (br s, 3H), 8.12 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 4.15 (s, 2H), 3.93-3.87 (m, 3H). (Preparation Example C-2 ) Preparation of 1-bromo-3-isopropoxy-5-nitrobenzene (Intermediate C-2) (Step 1) Preparation of 2-amino-3-bromo-5-nitrophenol

2-Amino-5-nitrophenol (1.00 g, 6.49 mmol) was dissolved in acetonitrile (40.6 ml), and after N-bromosuccinimide (1.19 g, 6.68 mmol) was added thereto at 0°C, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and a mixed solvent of ethyl acetate/n-hexane (1:1) was added to the remaining residue. The resulting solid was filtered to obtain the title compound (1.31 g, 87%) as a brown solid. MS m/z: 233 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 10.69 (s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 6.17 (brs, 2H). (Step 2) Preparation of 3-bromo-5-nitrophenol

The compound prepared in (Step 1) (1.31 g, 5.62 mmol) was dissolved in ethanol (22 ml), and after concentrated sulfuric acid (0.6 ml) was added thereto, the mixture was stirred at 75° C. for 30 minutes. After the reaction mixture was cooled to room temperature, sodium nitrite (0.97 g, 14.06 mmol) was added thereto, and then the resultant was further stirred at 75° C. for 1 hour. After completion of the reaction, the solvent was concentrated under reduced pressure, and then distilled water (50 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layers were collected, dried over anhydrous sodium sulfate, and the filtered filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 10:90) to obtain the title compound (0.62 g, 51%) as a brown solid. MS m/z: 218 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 10.94 (brs, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H). (Step 3) Preparation of 1-bromo-3-isopropoxy-5-nitrobenzene

The compound prepared in (Step 2) (0.30 g, 1.38 mmol) and potassium carbonate (0.76 g, 5.50 mmol) were dissolved in N,N-dimethylformamide (3 ml), and after 2-bromopropane (0.52 ml, 5.50 mmol) was added thereto at 0°C, the mixture was stirred at 80°C for 20 hours. After the reaction was completed, distilled water (50 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (70 ml). After washing the organic layer with saturated saline water, the organic layer was collected and dried with anhydrous sodium sulfate, and the filtered solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 0:100 to 10:90) to obtain the title compound (0.32 g, 90%) as an orange liquid. MS m/z: 260 [M+1] ⁺ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 7.93 (s, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 4.64-4.59 (m, 1H), 1.39 (s, 6H). (Preparation Example C-3 ) Preparation of 3-bromo- N , N -dimethyl-5-nitroaniline (Intermediate C-3)

3-Bromo-5-nitroaniline (0.50 g, 2.30 mmol) and 37% formaldehyde solution (0.56 ml) were dissolved in acetonitrile (23 ml), and after adding acetic acid (3.5 ml) and sodium cyanoborohydride (0.66 g, 10.55 mmol) thereto at 0°C, the mixture was stirred at room temperature for 36 hours. Distilled water (50 ml) was added thereto to terminate the reaction, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 20:80) to obtain the title compound (548 mg, 97%) as an orange solid. MS m/z: 245 [M+1] ⁺ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 7.64 (s, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 3.05 (s, 6H). (Preparation Example C-4 ) Preparation of 4-(3-bromo-5-nitrophenyl)morpholine (Intermediate C-4)

1-Bromo-3-fluoro-5-nitrobenzene (0.50 g, 2.27 mmol), morpholine (0.20 ml, 2.5 mmol) and cesium carbonate (0.74 g, 2.27 mmol) were dissolved in N,N-dimethylformamide (6 ml), and the mixture was stirred at 100° C. for 3 hours. After the reaction was completed, distilled water (30 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline water, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 20:80) to obtain the title compound (0.25 g, 38%) as a white solid. MS m/z: 288 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 7.77 (s, 1H), 7.61 (s, 1H), 7.26 (s, 1H), 3.87 (m, 4H), 3.25 (m, 4H). (Preparation Example C-5 ) Preparation of N- (1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfenamide (Intermediate C-5) (Step 1) Preparation of 1-(4-bromophenyl)-2,2-difluoroethan-1-one

1-Bromo-4-iodobenzene (1.5 g, 5.30 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and after adding a 2.5 mol/L n-butyl lithium hexane solution (2.55 ml, 6.36 mmol) thereto at -78°C, the mixture was stirred for 30 minutes. After adding ethyl 2,2-difluoroacetate (0.67 ml, 6.36 mmol) thereto, the resultant was stirred for 1 hour while maintaining -78°C, and after the temperature was raised to 0°C, the resultant was further stirred for 1 hour. The reaction material was neutralized with a 1 N aqueous hydrochloric acid solution to terminate the reaction, and the resultant was diluted with distilled water (20 ml), and then extracted three times with ethyl acetate (20 ml). The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to 2:8) to obtain the title compound (758 mg, 61%) as a colorless liquid. ¹ H NMR (CDCl ₃ , 400 MHz), δ ppm: 7.95 (d, 2H), 7.69 (d, 2H), 6.24 (td, 1H). (Step 2) Preparation of ( Z )-N-(1-(4-bromophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfenamide

After dissolving the compound prepared in (Step 1) (758 mg, 3.23 mmol) in anhydrous tetrahydrofuran (6.5 ml), tert-butylsulfenamide (586 mg, 4.84 mmol) and titanium tetraethanolate (2.0 ml, 9.68 mmol) were added dropwise thereto while stirring, and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, and a small amount of water was added thereto to terminate the reaction. Insoluble matter was removed by diatomaceous earth, and the filtrate washed with ethyl acetate and distilled water was collected and extracted. The organic layer was collected and washed again with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (293 mg, 27%) as a yellow solid. MS m/z: 339 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 7.95 (d, 1H), 7.69 (d, 1H), 7.58 (d, 2H), 6.24 (t, 1H), 1.34 (s, 9H). (Step 3) Preparation of N- (1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfenamide

After dissolving the compound prepared in (Step 2) (293 mg, 0.87 mmol) in anhydrous tetrahydrofuran (5.0 ml), sodium borohydride (65.5 mg, 1.73 mmol) was slowly added thereto while stirring at -10°C, and the mixture was stirred for 3 hours. The reaction material was diluted with distilled water (10 ml) and extracted three times with ethyl acetate (20 ml). The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (292 mg, 99%) as a yellow liquid. MS m/z: 341 [M+1] ⁺ [ Preparation Example 4] Preparation of Intermediate D (Preparation Example D-1 ) Preparation of 5-(3-aminophenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-1)

3-Bromoaniline (100 mg, 0.58 mmol) was dissolved in 1,4-dioxane (6 ml), and after adding intermediate A-3 (0.24 g, 0.70 mmol), tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.06 mmol) and 2N aqueous sodium carbonate solution (0.9 ml, 1.74 mmol), the mixture was stirred at 80° C. for 19 hours under a nitrogen atmosphere. After the reaction was completed, the resultant was cooled to room temperature. Insoluble matter was removed by diatomaceous earth, distilled water (30 ml) was added to the filtrate washed with ethyl acetate, and the resultant was extracted three times with ethyl acetate (30 ml). The organic layers were collected, washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=40:60) to obtain the title compound (0.16 g, 88%) as a brown solid. MS m/z: 303 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.52 (s, 2H), 7.57 (d, 1H), 7.23-7.13 (m, 4H), 7.08 (t, 1H), 6.76 (s, 1H), 6.73 (d, 1H), 6.53 (d, 1H), 5.13 (s, 2H), 4.68-4.63 (m, 1H), 3.30-3.24 (m, 2H), 2.95-2.89 (m, 2H).

Using the brominated compounds (reaction materials) according to the following Table 2 instead of 3-bromoaniline, the compounds according to Preparation Example D-2 to Preparation Example D-11 (Intermediate D-2 to Intermediate D-11) were synthesized in the same manner as in Preparation Example D-1. (Preparation Example D-2 ) Preparation of 5-(5-amino-2-methylphenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-2) (Preparation Example D-3 ) Preparation of 5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-amine (Intermediate D-3) (Preparation Example D-4 ) Preparation of 5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-amine (Intermediate D-4) (Preparation Example D-5 ) 5-(3-amino-1-methyl- 1H -pyrazol-5-yl) -N- (2,3-dihydro- 1H- Preparation of ( S )-5-(4-(1-aminoethyl)phenyl) -N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Intermediate D-6) (Preparation Example D-7) Preparation of (R)-5-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-N- ( 2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Intermediate D-7) (Preparation Example D - 8 ) Preparation of 5- ( 3- ( aminomethyl)phenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-8) (Preparation Example D -9 ) ( R ) Preparation of 5-(3-(1-aminoethyl)phenyl) -N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-9) (Preparation Example D-10 ) Preparation of 5-(3-(aminomethyl)-4-fluorophenyl) -N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-10) (Preparation Example D-11 ) Preparation of 3-(aminomethyl)-5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)benzoic acid methyl ester (Intermediate D-11) [Table 2] Preparation example Structure Reaction Materials MS, NMR D-2 3-Bromo-4-methylaniline MS m/z: 317 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.27 (s, 2H), 7.53 (s, 1H), 7.23-7.16 (m, 4H), 6.94-6.93 (m, 1H), 6.50-6.48 (m, 1H), 6.43 (s, 1H), 4.93 (s, 2H), 4.66 (m, 1H), 3.33-3.25 (m, 2H), 2.95-2.91 (m, 2H), 2.10 (s, 3H). D-3 5-Bromo-4-methylthiazol-2-amine MS m/z: 324 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.41 (s, 2H), 7.25-7.16 (m, 4H), 5.43 (d, 1H), 4.98 (s, 2H), 4.85-4.79 (m, 1H), 3.44-3.39 (m, 2H), 2.93-2.88 (m, 2H), 2.24 (s, 3H). D-4 5-Bromothiazol-2-amine MS m/z: 310 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.55 (s, 2H), 7.63 (s, 1H), 7.22-7.15 (m, 4H), 4.65 (m, 1H), 3.33-3.25 (m, 2H), 2.94-2.90 (m, 2H). D-5 5-Bromo-1-methyl-1H-pyrazol-3-amine MS m/z: 307 [M+1]+ 1H NMR (DMSO-d6, 500 MHz), δ ppm: 8.41 (s, 2H), 7.80 (d, 1H), 7.23-7.14 (m, 4H), 5.54(s, 1H), 4.68-4.61 (m, 1H), 4.59-4.57 (m, 2H), 3.57 (s, 3H), 3.29-3.24 (m, 2H), 2.95-2.90 (m, 2H). D-6 ( S )-1-(4-bromophenyl)ethan-1-amine MS m/z: 331 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.46 (s, 2H), 7.47-7.42 (m, 4H), 7.23-7.14 (m, 4H), 5.98 (d, 1H), 4.89-4.81 (m, 1H), 4.18-4.13 (m, 1H), 3.44-3.38 (m, 2H), 2.94-2.89 (m, 2H), 1.42 (d, 3H). D-7 ( R )-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine MS m/z: 385 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 9.73 (s, 2H), 8.74 (s, 2H), 7.81 (d, 2H), 7.69 (d, 2H), 7.22-7.12 (m, 4H), 5.74 (m, 1H), 4.67 (m, 1H), 3.27 (dd, 2H), 2.92 (dd, 2H). D-8 4-Bromobenzylamine MS m/z: 317 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.49 (s, 2H), 7.42-7.31 (m, 4H), 7.25-7.15 (m, 4H), 5.85 (d, 1H), 4.85 (m, 1H), 3.93 (s, 2H), 3.42 (dd, 2H), 2.91 (dd, 2H). D-9 ( R )-1-(3-bromophenyl)ethan-1-amine MS m/z: 331 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.50 (s, 2H), 7.45 (s, 1H), 7.41-7.26 (m, 3H), 7.25-7.14 (m, 4H), 5.82 (d, 1H), 4.84 (m, 1H), 4.19-4.06 (m, 1H), 3.41 (dd, 2H), 2.91 (dd, 2H), 1.43 (d, 3H). D-10 (5-Bromo-2-fluorophenyl)methanamine MS m/z: 335 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.45 (s, 2H), 7.42 (d, 1H), 7.31-7.08 (m, 6H), 5.76 (d, 1H), 4.88-4.81 (m, 1H), 3.96 (s, 2H), 3.45-3.39 (m, 2H), 2.94-2.89 (m, 2H). D-11 Intermediate C-1 MS m/z: 375 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.52 (s, 2H), 7.98 (d, 2H), 7.62 (s, 1H), 7.24-7.15 (m, 4H), 5.88 (d, 1H), 4.85 (m, 1H), 3.98 (s, 2H), 3.94 (s, 3H), 3.41 (dd, 2H), 2.92 (dd, 2H). (Preparation Example D-12 ) Preparation of 5-(4-(1-amino-2,2-difluoroethyl)phenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidine-2-amine hydrochloride (intermediate D-12) (Step 1) Preparation of N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfenamide

Using the same method, intermediate C-7 (0.29 g, 0.86 mmol) was used instead of 3-bromoaniline used in Preparation D-1 to obtain the title compound (0.17 g, 42%) as a yellow solid. MS m/z: 471 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 mHz), δ ppm: 8.51 (d, 2H), 7.51 (t, 2H), 7.48-7.42 (m, 2H), 7.26-7.22 (m, 2H), 7.21-7.15 (m, 2H), 6.17-5.80 (m, 1H), 5.59-5.52 (m, 1H), 4.93-4.79 (m, 1H), 4.74-4.65 (m, 1H), 3.90-3.81(m, 1H), 3.43 (dd, 2H), 2.92 (dd, 2H), 1.26 (s, 9H). (Step 2) Preparation of 5-(4-(1-amino-2,2-difluoroethyl)phenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine hydrochloride

The compound prepared in (Step 1) (0.17 g, 0.37 mmol) was dissolved in dichloromethane (1.5 ml), and after adding 4 mol/L hydrochloric acid dioxane solution (0.5 ml), the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was washed with diethyl ether and then dried to quantitatively obtain the title compound (147 mg) as a solid. MS m/z: 367 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 9.14 (s, 3H), 8.74 (s, 2H), 7.79 (d, 2H), 7.64-7.60 (m, 3H), 7.25-7.21 (m, 2H), 7.18-7.15 (m, 2H), 6.52 (td, 1H), 4.97 (s, 1H), 4.73-4.66 (m, 1H), 3.28 (dd, 2H), 2.94 (dd, 2H). (Preparation Example D-13 ) Preparation of 5-(3-amino-5-methoxyphenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-13) (Step 1) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-(3-methoxy-5-nitrophenyl)pyrimidin-2-amine

The title compound was synthesized in the same manner as in Preparation Example D-1 using 1-bromo-3-methoxy-5-nitrobenzene instead of 3-bromoaniline used in Preparation Example D-1. MS m/z: 363 [M+1] ^{+ 1} H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.53 (s, 2H), 7.94 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.24-7.18 (m, 4H), 5.53 (m, 1H), 4.85 (m, 1H), 3.92 (s, 3H), 3.42 (m, 2H), 2.90 (m, 2H). (Step 2) Preparation of 5-(3-amino-5-methoxyphenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine

The compound prepared in (Step 1) (0.27 g, 0.75 mmol) was dissolved in a mixed solvent of ethyl acetate/tetrahydrofuran (1/1, 14 ml), and after adding Pd/C (10 wt %, 30 mg) thereto, the mixture was stirred under 1 atmosphere of hydrogen at room temperature for 24 hours. Insoluble matter was removed by celite, and the filtrate washed with methanol was concentrated under reduced pressure to obtain the title compound (0.22 g, 88%) as a yellow solid. MS m/z: 333 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.52 (s, 2H), 7.60 (d, 1H), 7.22-7.15 (m, 4H), 6.36 (s, 1H), 6.32 (s, 1H), 6.11 (s, 1H), 5.17 (s, 2H), 4.66-4.64 (m, 1H), 3.71 (s, 3H), 3.29-3.25 (m, 2H), 2.94-2.88 (m, 2H).

Using intermediates C-2 to C-4 according to the following Table 3 instead of 1-bromo-3-methoxy-5-nitrobenzene, the compounds according to Preparation Examples D-14 to D-16 (Intermediate D-14 to Intermediate D-16) were synthesized using the two-step synthesis method in Preparation Example D-13. (Preparation Example D-14 ) Preparation of 5-(3-amino-5-isopropoxyphenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-14) (Preparation Example D-15 ) Preparation of 5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin- ^5-yl)-N1 , N1 ^- dimethylbenzene-1,3-diamine (Intermediate D-15) (Preparation Example D-16 ) Preparation of 5-(3-amino-5-oxolinylphenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-16) [Table 3] Preparation example Structure Reaction Materials MS, NMR D-14 Intermediate C-2 MS m/z: 361 [M+1]+ 1H NMR (CDCl3, 400 MHz), δ ppm: 8.48 (s, 2H), 7.26-7.18 (m, 4H), 6.41 (s, 1H), 6.36 (s, 1H), 6.22 (s, 1H), 5.39 (s, 1H), 4.85 (m, 1H), 4.56-4.54 (m, 1H), 3.74 (s, 2H), 3.44-3.40 (m, 2H), 2.93-2.89 (m, 2H), 1.35 (s, 6H). D-15 Intermediate C-3 MS m/z: 346 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.50 (s, 2H), 7.55 (d, 1H), 7.21-7.13 (m, 4H), 6.11 (s, 2H), 5.94 (s, 1H), 4.93 (s, 2H), 4.67-4.61 (m, 1H), 3.29-3.23 (m, 2H), 2.94-2.86 (m, 8H). D-16 Intermediate C-4 MS m/z: 388 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.46 (s, 2H), 7.23-7.16 (m, 4H), 3.69 (s, 1H), 6.30 (s, 1H), 6.22 (s, 1H), 5.65 (d, 1H), 4.82 (m, 1H), 3.84 (m, 4H), 3.40 (dd, 2H), 3.17 (m, 4H), 2.90 (m, 2H). (Preparation Example D-17 ) Preparation of 5-amino-1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)pyridin-2( 1H )-one (Intermediate D-17) (Step 1) Preparation of tert- butyl (6-oxo-1,6-dihydropyridin-3-yl)carbamate

5-Amino-2-hydroxypyridine (2.0 g, 18.2 mmol) was dissolved in tert-butyl alcohol (30 ml), and di-tert-butyl decarbonate (4.2 ml, 18.2 mmol) was added thereto at 0°C, and the mixture was stirred at 85°C for 16 hours. After the reaction was completed, distilled water (20 ml) was added thereto, and the resultant was extracted twice with ethyl acetate (30 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The solid obtained by adding diethyl ether to the residue was filtered to obtain the title compound (1.75 g, 46%) as a green solid. MS m/z: 211 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 11.28 (br s, 1H), 9.01 (br s, 1H), 7.52 (br s, 1H), 7.41 (dd, 1H), 6.31 (d, 1H), 1.44 (s, 9H). (Step 2) Preparation of 5-amino-1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)pyridin-2(1 H )-one

The compound prepared in (Step 1) (1.16 g, 5.51 mmol) was dissolved in dimethyl sulfoxide (15 ml), and after adding potassium carbonate (0.76 g, 5.51 mmol), cuprous iodide (53 mg, 0.28 mmol), L-proline (32 mg, 0.28 mmol) and intermediate A-1 (0.80 g, 2.76 mmol), the mixture was stirred at 100° C. for 5 days. After completion of the reaction, distilled water (40 ml) was added thereto, and the resultant was extracted three times with dichloromethane (50 ml). The organic layer was collected, washed with distilled water and saturated saline water, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99 to 10:90) to obtain the title compound (0.081 g, 5%) as a brown solid. MS m/z: 320 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.35 (br s, 2H), 7.84 (d, 1H), 7.25-7.14 (m, 5H), 6.81 (d, 1H), 6.37 (d, 1H), 4.63 (sxt, 1H), 4.40 (br s, 2H), 3.27 (dd, 2H), 2.93 (dd, 2H). (Preparation Example D-18 ) Preparation of 5-(3-amino- 1H -pyrazol-1-yl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-18)

Intermediate A-2 (2.23 g, 6.62 mmol), 3-amino-1H-pyrazole (0.50 g, 6.02 mmol), cesium carbonate (2.94 g, 9.03 mmol) and copper bromide (0.086 g, 0.60 mmol) were dissolved in N-methyl-2-pyrrolidone (12 ml), and the reaction mixture was then stirred at 120° C. for 6 hours under a nitrogen atmosphere. After the reaction was completed, the resultant was cooled to room temperature, and then filtered using diatomaceous earth and insoluble matter was removed. Distilled water (10 ml) was added to the filtrate, and the resultant was extracted three times with ethyl acetate (20 ml). The organic layers were collected, washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 9:1) to obtain the title compound (1.27 g, 72%) as a gray-brown solid. MS m/z: 293 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.56 (s, 2H), 7.92 (s, 1H), 7.48–7.47 (d, 1H), 7.17–7.08 (m, 4H), 5.65 (s, 1H), 4.97 (s, 2H), 4.58–4.53 (m, 1H), 3.24–3.18 (dd, 2H), 2.88–2.82 (dd, 2H), 2.39–2.37 (t, 2H). (Preparation Example D-19 ) Preparation of 5-(3-amino-5-methyl- 1H -pyrazol-1-yl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D-19)

The title compound was obtained in the same manner as in Preparation Example D-18 using 5-methyl-1H-pyrazol-3-amine instead of 3-amino-1H-pyrazole. MS m/z: 307 [M+1] ⁺ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.69 (s, 2H), 7.25-7.20 (m, 4H), 5.65 (br, 2H), 4.72 (m, 1H), 3.42 (dd, 2H), 2.92 (dd, 2H), 2.21 (s, 3H) (Preparation Example D-20 ) Preparation of 5-(4-amino- 1H -pyrazol-1-yl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine hydrochloride (Intermediate D-20) (Step 1) Preparation of ethyl 1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazole-4-carboxylate

1H-pyrazole-4-carboxylic acid ethyl ester (1.1 g, 7.85 mmol), intermediate A-2 (2.91 g, 8.63 mmol), cuprous iodide (149.5 mg, 0.79 mmol), L-proline (180.8 mg, 1.57 mmol) and potassium phosphate, tribasic (4.17 g, 19.62 mmol) were dissolved in N-methyl-2-pyrrolidone (26 ml), and after nitrogen was passed therethrough, the mixture was stirred at 160° C. for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then a saturated aqueous ammonium chloride solution (50 ml) was added thereto, and insoluble matter was removed by filtration using diatomaceous earth. The filtrate was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 30:70 → methanol:dichloromethane = 10:90) to obtain the title compound (0.15 g, 5%) as a white solid. MS m/z: 350 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.92 (s, 1H), 8.78 (s, 2H), 8.12 (s, 1H), 7.92 (s, 1H), 7.22-7.15 (m, 4H), 4.65 (m, 1H), 4.27 (m, 2H), 3.26 (m, 2H), 2.95-2.91 (m, 2H), 1.30 (m, 3H). (Step 2) Preparation of 1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazole-4-carboxylic acid

The compound prepared in (Step 1) (0.15 g, 0.42 mmol) was dissolved in a mixed solvent of tetrahydrofuran/methanol/distilled water (3/2/1, 24 ml), and after adding lithium hydroxide monohydrate (0.18 mg, 4.23 mmol) thereto, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the organic solvent was concentrated under reduced pressure. To the residue was added a 1 N aqueous hydrogen chloride solution to adjust the pH to 2, and the resulting solid was filtered and washed with distilled water to obtain the title compound (0.13 g, 96%) as a gray-brown solid. MS m/z: 322 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.84 (s, 1H), 8.78 (s, 2H), 8.07 (s, 1H), 7.91 (brs, 1H), 7.25-7.13 (m, 4H), 4.67-4.61 (m, 1H), 3.31-3.25 (m, 2H), 2.95-2.90 (m, 2H). (Step 3) Preparation of tert-butyl (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol- 4 -yl)carbamate

The compound prepared in (Step 2) (0.17 g, 0.54 mmol) was dissolved in a mixed solvent of tert-butyl alcohol (1.8 ml)/N,N-dimethylformamide (1 ml), and after adding diphenylphosphatidyl azide (0.23 ml, 1.09 mmol) and N,N-diisopropylethylamine (0.19 ml, 1.09 mmol), the mixture was stirred at 90° C. for 18 hours. After the reaction was completed, distilled water (30 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (50 ml). The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=30:70) to obtain the title compound (0.091 g, 43%) as a gray-brown solid. MS m/z: 393 [M+1] ⁺ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.55 (s, 2H), 8.03 (s, 1H), 7.56 (s, 1H), 7.25-7.16 (m, 4H), 4.80-4.79 (m, 1H), 3.99 (m, 1H), 3.26-3.15 (m, 2H), 2.94-2.89 (m, 2H), 1.52 (s, 9H). (Step 4) Preparation of 5-(4-amino- 1H -pyrazol-1-yl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine hydrochloride

The compound prepared in (Step 3) (0.091 g, 0.23 mmol) was dissolved in dichloromethane (0.8 ml), and after adding 4 mol/L hydrogen chloride 1,4-dioxane solution (0.8 ml) thereto, the mixture was stirred at 40° C. for 18 hours. After completion of the reaction, the resultant was concentrated under reduced pressure to obtain the title compound (0.094 g) as a gray-brown solid, and the title compound was directly used in the next reaction without separate purification. MS m/z: 293 [M+1] ⁺ (Preparation Example D-21 ) Preparation of 5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-amine (Intermediate D-21)

Intermediate A-6 (0.50 g, 2.12 mmol) and thiosemicarbazide (0.25 g, 2.75 mmol) were dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at 80° C. for 18 hours. After the reaction was completed, 25% aqueous ammonia (20 ml) was added thereto, and the resultant was stirred for 30 minutes. The resulting solid was filtered, washed with distilled water, and purified by silica gel column chromatography (methanol: dichloromethane = 5:95 to 10:90) to obtain the title compound (0.42 g, 64%) as a gray-brown solid. MS m/z: 311 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.66 (s, 2H), 8.03 (s, 1H), 7.32 (s, 2H), 7.22-7.15 (m, 4H), 4.67 (m, 1H), 3.26 (m, 2H), 2.95-2.91 (m, 2H). (Preparation Example D-22 ) Preparation of 3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)isoxazol-5-amine (Intermediate D-22)

Intermediate A-5 (0.10 g, 0.36 mmol) was dissolved in a 1 N aqueous sodium hydroxide solution (0.7 ml), and after adding ammonium hydroxychloride (27.5 mg, 0.40 mmol), the mixture was stirred at 100° C. for 5 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (30 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (30 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was filtered and washed with diethyl ether to obtain the title compound as a gray-brown solid (0.032 g, 30%). MS m/z: 294 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 12.71 (brs, 1H), 8.77-8.70 (m, 2H), 8.36 (s, 1H), 7.32-6.78 (m, 5H), 4.70 (m, 1H), 3.29-3.25 (m, 2H), 2.94-2.90 (m, 2H). (Preparation Example D-23 ) Preparation of 3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,2,4-oxadiazol-5-amine (Intermediate D-23) (Step 1) Preparation of 2-((2,3-dihydro- 1H -inden-2-yl)amino) -N' -hydroxypyrimidine-5-carboxamide

Intermediate A-6 (0.30 g, 1.27 mmol) was dissolved in ethanol (10 ml), and after adding hydroxylamine hydrochloride (0.7 g, 10.2 mmol) and triethylamine (1.03 g, 10.16 mmol), the mixture was stirred at 85° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. Distilled water (10 ml) was added to the residue, and the resultant was stirred at room temperature for 30 minutes to obtain the title compound (0.21 g, 61%) as a white solid. MS m/z: 270 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 9.51 (s, 1H), 8.53 (s, 2H), 7.72 (d, 1H), 7.26-7.18 (m, 2H), 7.17-7.09 (m, 2H), 5.82 (s, 2H), 4.73-4.55 (m, 1H), 3.25 (dd, 2H), 2.95-2.84 (m, 2H). (Step 2) Preparation of 3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,2,4-oxadiazol-5-amine

The compound obtained in (Step 1) (0.21 g, 0.78 mmol) was dissolved in toluene (8 ml), and after trifluoroacetic anhydride (0.26 g, 0.86 mmol) was added dropwise thereto, the reaction mixture was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. Then, the residue was dissolved in methanol (10 ml), 7 mol/L ammonia methanol solution (2 ml) was added thereto, and the resultant was stirred at room temperature for 16 hours. The resulting solid was filtered and washed with methanol to obtain the title compound (0.12 g, 50%) as a brown solid. MS m/z: 295 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.69 (d, 2H), 8.11 (d, 1H), 7.94 (s, 2H), 7.21 (dd, 2H), 7.17-7.10 (m, 2H), 4.77-4.59 (m, 1H), 3.26 (dd, 2H), 2.91 (dd, 2H). (Preparation Example D-24 ) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-(5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyrimidin-2-amine (Intermediate D-24) (Step 1) Preparation of (2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)methanol

Intermediate A-4 (2.34 g, 8.26 mmol) was dissolved in tetrahydrofuran (28 ml), and a 1 mol/L diisobutylaluminum hydride (DIBAL-H) toluene solution (27 ml) was slowly added dropwise at -78°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0°C again, and then a 1 N aqueous sodium hydroxide solution (40 ml) was slowly added thereto to terminate the reaction, and the insoluble matter was removed by diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (methanol:dichloromethane=10:90) to obtain the title compound (1.85 g, 93%) as a white solid. MS m/z: 242 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.24 (s, 2H), 7.38 (d, 1H), 7.22-7.12 (m, 4H), 5.02 (t, 1H), 4.62-4.57 (m, 1H), 4.30 (d, 2H), 3.26-3.21 (m, 2H), 2.90-2.84 (m, 2H). (Step 2) Preparation of 2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidine-5-carboxaldehyde

The compound prepared in (Step 1) (1.85 g, 7.67 mmol) was dissolved in a mixed solvent of dichloromethane (17 ml)/dimethyl sulfoxide (9 ml), and after adding Dess-Martin periodinane (DMP) (DMP, 5.2 g, 12.3 mmol) thereto, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was concentrated under reduced pressure, distilled water (20 ml) was added to the residue, and the resultant was extracted three times with ethyl acetate (30 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 10:90 to 30:70) to obtain the title compound (0.76 g, 41%) as a gray-brown solid. MS m/z: 240 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 9.74 (s, 1H), 8.81-8.80 (s, 1H), 8.73-8.68 (m, 2H), 7.24-7.13 (m, 4H), 4.90-4.72 (m, 1H), 3.29-3.25 (m, 2H), 2.97-2.91 (m, 2H). (Step 3) Preparation of ( E )-2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidine-5-carbaldehyde oxime

The compound prepared in (Step 2) (0.66 g, 2.75 mmol) was dissolved in ethanol (16 ml), and after adding ammonium hydroxychloride (0.57 g, 8.26 mmol) and pyridine (0.67 ml, 8.26 mmol), the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting solid was filtered and washed with ethanol to obtain the title compound (0.57 g, 81%) as a gray-brown solid. MS m/z: 255 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 11.03 (s, 1H), 8.50 (s, 2H), 7.98 (s, 1H), 7.87 (d, 1H), 7.22-7.13 (m, 4H), 4.66-4.61 (m, 1H), 3.28-3.22 (m, 2H), 2.93-2.87 (m, 2H). (Step 4) Preparation of 7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carboxylic acid tert- butyl ester

The compound prepared in (Step 3) (0.57 g, 2.23 mmol) was dissolved in N,N-dimethylformamide (5 ml), and after adding N-chlorosuccinimide (0.33 g, 2.46 mmol) thereto at 0°C, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, distilled water (20 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (30 ml). The organic layer was collected, washed with distilled water and saturated saline water, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (8 ml) and cooled to 0°C, and after adding 3-methyleneazitidine-1-carboxylate (0.84 ml, 4.86 mmol) and triethylamine (1.4 ml, 9.71 mmol), the resultant was stirred at 70°C for 3 hours. After the reaction was completed, distilled water (30 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (50 ml). The organic layer was collected, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 20:80 to 60:40) to obtain the title compound (0.36 g, 38%) as a yellow solid. MS m/z: 422 [M+1] ⁺ 1H NMR (CDCl ₃ , 400 mHz), δ ppm: 8.54 (s, 2H), 7.25-7.17 (m, 4H), 5.66 (d, 1H), 4.87-4.82 (m, 1H), 4.32 (d, 1H), 4.08 (d, 1H), 3.50 (s, 2H), 3.44-3.38 (m, 2H), 2.92-2.87 (m, 2H), 1.46 (s, 9H). (Step 5) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-(5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyrimidin-2-amine

The compound prepared in (Step 5) (0.36 g, 0.85 mmol) was dissolved in dichloromethane (3 ml), and after trifluoroacetic acid (2.8 ml) was added thereto, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the resultant was concentrated under reduced pressure to obtain the title compound (0.37 g) as a trifluoroacetic acid salt in the form of a light yellow solid. MS m/z: 322 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.91 (brs, 1H), 8.66 (brs, 1H), 8.56 (s, 2H), 8.13 (d, 1H), 7.23-7.14 (m, 4H), 4.69-4.63 (m, 1H), 4.34-.20 (m, 2H), 3.76 (s, 2H), 3.29-3.23 (m, 2H), 2.94-2.89 (m, 2H). (Preparation Example D-25 ) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-(1-oxa-2,7-diazaspiro[4.4]non-2-en-3-yl)pyrimidin-2-amine (Intermediate D-25)

Using the compound obtained in Preparation Example D-24 (Step 3) and using 3-methylenepyrrolidine-1-carboxylic acid tert-butyl ester instead of 3-methyleneazidecyclobutane-1-carboxylate, the title compound was obtained as a trifluoroacetic acid salt in the same manner as in Step 4 and Step 5 of Preparation Example D-24. MS m/z: 336 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.56 (s, 2H), 8.05 (d, 1H), 7.24-7.21 (m, 2H), 7.16- 7.14 (m, 2H), 4.70-4.63 (m, 1H), 3.43 (br, 2H), 3.27-3.23 (br, 2H), 3.13 – 2.89 (m, 6H), 2.11 – 1.96 (m, 2H). (Preparation Example D-26 ) Preparation of N- (2,3-dihydro- 1H -inden-2-yl)-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)pyrimidin-2-amine (Intermediate D-26)

Using the compound obtained in Preparation Example D-24 (Step 3) and using 4-methylenepiperidine-1-carboxylic acid tert-butyl ester instead of 3-methyleneazidecyclobutane-1-carboxylate, the title compound was obtained as a trifluoroacetic acid salt in the same manner as in Step 4 and Step 5 of Preparation Example D-24. MS m/z: 350 [M+1] ⁺ 1H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.53 (s, 2H), 8.26 (s, 1H), 8.03 (d, 1H), 7.22-7.18 (m, 2H), 7.14-7.09 (m, 2H), 4.70-4.57 (m, 1H), 3.58 (br s, 1H), 3.26 (d, 4H), 3.04-2.99 (m, 2H), 2.91-2.85 (m, 2H), 1.81-1.62 (m, 5H). Examples Example 1 : Preparation of N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 1)

Intermediate D-1 (38.7 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1.3 ml), and after N,N-diisopropylethylamine (0.07 ml, 0.52 mmol) and 1,1'-carbonyldiimidazole (25.3 mg, 0.16 mmol) were sequentially added thereto, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After checking by TLC that all the starting materials had reacted, intermediate B-1 (41 mg, 0.26 mmol) was slowly added thereto, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After completion of the reaction, distilled water (10 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (20 ml). The organic layers were collected, washed with aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 5:95) to obtain the title compound (16.7 mg, 28%) as a white solid. MS m/z: 453 [M+1] ^{+ 1} H NMR (DMSO- d ₆ , 400 MHz), δ ppm: 8.78 (s, 1H), 8.58 (s, 2H), 7.70-7.64 (m, 2H), 7.48 (d, 1H), 7.32 (m, 1H), 7.23-7.13 (m, 5H), 4.68 (m, 3H), 3.81 (m, 2H), 3.28 (dd, 2H), 2.92 (dd, 2H), 2.81 (m, 2H).

The compounds of the following Examples 2 to 10 were synthesized in the same manner as in Example 1 using the intermediates according to the following Table 4 instead of the intermediate D-1. Example 2 : Preparation of ( S ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 2) Example 3 : Preparation of ( R ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5 -yl )phenyl)-2,2,2-trifluoroethyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 3) Example 4 : -(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)benzyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 4) Preparation Example 5 : ( R ) -N- (1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5-c]pyridine-5-carboxamide (Compound 5) Preparation Example 6 : N- (5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 5 ) Preparation Example 7 of 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl) -5 -((4,5,6,7-tetrahydro- 1H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide)methyl)benzoic acid methyl ester (Compound 7) Preparation Example 8 of N- (1-(2-((2,3-dihydro -1H - inden-2-yl)amino)pyrimidin-5 - yl) -1H Preparation Example 9 of (7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa - 2,6-diazaspiro[3.4]oct-6-en-2-yl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c ]pyridin-5-yl)methanone (Compound 9) Preparation Example 10 of (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridin-5- yl )methanone (Compound 9) Preparation of (1,4,6,7-tetrahydro- 5H- [1,2,3]triazolo[4,5- c ]pyridin-5-yl)methanone (Compound 10) [Table 4] Examples Structure Intermediate D MS, NMR 2 D-6 MS m/z: 481 [M+1]+ 1H NMR (CD3OD, 400 MHz), δ ppm: 8.54 (s, 2H), 7.51–7.49 (d, 2H), 7.42–7.41 (d, 2H), 7.22–7.16 (m, 2H), 7.15–.12 (m, 2H), 5.00–4.94 (q, 1H), 4.77–4.70 (m, 1H), 4.60–4.59 (d, 2H), 3.83–3.73 (m, 2H), 3.38–3.31 (dd, 2H), 2.95–2.90 (dd, 2H), 2.83–2.80 (t, 2H), 1.51–1.49 (d, 3H) 3 D-7 MS m/z：535 [M+1]+ 1H NMR (CD ₃ OD, 400 MHz), δ ppm：8.70 (s, 2H), 7.65 (m, 4H), 7.25-7.14 (m, 4H), 5.71 (m, 1H), 4.79 (m, 1H), 4.70 (s, 2H), 3.86-3.78 (m, 2H), 3.39 (dd, 2H), 2.98 (dd, 2H), 2.83 (t, 2H) 4 D-8 MS m/z：467 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm：8.48 (s, 2H), 7.40-7.27 (m, 4H), 7.23 (m, 2H), 7.16 (m, 2H), 5.73 (d, 1H), 5.20 (m, 1H), 4.83 (m, 1H), 4.61 (s, 2H), 4.51 (d, 2H), 3.77 (m, 2H), 3.40 (dd, 2H), 2.93-2.83 (m, 4H) 5 D-9 MS m/z：481 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm：8.50 (s, 2H), 7.44-7.33 (m, 4H), 7.31-7.17 (m, 4H), 5.44 (m, 1H), 5.09 (m, 1H), 4.85 (m, 1H), 4.77 (d, 1H), 4.62 (m, 2H), 3.81-3.71 (m, 2H), 3.42 (dd, 2H), 2.94-2.87 (m, 4H), 1.55 (d, 3H) 6 D-10 MS m/z：485 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm：8.56 (s, 2H), 7.67 (d, 1H), 7.56-7.53 (m, 2H), 7.30-7.13 (m, 6H), 4.68-4.63 (m, 1H), 4.56 (s, 2H), 4.34 (d, 1H), 3.69 (t, 2H), 3.30-3.24 (m, 2H), 2.94-2.89 (m, 2H), 2.71 (t, 3H) 7 D-11 MS m/z：525 [M+1]+ 1H NMR (DMSO- d6, 400 MHz), δ ppm：8.65 (s, 2H), 7.99 (s, 1H), 7.81 (s, 2H), 7.78 (d, 1H), 7.43 (m, 1H), 7.23-7.13 (m, 4H), 4.69 (m, 1H), 4.56 (s, 2H), 4.36 (d, 2H), 3.86 (s, 3H), 3.69 (m, 2H), 3.27 (m, 2H), 2.90(m, 2H), 2.72(m, 2H) 8 D-18 MS m/z: 443 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 9.59 (s, 1H), 8.67 (s, 2H), 8.15 (d, 1H), 7.68 (d, 1H), 7.29–7.19 (m, 2H), 7.14 (dd, 2H), 6.60 (d, 1H), 4.66– 4.60 (m, 3H), 3.79 (t, 2H), 3.28–3.23 (m, 2H), 2.91 (dd, 2H), 2.77 (t, 2H). 9 D-24 MS m/z: 472 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 11.25 (br, 1H), 8.55 (s, 2H), 7.24–7.23 (m, 2H), 7.20–7.18 (m, 2H), 5.67–5.65 (d, 1H), 4.85–4.83 (m, 1H), 4.58 (s, 2H), 4.43–4.41 (d, 2H), 4.22–4.20 (d, 2H), 3.70–3.67 (t, 2H), 3.56–3.52 (s, 2H), 3.44–3.38 (dd, 2H), 2.93–2.87 (m, 4H). 10 D-25 MS m/z: 486 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 8.56 (s, 2H), 7.24-7.19 (m, 4H), 5.80 (d, 1H), 4.87-4.82 (m, 1H), 4.60-4.47 (m, 2H), 3.84-3.61 (m, 5H), 3.46-3.38 (m, 3H), 3.37-3.23 (m, 2H), 3.02-2.88 (m, 4H), 2.35-2.31 (m, 1H), 2.09-2.01 (m, 1H). Example 11 : Preparation of 3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro- 1H- [1,2,3]triazolo[4,5- c ]pyridine-5-carboxamido)methyl)benzoic acid (Compound 11)

The compound prepared in Example 7 (68.8 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1.5 ml), and after adding a 1 N aqueous lithium hydroxide solution (1.5 ml) thereto, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a 2 N aqueous hydrogen chloride solution was added to adjust the pH of the liquid to 2. The resulting solid was filtered, washed with distilled water, and then dried to obtain the title compound (47.2 mg, 70.5%) as a white solid. MS m/z: 511 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.64 (s, 2H), 7.97 (s, 1H), 7.81 (s, 1H), 7.74 (m, 2H), 7.42 (m, 1H), 7.23-7.14 (m, 4H), 4.67 (m, 1H), 4.57 (s, 2H), 4.35 (d, 2H), 3.69 (m, 2H), 3.27 (dd, 2H), 2.92 (dd, 2H), 2.72 (m, 2H). Example 12 : Preparation of ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 12)

Intermediate D-1 (30 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and after intermediate B-2 (25 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.74 mmol) were sequentially added thereto, the mixture was cooled to 0°C, and after benzotriazol-1-yloxy-tripyrrolidinephosphonium hexafluorophosphate (129 mg, 0.25 mmol) was slowly added thereto, the mixture was stirred at 40°C under nitrogen for 36 hours. After completion of the reaction, distilled water (10 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (20 ml). The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=5:95) to obtain the title compound (12.3 mg, 27%) as a white solid. MS m/z: 452 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 10.13 (m, 1H), 8.60 (d, 1H), 7.88-7.57 (m, 3H), 7.40-7.32 (m, 2H), 7.23-7.15 (m, 4H), 4.68 (m, 1H), 3.27 (m, 2H), 2.93-2.81 (m, 7H), 2.18 (m, 1H), 1.87 (m, 1H).

The compounds of Examples 13 to 55 were synthesized in the same manner as in Example 12 using the intermediates shown in Table 5 below instead of Intermediate B-2 and Intermediate D-1. Example 13 : Preparation of N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-fluoro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 13) Example 14 : Preparation of N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxamide (Compound 14) Example 15 : Preparation of N- (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-methoxy- 1H - benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 14) Preparation Example 16 of N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonylamino)isonicotinamide (Compound 15) Preparation Example 17 of N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(methylsulfonylamino)nicotinamide (Compound 16) Preparation Example 18 of N -(3- (2 -((2,3-dihydro-1 H -inden-2- yl )amino)pyrimidin-5-yl ) phenyl)-2-(methylsulfonylamino)thiazole- 4 -carboxamide ( Compound 17) Preparation Example 19 of (5-((3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)aminomethyl)pyridin-2-yl)methanesulfonic acid (Compound 19) Preparation Example 20 of N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-((methylsulfonyl)methyl)isonicotinamide (Compound 20) Preparation Example 21 of N - (3-(2-((2,3-dihydro- 1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl) -2 -((methylsulfonyl)methyl) isonicotinamide (Compound 20 ) Preparation Example 22 of (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(1H-tetrazolyl)nicotinamide (Compound 21) Preparation Example 23 of (S )-N- ( 3- ( 2 - ( (2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-4,5,6,7-tetrahydro -1H - benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 22 ) Preparation Example 24 of [1,2,3]triazole-5-carboxamide (Compound 23) : 6-(2,2-difluoroethoxy) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl) -1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 24) : Preparation Example 25 of ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2- yl )amino)pyrimidin-5-yl)-5-isopropoxyphenyl)-4,5,6,7- tetrahydro - 1H -benzo[ d ][ 1,2,3 ]triazole-5-carboxamide ( Compound 25) : -(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-(dimethylamino)phenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 26) Preparation Example 27 : ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxolinylphenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide (Compound 27) Preparation Example 28 : ( S ) -N- (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxolinylphenyl)-4,5,6,7-tetrahydro- 1H - benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 27) -inden-2-yl)amino)pyrimidin-5-yl)-4-methylphenyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 28) Preparation Example 29 : ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[d][1,2,3]triazole-5-carboxamide (Compound 29) Preparation Example 30 : 6-(2,2-difluoroethoxy) -N- (1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5,6,7-tetrahydro- 1H- benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 29) -inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6-dihydropyridin-3-yl) -1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 30) Preparation Example 31 : ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide (Compound 31) Preparation Example 32 : N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 31) -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 32) Preparation Example 33 : ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 33) Preparation Example 34 : ( R ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 34) Preparation Example 35 : N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl)-6-methoxy- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 35) Preparation Example 36 : 6-(2,2-difluoroethoxy) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl) -1H -benzo[ d [1,2,3]triazole-5-carboxamide (Compound 36) Preparation Example 37 : ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-4-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 37) Preparation Example 38 : ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 38) Preparation Example 39 : ( S )- N -(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-yl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 39) Preparation Example 40 : ( S )- N -(1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-methyl-1 H -pyrazol-3-yl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 40) Preparation Example 41 : ( S )- N -(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1-methyl- 1H -pyrazol-3-yl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 41) Preparation Example 42 : ( S ) -N -(( S )-1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide (Compound 42) Preparation Example 43 : ( S ) -N -(( R )-1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1H-benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 42 ) -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 43) Preparation Example 44 : ( R ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxamide (Compound 44) Preparation Example 45 : ( 5S ) -N- (1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-2- oxo -2,3-dihydrobenzo[d]oxazole-6-carboxamide (Compound 44) -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2-difluoroethyl)-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 45) Preparation Example 46 : ( R ) -N -(( R )-1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1H-benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 46) Preparation Example 47 : ( R ) -N- (1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro- 1H- benzo[d][1,2,3]triazole-5-carboxamide (Compound 46) 4-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxamide (Compound 47) Preparation Example 48 : ( S )-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazol-5-yl)methanone (Compound 48) Preparation Example 49 : ( R )-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2- yl) d ]oxazol-2(3H)-one (Compound 50): 6-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxazol-2,6-diazaspiro[3.4]oct-6-en-2-yl)(4,5,6,7-tetrahydro- 1H -benzo[d][1,2,3]triazol-5-yl)methanone (Compound 49) Preparation Example 50 : 6-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxazol-2,6-diazaspiro[3.4]oct-6-en-2-carbonyl)benzo[ d ]oxazol-2( 3H )-one (Compound 50) Preparation Example 51 : N- (4-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxazol-2,6-diazaspiro[3.4]oct-6-en-2-carbonyl)benzo[d]oxazol-2(3H ) -one Preparation Example 52 of N-(5-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide (Compound 51): Preparation Example 53 of N- ( 5-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -5 -oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide ( Compound 52) : Preparation Example 54 of (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl)((S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone (Compound 53) : Preparation Example 55 of ( S )-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)(4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazol-5-yl) methanone (Compound 54 ) ： Preparation of N- (4-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carbonyl)pyridin-2-yl)methanesulfonamide (Compound 55) [Table 5] Examples Structure Intermediate B Intermediate D MS, NMR 13 B-4 D-1 MS m/z: 466 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.58 (s, 1H), 8.58 (s, 2H), 8.30 (s, 1H), 7.93 (s, 1H), 7.85 (d, 1H), 7.69 (d, 2H), 7.39 (dd, 2H), 7.19 (s, 2H), 7.12 (d, 2H), 4.64 (d, 1H), 3.23 (m, 2H), 2.90 (m, 2H). 14 B-5 D-1 MS m/z: 478 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.35 (d, 1H), 8.62 (s, 2H), 8.18 (s, 1H), 7.96 (s, 1H), 7.73 (m, 2H), 7.52 – 7.32 (m, 3H), 7.23 (m, 2H), 7.15 (m, 2H), 4.68 (m, 1H), 3.97 (s, 3H), 3.27 (m, 2H), 2.93 (dd, 2H). 15 B-8 D-1 MS m/z: 501 [M+1]+ 1H NMR (DMSO- d6, 400 MHz), δ ppm: 10.85 (s, 1H), 10.56 (s, 1H), 8.62 (s, 2H), 8.47 (m, 1H), 7.96 (s, 1H), 7.71 (m, 1H), 7.51-7.39 (m, 3H), 7.23-7.13 (m, 4H). 16 B-7 D-1 MS m/z: 501 [M+1]+ 1H NMR (DMSO- d6, 400 MHz), δ ppm: 10.33 (s, 1H), 8.84 (s, 1H), 8.62 (s, 2H), 8.26-8.23 (m, 1H), 7.97 (s, 1H), 7.74-7.70 (m, 2H), 7.45-7.37 (m, 2H), 7.23-7.06 (m, 5H), 4.67 (m, 1H), 3.28 (m, 5H), 2.93 (dd, 2H). 17 B-9 D-1 MS m/z: 507 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.32 (s, 1H), 8.61 (s, 2H), 7.89 (s, 1H), 7.79 (s, 1H), 7.68 (m, 2H), 7.42 (m, 2H), 7.22-7.14 (m, 4H), 4.68 (m, 1H), 3.25 (m, 2H), 3.00 (s, 1H), 2.92 (m, 2H). 18 B-10 D-1 MS m/z: 500 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.56 (s, 1H), 9.12 (s, 1H), 8.63 (s, 2H), 8.36 (d, 1H), 7.99 (s, 1H), 7.82 – 7.63 (m, 3H), 7.44 (m, 2H), 7.23-7.15 (m, 4H), 4.79 (s, 2H), 4.68 (m, 1H), 3.26 (d, 3H), 3.08 (s, 3H), 2.93 (dd, 2H). 19 B-12 D-1 MS m/z: 502 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.72 (s, 1H), 9.20 (s, 1H), 8.69 (d, 1H), 8.64 (s, 2H), 7.98 (s, 2H), 7.81 (s, 1H), 7.76 (d, 1H), 7.46 (m, 2H), 7.23 (m, 2H), 7.18 – 7.13 (m, 2H), 4.68 (m, 1H), 4.20 (s, 2H), 3.29 (dd, 2H), 2.93 (dd, 2H). 20 B-11 D-1 MS m/z: 500 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.64 (s, 1H), 8.83 (d, 1H), 8.63 (s, 2H), 7.98-7.92 (m, 3H), 7.77-7.72 (m, 2H), 7.49-7.42 (m, 2H), 7.24-7.14 (m, 4H), 4.78 (s, 2H), 4.71-4.65 (m, 1H), 3.29-3.25 (m, 2H), 3.08 (s, 3H), 2.96-2.90 (m, 2H). twenty one B-13 D-1 MS m/z: 476 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.93 (s, 1H), 8.26 (s, 2H), 8.03 (s, 1H), 7.63 (s, 1H), 7.47 – 7.31 (m, 2H), 7.07 (s, 2H), 6.85 (s, 2H), 6.78 (s, 2H), 4.31 (s, 1H), 2.58 (s, 2H), 2.30 (s, 2H). twenty two B-2 D-13 MS m/z: 482 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.10 (s, 1H), 8.59 (s, 2H), 7.70 (d, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.22-7.13 (m, 4H), 6.89 (s, 1H), 4.66 (m, 1H), 3.79 (s, 3H), 3.27 (dd, 2H), 2.92 (dd, 2H), 2.80-2.66 (m, 5H), 2.18 (m, 1H), 1.85 (m, 1H). twenty three B-4 D-13 MS m/z: 496 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.59 (s, 1H), 8.62 (s, 2H), 8.33 (d, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.23-7.13 (m, 4H), 6.98 (s, 1H), 4.70-4.65 (m, 1H), 3.83 (s, 3H), 3.29-3.25 (m, 2H), 2.96-2.90 (m, 2H). twenty four B-6 D-13 MS m/z: 558 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 15.76 (brs, 1H), 8.65-8.62 (m, 3H), 8.13 (s, 1H), 7.66 (d, 1H), 7.46 (s, 1H), 7.36 (d, 1H), 7.23-7.13 (m, 5H), 7.06 (s, 1H), 6.51-6.24 (m, 1H), 4.68-4.63 (m, 1H), 4.51-4.43 (m, 2H), 3.32-3.17 (m, 5H), 2.95-2.89 (m, 2H). 25 B-2 D-14 MS m/z: 510 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.45 (brs, 1H), 10.06 (s, 1H), 8.57 (s, 2H), 7.69 (m, 1H), 7.33-7.30 (m, 2H), 7.22-7.15 (m, 4H), 6.85 (s, 1H), 4.67-4.65 (m, 2H), 3.31-3.25 (m, 2H), 2.94-2.67 (m, 7H), 2.17-2.15 (m, 1H), 1.85 (m, 1H), 1.30 (s, 6H). 26 B-2 D-15 MS m/z: 495 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.41 (brs, 1H), 9.93 (s, 1H), 8.56 (s, 2H), 7.64 (s, 1H), 7.22-7.07 (m, 6H), 6.62 (s, 1H), 4.65 (m, 1H), 3.26 (m, 2H), 2.95-2.67 (m, 13H), 2.15 (m, 1H), 1.86 (m, 1H). 27 B-2 D-16 MS m/z: 537 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 9.99 (s, 1H), 8.57 (s, 2H), 7.67 (d, 1H), 7.29-7.13 (m, 6H), 6.88 (s, 1H), 4.66 (m, 1H), 3.75 (m, 4H), 3.26 (m, 2H), 3.15 (m, 4H), 2.94-2.79 (m, 6H), 2.65 (m, 1H), 2.18 (m, 1H), 1.86 (m, 1H). 28 B-2 D-2 MS m/z: 466 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.45 (brs, 1H), 10.03 (s, 1H), 8.33 (s, 2H), 7.63 (m, 1H), 7.51 (m, 2H), 7.23-7.16 (m, 5H), 4.67 (m, 1H), 3.30 (m, 2H), 2.96-2.91 (m, 3H), 2.82-2.79 (m, 3H), 2.74-2.68 (m, 1H), 2.17 (s, 3H), 2.14 (m, 1H), 1.85 (m, 1H). 29 B-2 D-17 MS m/z: 469 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.46 (brs, 1H), 9.93 (s, 1H), 8.38 (s, 2H), 8.15 (s, 1H), 7.91-7.89 (m, 1H), 7.54 (d, 1H), 7.22-7.14 (m, 4H), 6.53 (d, 1H), 5.76 (s, 1H), 4.65-4.63 (m, 1H), 3.28-3.24 (m, 2H), 2.97-2.64 (m, 7H), 2.14-2.11 (m, 1H), 1.80 (m, 1H). 30 B-6 D-17 MS m/z: 545 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 15.84 (brs, 1H), 10.10 (s, 1H), 8.43 (s, 2H), 8.26 (s, 1H), 8.18 (s, 1H), 7.93 (m, 1H), 7.61 (m,, 1H), 7.54 (m, 1H), 7.23-7.16 (m, 4H), 6.60-6.34 (m, 2H), 4.66 (m, 1H), 4.57-4.50 (m, 2H), 3.32 (m, 2H), 2.97-2.93 (m, 2H). 31 B-2 D-21 MS m/z: 460 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.45 (brs, 1H), 12.78 (s, 1H), 8.83 (s, 2H), 8.18 (s, 1H), 7.24-7.15 (m, 4H), 4.70 (m, 1H), 3.29-3.25 (m, 2H), 3.01-2.66 (m, 7H), 2.33 (m, 1H), 1.91 (m, 1H). 32 B-5 D-21 MS m/z: 486 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.83 (s, 2H), 8.21-8.17 (m, 2H), 7.35 (s, 1H), 7.19-7.10 (m, 4H), 4.67-4.66 (m, 1H), 3.91 (s, 3H), 3.29-3.22 (m, 2H), 2.93-2.88 (m, 2H). 33 B-2 D-18 MS m/z: 442 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.36 (s, 1H), 10.82 (s, 1H), 8.69 (s, 2H), 8.22 (d, 1H), 7.74 (d, 1H), 7.24–7.22 (m, 2H), 7.16–7.14 (m, 2H), 6.80 (d, 1H), 4.64 (m, 1H), 3.30–3.24 (m, 2H), 2.97–2.74 (m, 6H), 2.68–2.59 (m, 1H), 2.14–2.11 (m, 1H), 1.93–1.76 (m, 1H). 34 B-3 D-18 MS m/z: 442 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.81 (s, 1H), 8.68 (s, 2H), 8.22 (s, 1H), 7.73 (d, 1H), 7.22-7.14 (m, 4H), 6.80 (s, 1H), 4.66-4.61 (m, 1), 3.30-3.17 (m, 2H), 2.95-2.76 (m, 6H), 2.67-2.63 (m, 1H), 2.14-2.11 (m, 1H), 1.86-1.82 (m, 1H). 35 B-5 D-18 MS m/z: 468 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.83 (s, 1H), 8.71 (s, 2H), 8.24 (d, 2H), 7.77 (s, 1H), 7.37 (s, 1H), 7.19 (d, 4H), 6.93 (s, 1H), 4.65–4.32 (m, 1H), 3.98 (s, 3H), 3.30–3.24 (m, 2H), 2.94–2.89 (m, 2H). 36 B-6 D-18 MS m/z: 518 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 15.79 (s, 1H), 10.83 (s, 1H), 8.71 (s, 2H), 8.28 (s, 2H), 7.77 (s, 1H), 7.45 (s, 1H), 7.23 (d, 2H), 7.19–7.09 (m, 2H), 6.93 (s, 1H), 6.47 (t, 1H), 4.71–4.42 (m, 3H), 3.30–3.24 (m, 2H), 2.93–2.89 (m, 2H). 37 B-2 D-20 MS m/z: 442 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.35 (brs, 1H), 10.27 (s, 1H), 8.70 (s, 2H), 8.42 (s, 1H), 7.76-7.75 (m, 2H), 7.24-7.13 (m, 4H), 4.66-4.61 (m, 1H), 3.30-3.25 (m, 2H), 2.95-2.76 (m, 6H), 2.69-2.61 (m, 1H), 2.15-2.12 (m, 1H), 1.88-1.83 (m, 1H). 38 B-2 D-4 MS m/z: 459 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.57 (s, 2H), 7.75 (m, 2H), 7.22-7.15 (m, 4H), 4.64 (m, 1H), 3.31-3.25 (m, 2H), 2.98-2.63 (m, 8H), 2.15 (m, 1H), 1.90-1.86 (m, 1H). 39 B-2 D-3 MS m/z: 473 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 14.80-14.38 (m, 1H), 12.27 (s, 1H), 8.40 (s, 2H), 7.77 (d, 1H), 7.23-7.13 (m, 4H), 4.68-4.60 (m, 1H), 3.28-3.24 (m, 2H), 2.96-2.90 (m, 4H), 2.85-2.61 (m, 3H), 2.30 (s, 3H), 2.17-2.14 (m, 1H), 1.91-1.84 (m, 1H). 40 B-2 D-19 MS m/z: 456 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 9.18 (s, 1H), 8.36 (s, 2H), 7.26–7.23 (m, 2H), 7.20–7.17 (m, 2H), 6.83 (s, 1H), 5.72 (d, 1H), 4.84 (q, 1H), 3.46–3.33 (m, 3H), 3.15–2.88 (m, 4H), 2.87–2.71 (m, 2H), 2.52 (d, 1H), 2.29 (s, 3H), 1.97 (m, 1H). 41 B-2 D-5 MS m/z: 456 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.55 (s, 1H), 8.48 (s, 2H), 7.87 (d, 1H), 7.22 (d, 2H), 7.18–7.12 (m, 2H), 6.64 (s, 1H), 4.67 (q, 1H), 3.74 (s, 3H), 3.30–3.24 (m, 2H), 2.94 (dd, 2H), 2.90–2.71 (m, 5H), 2.08 (s, 1H), 1.81 (s, 1H). 42 B-2 D-6 MS m/z：480 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm：8.64 (s, 2H), 8.38 (d, 1H), 7.63-7.58 (m, 3H), 7.38 (d, 2H), 7.22-7.14 (m, 4H), 4.98-4.91 (m, 1H), 4.69-4.64 (m, 1H), 3.28-3.24 (m, 2H), 2.95-2.90 (m, 2H), 2.82-2.58 (m, 5H), 2.07-2.04 (m, 1H), 1.77-1.76 (m, 1H), 1.38 (d, 3H) 43 B-2 D-7 MS m/z：534 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm：8.60 (s, 2H), 7.64 (d, 2H), 7.59 (d, 2H), 7.22 (m, 2H), 7.13 (m, 2H), 5.78 (m, 1H), 4.77 (m, 1H), 3.35 (dd, 2H), 2.94 (dd, 2H), 2.88 (m, 4H), 2.77 (m, 1H), 2.19 (m, 1H), 1.98 (m, 1H) 44 B-15 D-7 MS m/z：546 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm：9.41 (m, 1H), 8.69 (s, 2H), 7.87-7.70 (m, 7H), 7.23-7.13 (m, 4H), 6.07 (m, 1H), 3.27 (dd, 2H), 2.92 (dd, 2H), 1.51 (d, 3H) 45 B-2 D-12 MS m/z：516 [M+1] ^{+ 1} H NMR (DMSO-d ₆ ，400 MHz), δ ppm：8.97-8.85 (m, 1H), 8.68 (s, 2H), 7.70-7.67 (m, 3H), 7.53 (d, J=7.8 Hz, 2H), 7.27-7.20 (m, 2H), 7.17-7.14 (m, 2H), 6.48-6.09 (t, J=55.0, 58.2 Hz,1H), 5.43-5.33 (m, 1H), 4.70-4.65 (m, 1H), 3.29-3.23 (m, 2H), 2.94 (dd, J=15.8, 7.0 Hz, 2H), 2.89-2.72 (m, 3H), 2.72-2.59 (m, 2H), 2.13-1.98 (m, 1H), 1.86-1.77 (m, 1H). 46 B-3 D-9 MS m/z：480 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm：8.67 (s, 2H), 8.39 (d, 1H), 7.59 (s, 1H), 7.50 (d, 1H), 7.40 (m, 1H), 7.28 (d, 1H), 7.29-7.14 (m, 4H), 5.00 (m, 1H), 4.67 (m, 1H), 3.28 (dd, 2H), 2.93 (dd, 2H), 2.83-2.62 (m, 5H), 2.05 (m, 1H), 1.76 (m, 1H), 1.40 (d, 3H) 47 B-15 D-9 MS m/z：331 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm：8.50 (s, 2H), 7.45 (s, 1H), 7.41-7.26 (m, 3H), 7.25-7.14 (m, 4H), 5.82 (d, 1H), 4.84 (m, 1H), 4.19-4.06 (m, 1H), 3.41 (dd, 2H), 2.91 (dd, 2H), 1.43 (d, 3H) 48 B-2 D-24 MS m/z: 471 [M+1]+ 1H NMR (CD3OD, 400 MHz), δ ppm: 11.28 (br, 1H), 8.56 (s, 2H), 7.26–7.24 (m, 2H), 7.21–7.18 (m, 2H), 5.68–5.66 (d, 1H), 4.87–4.81 (m, 1H), 4.59–4.57 (d, 1H), 4.47–4.43 (m, 1H), 4.37–4.35 (d, 1H), 4.28–4.24 (m, 1H), 3.57 (s, 2H), 3.44–3.38 (dd, 2H), 3.01–2.88 (m, 5H), 2.72–2.64 (m, 2H), 2.14–2.04 (m, 1H), 2.01–1.93 (m, 1H), 1.50–1.44 (m, 1H). 49 B-3 D-24 MS m/z：471 [M+1]+ 1H NMR (CDCl ₃ ，400 MHz), δ ppm：11.29 (br, 1H), 8.57 (s, 2H), 7.26–7.23 (m, 2H), 7.22–7.19 (m, 2H), 5.71–5.69 (d, 1H), 4.89–4.84 (m, 1H), 4.61–4.59 (d, 1H), 4.48–4.44 (m, 1H), 4.39–4.37 (d, 1H), 4.26–4.13 (m, 1H), 3.70–3.71 (m, 5H), 3.85–3.84 (m, 2H), 3.14–3.19 (m, 2H), 3.24–3.30 (m, 2H), 2.76–2.67 (m, 2H), 2.16–2.06 (m, 1H), 2.05–1.96 (m, 1H). 50 B-15 D-24 MS m/z: 483 [M+1]+ 1H NMR (CD3OD, 400 MHz), δ ppm: 8.58 (s, 2H), 7.59–7.57 (d, 2H), 7.24–7.14 (m, 5H), 4.80–4.76 (m, 1H), 4.67–4.62 (bs, 2H), 4.46 (bs, 2H), 3.73 (s, 2H), 3.38–3.32 (dd, 2H), 2.97–2.91 (dd, 2H). 51 B-8 D-24 MS m/z: 520 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.55 (s, 2H), 8.37 (s, 2H), 8.09 (d, 1H), 7.23-7.13 (m, 5H), 4.66 (m, 1H), 4.55 (s, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 3.73 (d, 2H), 3.26 (m, 5H), 2.91 (dd, 2H). 52 B-7 D-24 MS m/z: 520 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 11.04 (s, 1H), 8.55 (s, 3H), 8.09 (d, 1H), 8.02-7.99 (m, 1H), 7.22-7.13 (m, 4H), 7.01 (d, 1H), 4.64 (m, 3H), 4.42-4.24 (m, 2H), 3.73 (m, 2H), 3.28 (m, 5H), 2.90 (dd, 2H). 53 B-2 D-25 MS m/z: 485 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm: 12.01 (brs, 1H), 8.56 (s, 2H), 7.26-7.18 (m, 4H), 5.82-5.79 (m, 1H), 4.87-4.84 (m, 1H), 4.05-4.01 (m, 1H), 3.92-3.80 (m, 2H), 3.69-3.62 (m, 1H), 3.44-3.26 (m, 4H), 3.05-2.69 (m, 7H), 2.42 (m, 1H), 2.22-2.05 (m, 2H), 2.03-1.98 (m, 1H). 54 B-2 D-26 MS m/z：499 [M+1]+ 1H NMR (CDCl ₃ , 400 MHz), δ ppm：11.43 (bs, 1H), 8.56 (s, 2H), 7.24-7.18 (m, 4H), 5.66 (d, 1H), 4.87-4.82 (m, 1H), 4.42-4.33 (m, 1H), 3.77-3.51 (m, 2H), 3.42-3.28 (m, 3H), 3.01-2.88 (m, 5H), 2.78-2.70 (m, 1H), 2.17-2.01 (m, 5H), 1.81-1.75 (m, 2H), 1.50-1.44 (m, 1H), 1.28-1.24 (m, 1H). 55 B-8 D-26 MS m/z: 548 [M+1]+ 1H NMR (DMSO-d6, 400 MHz), δ ppm: 10.82 (brs, 1H), 8.56 (s, 2H), 8.33 (s, 1H), 8.01 (d, 1H), 7.23-7.13 (m, 4H), 7.05-7.03 (m, 1H), 6.93 (s, 1H), 4.68-4.63 (m, 1H), 3.86-3.82 (m, 1H), 3.60-3.59 (m, 1H), 3.31-3.22 (m, 9H), 2.94-2.88 (m, 2H), 1.84-1.75 (m, 4H). Example 56 : Preparation of N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl) -1H -benzo[ d ][1,2,3]triazole-5-sulfonamide (Compound 56)

Intermediate D-13 (84 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 ml), and after triethylamine (0.07 ml, 0.5 mmol) was added thereto, the mixture was stirred at room temperature for 30 minutes. Then, the temperature was lowered to 0°C, a solution obtained by dissolving intermediate B-14 (55 mg, 0.25 mmol) in dichloromethane (1 ml) was added dropwise thereto, and after the temperature was raised to room temperature, the mixture was stirred for 18 hours. After the reaction was completed, a saturated ammonium chloride aqueous solution (10 ml) was added thereto, and the resultant was extracted three times with ethyl acetate (20 ml). The organic layers were collected, dried over anhydrous sodium sulfate and filtered, and the collected filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100 to 10:90) to obtain the title compound (5.0 mg, 4%) as a gray-brown solid. MS m/z: 514 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 mHz), δ ppm: 8.46 (s, 2H), 8.33 (s, 1H), 7.92 (m, 2H), 7.71-7.66 (m, 2H), 7.22-7.15 (m, 4H), 6.88 (s, 1H), 6.79 (s, 1H), 6.65 (s, 1H), 4.66 (m, 1H), 3.70 (s, 3H), 3.32 (m, 2H), 2.94-2.90 (m, 2H). Example 57 : Preparation of N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-3-yl) -1H -benzo[ d ][1,2,3]triazole-5-sulfonamide (Compound 57)

The title compound was synthesized in the same manner as in Example 56 using Intermediate D-18 instead of Intermediate D-13 used in Example 56. MS m/z: 474 [M+1] ^{+ 1} H NMR (DMSO-d ₆ , 400 MHz), δ ppm: 8.51 (s, 2H), 8.46 (s, 1H), 8.10 (d, 2H), 7.88 (s, 1H), 7.71 (s, 1H), 7.20 (s, 2H), 7.14 (s, 2H), 6.29 (s, 1H), 4.60 (s, 1H ), 3.29–3.24 (m, 2H), 2.89 (d, 2H).

In order to measure the phosphatidic acid synthase inhibitory activity of the compounds according to the present disclosure, the following test was performed. Experimental Example 1 : Measurement of the inhibitory activity against human phosphatidic acid synthase (in vitro ATX activity assay ( FS-3 ))

Each test compound solution (10 μM, 100% DMSO) was diluted 4-fold in a 96-well V bottom plate (Costar 3363). After each of the test compound solutions (100% DMSO) was diluted 10-fold with tertiary distilled water, 10 μL thereof (10% DMSO) was aliquoted into a black flat bottom 96-well plate (Costar 3915). 50 μL of 1.6X assay solution (224 mM NaCl, 80 mM tris(hydroxymethyl)aminomethane hydrochloride (tris-HCl) (pH 8.0), 8 mM KCl, 1.6 mM CaCl ₂ , 1.6 mM MgCl ₂ , 1.6 mg/mL fatty acid-free bovine serum albumin (BSA)) was added thereto, and then 20 μL of 20 nM human ENPP2 solution (buffer solution: 140 mM NaCl, 50 mM tris(hydroxymethyl)aminomethane hydrochloride (pH 8.0), 5 mM KCl, 1 mM CaCl ₂ , 1 mmol/L MgCl ₂ , 1 mg/mL fatty acid-free BSA, 0.01% Brij35) and 20 μL 5 μM FS-3 solution (mixed solution: three-grade distilled water) were each added to the above mixture, followed by mixing. While the mixture was reacted at 37°C for 60 minutes, fluorescence intensity was measured every 5 minutes using an Envision Xcite Multilabel Reader (Excitation Wavelength (Ex): 485 nm, Emission Wavelength (Em): 535 nm). The ΔCFU _{30 min} value (colony forming unit (CFU) value measured at 30 min - CFU value measured at 0 min) of each of the test solutions was obtained, and the inhibition activity percentage value (% inhibition) was obtained by the equation 100 - (ΔCFU _{30 min} of the test solution / average value of ΔCFU _{30 min} of the control group) × 100. In addition, the IC ₅₀ values listed in Table 6 were calculated by fitting the inhibition curve based on the inhibition activity percentage values using the 4-parameter variable method of GraphPad Prism® software [GraphPad Version 9.3.1 (GraphPad Software for Microsoft Systems, La Jolla, CA, USA, www.graphpad.com]. [Table 6] Examples IC ₅₀ ( nM ) Examples IC ₅₀ ( nM ) Examples IC ₅₀ ( nM ) 1 B 20 B 39 A 2 A twenty one B 40 A 3 A twenty two A 41 A 4 A twenty three A 42 A 5 A twenty four A 43 A 6 A 25 A 44 B 7 A 26 B 45 A 8 A 27 B 46 A 9 A 28 A 47 A 10 A 29 A 48 A 11 A 30 A 49 A 12 B 31 A 50 A 13 B 32 A 51 C 14 B 33 A 52 C 15 A 34 A 53 A 16 A 35 B 54 A 17 C 36 A 55 C 18 B 37 A 56 C 19 B 38 A 57 A (Inhibitory activity is shown as A: IC ₅₀ <5 nanomolar/liter; B: IC ₅₀ =5 nanomolar/liter to 10 nanomolar/liter; C: IC ₅₀ >10 nanomolar/liter)

According to the results in Table 6, the compounds disclosed herein are identified to have significant phosphatidic acid synthase hydrolysis inhibitory activity. Experimental Example 2 : Measurement of phosphatidic acid synthase hydrolysis inhibitory activity in human or mouse serum ( Measurement of LysoPLD inhibitory activity by liquid chromatography - mass spectrometry ( LC -MS ) /MS analysis )

5 μl of each test compound solution (2 mmol/l, 100% dimethyl sulfoxide) was diluted 100-fold with 495 μl of methanol, and then 3 μl of the diluted methanol solution (1% dimethyl sulfoxide) was mixed with 57 μl of human or mouse serum solution in a 1.5 ml test tube. The mixed test compound solution was sequentially diluted in 48 μl of 100% serum, 12 μl per dilution, to have 5 different concentrations, and each test tube was kept in a constant temperature water bath at 37°C for 15 minutes. Subsequently, a solution obtained by diluting 10 mg/ml of 18:1 LPC solution (50% ethanol) to a concentration of 375 μg/ml with serum was aliquoted in an amount of 2 μl to each test tube to make 50 μl. Each of the test tubes was reacted in a 37°C constant temperature water bath for 3 hours. 200 μL of 0.5 μM 17:0 LPA solution (chloroform/methanol/water = 65/35/8) was aliquoted to the test tubes where the reaction was completed, and mixed therein. The resultant was centrifuged in a centrifuge at 14,000 revolutions per minute (rpm) and 4°C for 10 minutes. First, 100 μL of 50% methanol solution was aliquoted to a 96-well polypropylene plate (Agilent Technology 5042-1385), and 50 μL of the supernatant of the test tube where the centrifugation was completed was carefully transferred to the plate, and mixed therein. After covering the plate with a Well cap (Thermo 276011), it was analyzed by LC-MS/MS (Agilent 1260).

Percent values (% inhibition) were obtained by the equation 100-(3-hour serum + test solution/3-hour serum + control group)×100, and the _IC50 values listed in Table 7 were determined by fitting the inhibition curves using the 4-parameter variable method using GraphPad Prism® software [GraphPad version 9.3.1 (GraphPad Software for Microsoft Systems, La Jolla, CA, USA, www.graphpad.com].

In the following Table 7, mouse serum is indicated as (m), and human serum is indicated as (h). [Table 7] Examples IC ₅₀ ( nM ) Examples IC ₅₀ ( nM ) 1 A (h) 16 B (h) 5 A (h) twenty two A (h) 7 A (h) 33 A (h) 11 A (h) 34 B (h) 12 A (h) 48 A (h) 15 C (h) (Inhibitory activity is indicated as A: IC ₅₀ <10 nanomolar/liter; B: IC ₅₀ =10 nanomolar/liter to 100 nanomolar/liter; C: IC ₅₀ >100 nanomolar/liter)

According to the results of Table 7, it is determined that the compounds disclosed herein can reduce lysophosphatidic acid in the presence of mouse serum or human serum, and can inhibit the production of lysophosphatidic acid caused by hydrolyzing phosphatidic acid synthase. Experimental Example 3 : Measurement of the inhibitory activity of hydrolyzing phosphatidic acid synthase in human serum ( LysoPLD ( N - ethyl -N-[2 - hydroxy - 3 - sulfopropyl ] -3-methylaniline , TOOS )))

Each test compound solution (0.5 mmol/L, 100% DMSO) was diluted 4-fold in a 96-well V-bottom plate (Costa 3363). After each of the test compound solutions (100% DMSO) was diluted 10-fold with 1X lysoPLD buffer (100 mmol/L tris(hydroxymethyl)aminomethane hydrochloride (pH 9.0), 500 mmol/L NaCl, 5 mmol/L MgCl ₂ , 0.05% Triton X-100), 10 μL thereof (10% DMSO) was aliquoted into a 96-well plate (Thermo ^{Scientific™ ,} Catalog No. 269620). 5 μl of 1X lysoPLD buffer was added thereto, and then, 10 μl of stored human plasma (Innovative research, Inc., catalog number IPLANAH50ML-32895) was added thereto, followed by mixing, and the mixture was then reacted in a 37°C incubator for 30 minutes. Subsequently, 25 μl of 2 mg/ml 18:1 Lyso PC (Avanti Polar Lipid, Inc., catalog number 845875P) diluted in 1X lysoPLD buffer was each added thereto, followed by additional reaction in a 37°C incubator for 24 hours. 50 μL of detection solution (4.5 mmol/L 4-animoantioyrine, 2.7 mmol/L TOOS (N-ethyl-N-[2-hydroxy-3-sulfopropyl]-3-methylaniline), 20 U/mL horseradish peroxidase, 3 U/mL choline oxidase, 50 mmol/L tris(hydroxymethyl)aminomethane hydrochloride (pH 8.0), 4.5 mmol/L MgCl ₂ ) was added to each sample, followed by reaction at room temperature for 10 minutes. The absorbance was measured at 555 nm using an EPOCH2 microplate spectrophotometer (BioTek). IC50 values were calculated using the 4-parameter variable method of GraphPad Prism® software [GraphPad version 9.3.1 (GraphPad Software for Microsoft Systems, La Jolla, CA, USA, www.graphpad.com] after obtaining the percentage value (% inhibition) by the following equation [100-[(test solution optical density (OD)-blank OD)/(control group OD-blank OD)] × ₁₀₀ ]. [Table 8] Examples IC ₅₀ ( nM ) Examples IC ₅₀ ( nM ) Examples IC ₅₀ ( nM ) 8 B 33 A 45 A 9 A 34 B 48 A 10 A 40 B 53 A 15 C 41 B (Inhibitory activity is indicated as A: IC ₅₀ <10 nmol/L; B: IC ₅₀ =10 nmol/L to 50 nmol/L; C: IC ₅₀ >50 nmol/L)

According to the results in Table 8, it is determined that the compounds disclosed herein can reduce lysophosphatidic acid in the presence of human serum and can inhibit the production of lysophosphatidic acid caused by hydrolyzing phosphatidic acid synthase. Experimental Example 4 : Measurement of Connective Tissue Growth Factor ( CTGF ) Expression Inhibition Activity Assay

Primary lung fibroblast cell line LL29 (CCL-134) was plated at 200,000 cells per well in 12-well plates overnight. The cells were cultured in Ham's F-12K medium (Gibco, catalog number 21127022) supplemented with 15% fetal bovine serum (FBS) and antibiotics (100 units/ml penicillin, 100 μg/ml streptomycin) at 37°C and 5% CO _2. Afterwards, the medium was changed to serum-free medium and serum starvation state was maintained for 4 hours. Serum-starved LL29 cells were treated with 25 μM 18:1 LPC solution (Aventi, catalog number 845875) and 1 nmol/L human ENPP2 enzyme, and 1 μM compound, and then incubated for one day. Afterwards, RNA was extracted using AccuPrep® Universal RNA Extraction Kit (Bioneer, catalog number K-3140), and complementary deoxyribonucleic acid (cDNA) was synthesized from RNA using AccuPower® RT PreMix & Master Mix (Bioneer, catalog number K-2044). A total of 10 μl of qPCR reaction solution was prepared by adding 2 ng (based on total RNA) of Luna® Universal qPCR Master Mix (New England biolabs, catalog number M3003S) and 1 μl of each 10 μM primer. 40 qPCRs were performed using QuantStudio 1 Real-Time PCR (Applied Biosystems) under the conditions of denaturation at 95°C for 10 min and then reaction at 95°C for 15 sec and 60°C for 1 min. To quantify the CTGF gene copy number, the target gene copy number between samples was corrected using the 18s rRNA internal standard gene (housekeeping gene). The copy number between samples was corrected by subtracting the Ct of the housekeeping gene from the Ct of the CTGF gene of each sample treated with the compound. Thereafter, the % inhibitory activity value was calculated by comparing the Ct value of the target gene with the difference (ΔCt) between the Ct value of the sample treated with LPC and the sample treated with each compound, and the results are shown in Table 9 below. [Table 9] Examples % Inhibitory activity Examples % Inhibitory activity Examples % Inhibitory activity 1 B twenty one B 38 B 3 B twenty two A 39 B 4 B twenty three B 42 C 5 B twenty four B 43 B 6 B 25 B 44 B 7 B 26 A 46 A 9 B 27 A 47 B 11 B 28 B 48 B 12 A 29 B 49 B 13 B 30 B 50 B 14 A 31 B 54 B 17 B 33 B 55 B 18 B 34 C 56 A 19 B 37 B (% inhibitory activity means A: >70%; B: 30% to 70%; C: <30%).

According to the results in Table 9, it was identified that the compounds of the present disclosure were capable of inhibiting the expression of CTGF caused by hydrolysis of phosphatidic acid synthase.

In the above, the embodiments of the present disclosure have been described. However, those skilled in the art should understand that the present disclosure can also be implemented in other specific forms without changing the technical concept or essential characteristics. Therefore, the above embodiments need to be understood as being illustrative in all aspects, rather than restrictive.

without

Claims (15)

A compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following Chemical Formula 1: [Chemical Formula 1] Wherein, in Chemical Formula 1, A is a substituted or unsubstituted 5- to 11-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L is a single bond, -C(=O)-, -C(=O)-NR ₁ -, -C(=O)-NR ₂ -(CR ₃ R ₄ ) _a - or -S(=O) ₂ -NR ₅ -; B is a substituted or unsubstituted carbocyclic ring; or a substituted or unsubstituted heterocyclic ring; R ₁ to R ₅ are each independently hydrogen or a substituted or unsubstituted C1-C10 alkyl group; and a is an integer from 1 to 5. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or pharmaceutically acceptable salt thereof as described in claim 1, wherein A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing a triazole group; or a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing an oxazolidinone group. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or pharmaceutically acceptable salt thereof as described in claim 1, wherein A is substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted benzoxazolone, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted tetrahydrobenzotriazolyl, substituted or unsubstituted triazolopyridyl or substituted or unsubstituted tetrahydrotriazolopyridyl. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein A is selected from the following structures: Ra is hydrogen, _R6 -S(=O) ₂ -NH-, _R6 -S(=O) ₂ - _CH2- or tetrazolyl; Rb is halogen or substituted or unsubstituted C1-C10 alkoxy; _R6 is hydroxyl or substituted or unsubstituted C1-C10 alkyl; d is an integer from 0 to 6; and e is an integer from 0 to 3. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein A is selected from the following structures: Rb is halogen or substituted or unsubstituted C1-C10 alkoxy; and e is an integer from 0 to 1. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein L is selected from the following structures: _R3 and _R4 are each independently hydrogen or substituted or unsubstituted C1-C5 alkyl. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or pharmaceutically acceptable salt thereof as described in claim 1, wherein B is a substituted or unsubstituted C6-C10 carbon ring; or a substituted or unsubstituted 5- to 11-membered mono- or di-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or pharmaceutically acceptable salt thereof as described in claim 1, wherein B is a substituted or unsubstituted C6-C10 aryl group; a substituted or unsubstituted 5- to 6-membered aryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a substituted or unsubstituted 8- to 11-membered spiro ring containing an isoxazolyl group. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or pharmaceutically acceptable salt thereof as described in claim 1, wherein B is substituted or unsubstituted phenyl, substituted or unsubstituted pyridone, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl or substituted or unsubstituted thiadiazolyl. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein B is selected from the following structures: Rc and Rc1 to Rc6 are each independently hydrogen, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, _-NR7R8 or -C(=O) _OR9 , wherein _R7 and _R8 are linked to each other to form a saturated monocyclic ring, and the saturated monocyclic ring formed includes one or more heteroatoms selected from nitrogen or oxygen, and is further substituted with one or more substituents selected from hydroxyl and substituted or unsubstituted _C1 -C10 alkyl; _R9 is hydrogen, substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C3-C10 cycloalkyl; f is an integer from 0 to 4; g is an integer from 0 to 2; h is an integer from 0 to 3; and s and t are the same as or different from each other and are each independently an integer from 0 to 4, and the sum of s and t is 2 to 5. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein B is selected from the following structures: Rc is hydrogen, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy _{, -NR7R8} or -C(=O) _OR9 ; _R7 and _R8 are linked to each other to form a saturated monocyclic ring, and the saturated monocyclic ring formed includes one or more heteroatoms selected from nitrogen or oxygen; _R9 is hydrogen or substituted or unsubstituted C1-C10 alkyl; and f is an integer from 0 to 4. The compound, stereoisomer thereof, hydrate thereof, solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein the compound is selected from compounds having the following structures: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 . A hydrolyzed phosphatidic acid synthase inhibitor composition comprises: as an active substance, a compound as described in any one of claims 1 to 12, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating a disease associated with the activity of hydrolyzing phosphatidic acid synthase, comprising as an active substance a compound as described in any one of claims 1 to 12, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating a disease selected from cardiovascular disease, cancer, obesity, diabetes, acute renal failure, chronic renal disease, diabetic nephropathy, acute renal transplant rejection, chronic allograft nephropathy, liver cirrhosis, liver hemorrhage, pruritus, nonalcoholic fatty hepatitis, acute and chronic liver transplant rejection, arthritis, atopic dermatitis, asthma, neuropathic pain, schizophrenia, neuroinflammation, peripheral neuropathy, autonomic neuropathy, systemic disease, vasculitis, sarcoidosis, allergic pneumonia, alveolar proteinosis, Langerhan cell granulomatosis, lymphangioleiomyomatosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome Acute myocardial insufficiency syndrome (ARDS), myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, cystic peritonitis, renal interstitial fibrosis, glomerulosclerosis, nonalcoholic hepatic steatosis, spontaneous pulmonary fibrosis, proliferative and nonproliferative retinopathy, dry and wet age-related macular degeneration (AMD) , macular edema, central arterial/venous embolism, traumatic injury, glaucoma, chronic pruritus of cholestatic type, and acute or chronic organ transplant rejection, the pharmaceutical composition comprising: as an active substance, a compound as described in any one of claims 1 to 12, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt.