WO2020263058A1 - Aminocyanopyridine derivative and use thereof - Google Patents

Abstract

Provided are: a compound, which is a 3-cyano-6-aminopyridine derivative of chemical formula 1, an optical isomer or solvate thereof, or a pharmaceutically acceptable salt thereof; and a use of the compound as an active ingredient for prevention or treatment of cancer or an inflammatory disease.

Description

Aminocyanopyridine derivatives and uses thereof

The present invention relates to a novel compound having an aminocyanopyridine skeleton having antagonistic activity against adenosine receptors and a pharmaceutical composition comprising the same as an active ingredient.

Adenosine is a modulator of various physiological activities in the cardiovascular and nervous systems that regulate various physiological functions through interaction with specific cell surface receptors. In addition, adenosine is an immunosuppressive metabolite produced at a high level in the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are very important factors in the production of adenosine.

In particular, the tumor microenvironment is one of the important regulators of immune functions that influence cancer progression and metastasis. High concentrations of adenosine in the tumor microenvironment inhibit the responses of anti-tumor cytotoxic lymphocytes. T cells express the inhibitory adenosine A2A receptor (A2AR), which inhibits their action and blocks the removal of tumors by immune.

Adenosine, produced by the breakdown of adenosine triphosphate (ATP) in cells, promotes the survival of tumors through various mechanisms. Adenosine regulates many physiological functions through binding to specific purinergic receptors in different cell membranes. Adenosine is a neuromodulator that promotes sleep and inhibits arousal. It also expands blood vessels to improve blood flow. It is used for malignant tachycardia that does not improve as a treatment for arrhythmia In addition, it accumulates in solid tumors, promotes tumor proliferation and angiogenesis, and plays an important role in mediating the immune system's tumor avoidance, conferring resistance to the immune system to the tumor.

Adenosine action is mediated by interactions with different membrane specific receptors belonging to the family of receptors coupled with the G protein. There are four types of adenosine receptors, A1, A2A, A2B and A3, and each receptor has a specific action. Among them, A1 and A3 receptors inhibit adenylyl cyclase by binding to the inhibitory G protein, thereby reducing cellular cAMP (3',5'-cyclic AMP) levels, whereas A2A and A2B receptors are active G By binding to the protein, it activates adenylyl cyclase, increasing cellular cAMP levels. The A1 and A2A receptors regulate myocardial oxygen consumption and coronary blood flow in the heart, and regulate the secretion of neurotransmitters in the brain.

Each of these four adenosine receptors on the cell surface is known to be upregulated in various tumor cells. Adenosine receptors are overexpressed in inflammatory and cancer cells, but low-expressed in normal cells. By promoting A2A receptors, adenosine inhibits the proliferation of T-cells in the immune system and reduces the ability of T-cells to destroy cancer cells. Therefore, inhibition of A2A receptors can activate the anticancer response of T-cells within the microenvironment of tumor cells. Adenosine receptors play an essential role in many physiological processes in the cardiovascular and central nervous system and regulate anti-inflammatory and immune suppression responses. As a result, this group of receptors has attracted excellent interest as a drug target for cardiovascular diseases, neurodegenerative diseases, autoimmune diseases and cancer. In particular, there is growing interest in the development of new compounds as antagonists of A2A receptors suitable for the prevention or treatment of cancer or inflammation-related diseases.

[Prior technical literature]

[Patent Literature]

(Patent Document 001) International Publication Patent WO 2009/156737, "TRIAZOLO [4, 5-D] PYRAMIDINE DERIVATIVES AND THEIR USE AS PURINE RECEPTOR ANTAGONISTS"

(Patent Document 002) International Publication Patent WO 2017/112917, "Methods of treating cancer"

One aspect is to provide novel compounds with antagonistic activity against human adenosine A2A receptors.

Another aspect is to provide a pharmaceutical composition comprising the novel compound.

Another aspect is to provide a pharmaceutical use of the novel compound as an anticancer agent or an inflammatory agent.

According to one aspect, there is provided a compound of the following formula (1), an optical isomer, solvate, or a pharmaceutically acceptable salt thereof:

<Formula 1>

In Formula 1,

X is H or halogen;

A and B are each independently C _6-12 aryl or C _2-14 heteroaryl, wherein aryl and heteroaryl are each independently halogen, -R ¹ , -CHR ¹ R ² , -CN, -OR ¹ ,- SR ¹ , -S(=O) _m R ¹ , C _1-6 alkylsulfonylamino, -C(=O)NR ¹ R ² , -R ¹ OR ² , -R ¹ OCR ² , -NR ¹ R ² , -NR ¹ C(=O)R ² , -NR ¹ S(=O) _m R ² , -N(R ¹ ) _m OR ² , C _3-20 C _3-20 cycloalkyl, and C _2-20 May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl, wherein m is an integer from 0 to 3, and R ¹ and R ² are each independently H, halogen, CH ₂ F, CF ₃ , C _{1 -6} alkyl, C _2-6 alkenyl, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl;

When the above substituents are more than one, they are the same or different from each other, and two adjacent substituents may be optionally bonded to form a fused ring;

Among the substituents of A and B, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl and C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl and C among R ¹ and R ² Each _2-14 heteroaryl is independently halogen, -CN, -OH, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkylsulfonylamino, NQ ¹ C( =O)Q ² (wherein Q ¹ and Q ² are each independently H, halogen, -CF ₃ , C _1-6 alkyl, C _2-6 alkenyl, or C _3-20 cycloalkyl, C _2-20 Heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl), -CH ₂ F, -CF ₃ , C _2-20 may be substituted with one or more substituents selected from the group consisting of heterocycloalkyl;

If the each independently a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl optionally substituted by the substituents, may form a fused or spiro derivatives each other ;

The C _2-14 heteroaryl or C _2-20 heterocycloalkyl each independently includes 1 to 3 heteroatoms selected from the group consisting of N, O and S.

According to another aspect, there is provided a pharmaceutical composition comprising the compound of Formula 1, its optical isomer, solvate, or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition may be a pharmaceutical composition for preventing or treating cancer or inflammatory diseases.

According to another aspect, there is provided a pharmaceutical use of the compound of Formula 1, an optical isomer, a solvate, or a pharmaceutically acceptable salt thereof.

The pharmaceutical use may be used for preventing or treating cancer or inflammatory diseases.

The cancer is lung cancer, stomach cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, germ cell cancer, bone cancer, liver cancer, Thyroid cancer, skin cancer, neoplasms of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.

The inflammatory disease may be selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Crohns disease, ulcerative colitis, transplant versus host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin dependent diabetes.

The compound of Formula 1, an optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, according to an aspect, has an aminocyanopyridine skeleton, and is treated with various cancers or inflammatory diseases by antagonistic activity against adenosine receptors. And is effective in prevention, and in particular, it is promising for the development of a drug for the prevention or treatment of immuno-oncology.

Hereinafter, the present invention will be described in more detail to aid understanding of the present invention.

The terms or words used in the specification and claims should not be construed as being limited to their usual or dictionary meanings, and the inventor may appropriately define the concept of terms in order to describe his own invention in the best way. It should be interpreted as a meaning and concept consistent with the technical idea of the present invention based on the principle that there is.

Definition of Terms

As used herein, the term “halogen” means fluorine, chlorine, bromine or iodine unless otherwise stated.

The term "alkyl", as used herein, refers to a linear or branched saturated C1 to C6 hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.

The term "cycloalkyl" as used herein refers to a C3 to C20 cyclic alkyl which may be substituted or unsubstituted unless otherwise stated, and may mean, for example, mono- or bicycloaliphatic. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2] Octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, or all possible isomers thereof Can be included without limitation.

The term "heterocycloalkyl" as used herein, unless otherwise stated, is a monocyclic or bicyclic or more polycyclic containing one or more, more specifically, 1 to 3 heteroatoms selected from O, N and S. Or, it represents a C2 to C20 cyclic hydrocarbon in the form of a spiro ring. Examples of mono heterocycloalkyl include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar functional groups, but are limited thereto. no. In addition, when the heterocycloalkyl is in a bicyclic form, it may contain at least one aromatic compound.

Cycloalkyl or heterocycloalkyl is each independently substituted with cycloalkyl or heterocycloalkyl, so that "fusion" with each other means that two atoms are shared between two fused ring compounds, and "spiro derivative" Forming means that one atom is shared between the cyclic compounds forming the derivative. Examples of the fused cyclic compound include, but are not limited to, tetrahydro-1H-furo[3,4-c]pyrrole, and hexahydropyrrolo[3,4-c]pyrrole. Examples of the spiro derivatives include azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-7-azaspiro[4.4]nonane, 2-oxa-7-azaspiro[3.5] Noan may be mentioned, but is not limited to these.

The term "aryl" as used herein refers to an aromatic compound of C6 to C30, more specifically C6 to C12, which may be substituted or unsubstituted unless otherwise stated, and only fused groups such as naphthyl, phenanthrenyl, etc. As well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl and the like. The aryl group optionally has one or more substituents, i.e. halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O)n ( n = 1,2,3) or may be substituted with thiol, but is not limited thereto.

The term "heteroaryl" as used herein, unless otherwise stated, is a monocyclic or bicyclic containing one or more, for example, 1 to 4, or 1 to 3 heteroatoms selected from O, N and S. It means an aromatic group having more than a click C2 to C30, more specifically C2 to C14. Examples of heteroaryl include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, Pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazineyl, 1,2,3-triazineyl, 1,3,5-triazineyl, cinnolinyl, pteridineyl, purinyl , 6,7-dihydro-5H-[1]pyridinyl, or 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzo[b]thiophene as bicyclic Il, benzisothiazolyl, benzisooxazolyl, benzimidazolyl, tianaftenyl, isotianaptenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, iso Quinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolo[3,4-b]pyridinyl, or benzoxazineyl and similar groups, but are not limited thereto.

As used herein, the term "isomer" refers to different compounds having the same molecular formula, and "optical isomer" refers to various stereoisomers and geometric isomers that may exist for the compounds according to the present invention. Compounds of Formula 1 according to one aspect may have an asymmetric carbon center (free carbon), and thus may exist as optical isomers ( R or S isomers), racemates, diastereomers, or any mixture thereof, and all of these Isomers and mixtures are included within the scope of the present invention. The optically active ( R )- and ( S )-isomers can be decomposed using conventional techniques, or can be prepared using chiral synthons or chiral reagents. When the compound contains a double bond, the substituent may be in the E or Z form. When the compound contains a disubstituted cycloalkyl, it may be in cis- or trans form. Any tautomeric form may also be included in a compound according to one aspect.

In the present specification, the term "solvate" may include a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules, for example ethanol or water. A complex in which the solvent molecule is water is also referred to as a "hydrate".

In the present specification, the term "derivative" refers to a compound obtained by substituting part of the structure of a compound with another atom or group of atoms.

In this specification, the numerical range indicated by using the term "to" refers to a range including the numerical values described before and after the term "to" as lower and upper limits, respectively.

The term "treating" or "treatment" as used herein refers to inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, ie, Preventing the further occurrence of pathology and/or symptoms, or improving a disease, e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, i.e. It refers to reversing pathology and/or symptoms, such as reducing disease severity.

As used herein, the term "preventing" or "prevention" means preventing a disease, for example, a disease in an individual who may have a tendency to a disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease, It refers to preventing a condition or disorder.

As used herein, the term "individual" or "patient" refers to any animal including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. .

New compound

One aspect relates to a novel compound having antagonistic activity against the adenosine receptor, in particular, the A2A receptor, which is a compound of Formula 1, an optical isomer thereof, a solvate, or a pharmaceutically acceptable salt thereof:

<Formula 1>

In Formula 1,

X is H or halogen;

A and B are each independently C _6-12 aryl or C _2-14 heteroaryl, wherein aryl and heteroaryl are each independently halogen, -R ¹ , -CHR ¹ R ² , -CN, -OR ¹ ,- SR ¹ , -S(=O) _m R ¹ , C _1-6 alkylsulfonylamino, -C(=O)NR ¹ R ² , -R ¹ OR ² , -R ¹ OCR ² , -NR ¹ R ² , -NR ¹ C(=O)R ² , -NR ¹ S(=O) _m R ² , -N(R ¹ ) _m OR ² , C _3-20 C _3-20 cycloalkyl, and C _2-20 May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl, wherein m is an integer from 0 to 3, and R ¹ and R ² are each independently H, halogen, CH ₂ F, CF ₃ , C _{1 -6} alkyl, C _2-6 alkenyl, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl;

When the above substituents are more than one, they are the same or different from each other, and two adjacent substituents may be optionally bonded to form a fused ring;

Among the substituents of A and B, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl and C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl and C among R ¹ and R ² Each _2-14 heteroaryl is independently halogen, -CN, -OH, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkylsulfonylamino, NQ ¹ C( =O)Q ² (wherein Q ¹ and Q ² are each independently H, halogen, -CF ₃ , C _1-6 alkyl, C _2-6 alkenyl, or C _3-20 cycloalkyl, C _2-20 Heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl), -CH ₂ F, -CF ₃ , C _2-20 may be substituted with one or more substituents selected from the group consisting of heterocycloalkyl;

If the each independently a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl optionally substituted by the substituents, may form a fused or spiro derivatives each other ;

The C _2-14 heteroaryl or C _2-20 heterocycloalkyl each independently includes 1 to 3 heteroatoms selected from the group consisting of N, O and S.

The "pharmaceutically acceptable salt" of the compound of Formula 1 may be prepared by a person skilled in the art using known techniques, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate , Salts with inorganic acids such as phosphoric acid, nitric acid and carbonic acid; Such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gastisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin). Salts with organic acids; Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, and the like; Salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.; metal salts obtained by reaction with alkali metals such as sodium and potassium; Or, it may include a salt with an ammonium ion.

In one embodiment, the C _2-20 heterocycloalkyl may be one containing 1 to 3 N, O and S groups as heteroatoms.

In one embodiment, the C _2-20 heterocycloalkyl may be pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl, but is not limited thereto.

In one embodiment, A is C _6-12 aryl or C _2-14 heteroaryl, and may be substituted with C _2-20 heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, such The C _2-20 heterocycloalkyl can be, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl.

In one embodiment, B is C _6-12 aryl or C _2-14 heteroaryl substituted with at least one substituent selected from the group consisting of halogen, -CN, C _1-6 alkyl, and C _1-6 alkoxy. For example, B may be selected from the group consisting of substituted or unsubstituted pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, and phenyl.

In one embodiment, B is a C _6-12 aryl substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, -CF ₃ , C _1-6 alkyl, and C _1-6 alkoxy Can be

In one embodiment, B is a C _2-14 hetero substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, -CF ₃ , C _1-6 alkyl, and C _1-6 alkoxy Aryl, for example pyrazolyl, imidazolyl, triazolyl, furyl, or thiophenyl.

In one embodiment, in Formula 1, A is C _6-12 aryl or C _2-14 heteroaryl, wherein C _6-12 aryl or C _2-14 heteroaryl are each independently C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, -OR ^1, -SR ¹ and which is substituted by one substituent selected from (where R ¹ is a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl); Additionally -OCF ₃ , -R ¹ , -OR ¹ , -SR ¹ (wherein R ¹ is C _1-6 alkyl or C _2-6 alkenyl) may be substituted with one substituent selected from the group consisting of; Here, C _3-20 cycloalkyl and C _2-20 heterocycloalkyl are independently halogen, -CN, -OH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _{1 -6} alkylsulfonylamino, NQ ¹ C(=O)Q ² (wherein Q ¹ and Q ² are each independently H, halogen, -CF ₃ , C _1-6 alkyl, C _2-6 alkenyl, or C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl), -CH ₂ F, -CF ₃ , C _3-20 cycloalkyl, C _2-20 It can be optionally substituted with one or more substituents selected from the group consisting of heterocycloalkyl, in the substituents each independently represent a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl C _3-20 cycloalkyl or C _2-20 When heterocycloalkyl is substituted, it may be fused with each other or form a spiro derivative;

Wherein B is C _6-12 aryl or C _2-14 heteroaryl, wherein C _6-12 aryl or C _2-14 heteroaryl are each independently H, halogen, -R ¹ , -CHR ¹ R ² , -CN , -OH, -OCF ₃ , C _1-6 alkyl, C _1-6 alkoxy, and -SR ¹ may be substituted with one or more substituents selected from the group consisting of, where m is an integer from 0 to 3, and R ¹ and R ² may each independently be a compound that is H, halogen, -CF ₃ , C _1-6 alkyl, or C _2-6 alkenyl.

In one embodiment, the compound of Formula 1 may be selected from the group consisting of the following compounds, but is not limited thereto:

1) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile ;

2) (S)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile ;

3) (R)-6-amino-4-(3-(3-ethoxypyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ;

4) (S)-6-amino-4-(3-(3-ethoxypyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ;

5) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-isopropoxypyrrolidin-1-yl)-5-methoxyphenyl)nico Tinonitrile;

6) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)nicotinonitrile;

7) 6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

8) 6-amino-4-(3-(3,3-difluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ;

9) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile;

10) 6-amino-4-(3-(3,3-dimethylpyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

11) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(5-azaspiro[2.4]heptan-5-yl)phenyl)nicotinonitrile;

12) 6-Amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- Day) phenyl) nicotinonitrile;

13) 6-amino-4-(3-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-5-methoxyphenyl)-2-(1H-imidazole-1- I) nicotinonitrile;

14) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)phenyl)nico Tinonitrile;

15) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(2-oxa-7-azaspiro[4.4]nonan-7-yl)phenyl)nico Tinonitrile;

16) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(piperidin-1-yl)phenyl)nicotinonitrile;

17) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methylpiperidin-1-yl)phenyl)nicotinonitrile;

18) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(4-methylpiperidin-1-yl)phenyl)nicotinonitrile;

19) 6-amino-4-(3-(3-fluoropepyridin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

20) 6-amino-4-(3-(3,3-difluoropiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ;

21) 6-amino-4-(3-(4-fluoropiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

22) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypiperidin-1-yl)phenyl)nicotinonitrile;

23) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(4-methoxypiperidin-1-yl)phenyl)nicotinonitrile;

24) 6-amino-4-(3-(3,5-dimethylpiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

25) 6-amino-4-(3-((3R,5S)-3,5-dimethylpiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl ) Nicotinonitrile;

26) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)nico Tinonitrile;

27) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(4-methylpiperazin-1-yl)phenyl)nicotinonitrile;

28) 6-amino-4-(3-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotino Nitrile;

29) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-morpholinophenyl)nicotinonitrile;

30) 6-amino-4-(3-(azepan-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

31) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-methoxypyrrolidin-1-yl)-5-methylphenyl)nicotinonitrile;

32) 6-amino-4-(3-ethyl-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

33) 6-amino-2-(1H-imidazol-1-yl)-4-(3-isopropyl-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile;

34) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-methoxypyrrolidin-1-yl)-5-(trifluoromethoxy)phenyl)nicotinonitrile ;

35) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-methoxypiperidin-1-yl)-5-(trifluoromethoxy)phenyl)nicotinonitrile ;

36) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(4-methoxypiperidin-1-yl)-5-(trifluoromethoxy)phenyl)nicotinonitrile ;

37) 6-amino-4-(3-(cyclopentyloxy)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile;

38) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-((tetrahydrofuran-3-yl)oxy)phenyl)nicotinonitrile ;

39) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)azetidine-3- Yl)-1-methylcyclopropane-1-carboxamide;

40) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)azetidine-3- One) cyclopentanecarboxamide;

41) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)-1-methylcyclopropane-1-carboxamide;

42) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)cyclopentanecarboxamide;

43) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)cyclohexanecarboxamide;

44) 6-amino-2,4-di(1H-pyrazol-1-yl)nicotinonitrile;

45) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(4-methyl-1H -Pyrazol-1-yl)nicotinonitrile;

46) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(4-methyl-1H -Imidazol-1-yl)nicotinonitrile;

47) 6-amino-4-(3-methoxy-5-morpholinophenyl)-2-(4-methyl-1H-pyrazol-1-yl)nicotinonitrile;

48) 6-amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Tinonitrile;

49) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-pyrazol-1-yl)nicotinonitrile;

50) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(3-methyl-1H-pyrazol-1-yl)nicotinonitrile ;

51) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(4-methyl-1H-pyrazol-1-yl)nicotinonitrile ;

52) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(3-(trifluoromethyl)-1H-pyrazole-1- I) nicotinonitrile;

53) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-1,2,3-triazol-1-yl)nico Tinonitrile;

54) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile;

55) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(4-methyl-1H-imidazol-1-yl)nicotinonitrile ;

56) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2-methyl-1H-imidazol-1-yl)nicotinonitrile ;

57) 6-amino-2-(2,4-dimethyl-1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Tinonitrile;

58) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-1,2,4-triazole-1 -Yl)nicotinonitrile;

59) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methyl-1H-1,2,4- Triazol-1-yl)nicotinonitrile;

60) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(3-methyl-1H-1,2,4- Triazol-1-yl)nicotinonitrile;

61) (R)-6-amino-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-(3-methoxy-5-(3-methoxypy) Rolidin-1-yl)phenyl)nicotinonitrile;

62) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(4-methyl-2H-1,2,3- Triazol-2-yl)nicotinonitrile;

63) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2H-1,2,3-triazole-2 -Yl)nicotinonitrile;

64) 6-amino-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile;

65) (R)-6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(2H-1,2,3-triazole- 2-yl)nicotinonitrile;

66) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(2H-1,2 ,3-triazol-2-yl)nicotinonitrile;

67) 6-amino-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile;

68) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile ;

69) (S)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile ;

70) (R)-6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(5-methylfuran-2-yl)nicotino Nitrile;

71) (S)-6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(5-methylfuran-2-yl)nicotino Nitrile;

72) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(5-methylfuran- 2-yl)nicotinonitrile;

73) N-(1-(3-(6-amino-3-cyano-2-(5-methylfuran-2-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)-1-methylcyclopropane-1-carboxamide;

74) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinonitrile ;

75) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile;

76) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylthiophen-2-yl)nicotinonitrile;

77) 6-amino-2-(3-cyanophenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile;

78) 6-amino-2-(3-fluorophenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile;

79) 6-amino-2-(4-fluorophenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile;

80) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(oxazol-2-yl)nicotinonitrile;

81) (R)-6-amino-2-(3-cyano-2-methylphenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile ;

82) (R)-6-amino-5-fluoro-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl) Phenyl)nicotinonitrile;

83) (R)-6-amino-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-1,2,3 -Triazol-1-yl)nicotinonitrile;

84) (R)-6-amino-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2H-1,2,3 -Triazol-2-yl)nicotinonitrile;

85) (R)-6-amino-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2- I) nicotinonitrile;

86) (R)-6-amino-2-(3-cyano-2-methylphenyl)-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl) Phenyl)nicotinonitrile;

87) 6-amino-5-fluoro-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-( 5-methylfuran-2-yl)nicotinonitrile.

Pharmaceutical composition

Another aspect relates to a pharmaceutical composition comprising the compound of Formula 1, an optical isomer, solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition may be a pharmaceutical composition for preventing or treating cancer or inflammatory diseases.

Another aspect provides a pharmaceutical use of the compound of Formula 1, an optical isomer, solvate, or a pharmaceutically acceptable salt thereof.

The pharmaceutical use may be used for preventing or treating cancer or inflammatory diseases.

Substances having antagonistic activity against A2A receptors are known to be effective in the treatment of various cancers and inflammatory diseases (WO 2017/112917, J. Immunol, 2012, 188(11), 5713-22), and the compound of Formula 1 Has been shown to have antagonistic activity against adenosine receptors, in particular, A2A receptors (see Experimental Example 1). Therefore, the compound of Formula 1 may act to increase immune recognition of cancer cells and destruction of cancer cells, and thus may be suitably used for the prevention and/or treatment of cancer, and for the prevention and/or treatment of inflammatory diseases. have.

The cancer is, for example, lung cancer, stomach cancer, testicular cancer, bladder cancer, breast cancer, uterine or cervical cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, germ cell cancer, bone cancer. , Liver cancer, thyroid cancer, skin cancer, neoplasms of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, or virus-related cancer, but is not limited thereto. In one embodiment, the cancer may be metastatic cancer, refractory cancer, or recurrent cancer.

The inflammatory disease may be, for example, rheumatoid arthritis, multiple sclerosis, Crohns disease, ulcerative colitis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, insulin dependent diabetes, or inflammatory tumors, but is limited thereto. It is not.

In addition, the pharmaceutical composition of the present invention may be administered alone or in combination with one or more additional therapeutic agents. "Concurrent administration" means administering a pharmaceutical composition according to an aspect and one or more additional therapeutic agents to an individual or patient to be treated at the same time or at different time points in any order. Accordingly, each component may be administered separately or may be administered in a sufficiently close time to provide the desired therapeutic effect.

For example, therapeutic agents that can be administered together with the pharmaceutical composition according to one aspect are therapeutic agents that stimulate the immune system (e.g., PD-1 antagonist, PD-L1 antagonist, CTLA-4 antagonist, LAG-3 antagonist, GITR antagonist, anti -CD39 antibody, anti-CD73 antibody, anti-A2AR antibody) cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, Growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, immunoregulatory agents, biological reaction modifiers, antihormonal agents ), antiandrogens, cell differentiation/proliferation/survival inhibitors, apoptosis inhibitors, inflammation inhibitors and P-glycoprotein inhibitors ) May be selected from the group consisting of, but is not limited thereto.

The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient, and can be administered orally or parenterally as desired. When administered orally, the active ingredient is 70 kg of active ingredient 1 kg of body weight per day based on an adult 0.01 to 1000 mg per day, more specifically 0.1 to 300 mg per day, based on the active ingredient when administered parenterally, 0.01 to 100 mg per 1 kg of body weight per day, more specifically 0.1 to 50 mg It can be administered in divided doses from 1 to several times so as to be administered in amounts. The dosage to be administered for a specific individual or patient should be determined in the light of a number of related factors such as the patient's weight, age, sex, health status, diet, administration time, administration method, and disease severity, and can be appropriately adjusted by a specialist. It should be understood that there is, and the above dosage is not intended to limit the scope of the present invention in any way.

In one embodiment, the pharmaceutical composition may include a conventional pharmaceutically acceptable carrier, excipient, or additive. The pharmaceutical composition can be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, trochees, powders, capsules, syrups, emulsions, microemulsions, suspensions, solutions, or intramuscular, intravenous or It can be prepared in parenteral dosage forms such as subcutaneous administration.

When the pharmaceutical composition is prepared in the form of an oral dosage form, the carriers, excipients, or additives to be used include binders, disintegrants, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, antioxidants, preservatives, lubricants. , Fillers, fragrances, sweeteners, etc. may be included. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, alginic acid, sodium Alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

When the pharmaceutical composition is prepared in the form of an injection, the carrier, excipient, or additive may include water, saline, pseudo-glucose solution, alcohols, glycol ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, Glycerides, surfactants, suspending agents, emulsifying agents, and the like.

Another aspect is a method for preventing or treating cancer or inflammatory disease comprising administering to an individual or a patient the compound of Formula 1, an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. to provide.

Details of the method of preventing or treating the above description of the pharmaceutical composition according to an aspect of the present invention may be applied as it is.

In addition, the dosage used in the method of preventing or treating is an amount effective for treating or preventing an individual or patient, and the description of the dosage of the pharmaceutical composition may be applied as it is.

In one embodiment, the compound of Formula 1 according to the above aspect may be prepared according to the method shown in the following Examples, but is not limited thereto. Those of ordinary skill in the field of organic compounds may prepare other synthetic methods by appropriately controlling specific reaction routes, reaction conditions, reaction amounts, and the like in a method different from the method specifically shown in the following Examples.

[Example]

Hereinafter, examples are presented to aid in the understanding of the present invention, but the following examples are only illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention. It is natural that changes and modifications fall within the scope of the appended claims.

Explanation of abbreviations

The abbreviations used below are as follows.

NAHMDS: sodium bis(trimethylsilyl)amide

THF; Tetrahydrofuran

DIPEA: N,N-diisopropylethylamine

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binapthyl

Pd(OAc) ₂ : Palladium acetate

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrosine] dichloropalladium(II)

Pd(PPh ₃ )Cl ₂ : Bis(triphenylphosphine)palladium(II) dichloride

MC: dichloromethane

HATU: 2-(1H-9-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

TFA: trifluoro acetic acid

FRET: Fluorescence resonance energy transfer

Preparation Example 1: Synthesis of tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl)carbamate

An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.

<Reaction Scheme 1>

(Step 1) Preparation of tert-butyl (4,6-dichloropyridin-2-yl) carbamate

<Reaction Scheme 1-1>

After dissolving 4,6-dichloropyridin-2-amine (60 g, 0.37 mol) in tetrahydrofuran (4.5 L), sodium bis(trimethylsilyl)amide (405 mL, 1M solution in THF, 0.81 at -78°C) mol) was slowly added, and then di-tert-butyl dicarbonate (102 mL, 0.44 mol) was slowly added. The reaction solution was stirred at room temperature for 12 hours, the reaction was terminated with a supersaturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography under a solution of hexane/ethyl acetate = 30/1. The title compound (54 g, 56%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.24 (s, 1H), 6.99 (s, 1H), 1.52 (s, 9H)

MS (ESI ⁺ ): m/z 264 [M+H] ⁺ .

(Step 2) Preparation of tert-butyl (4,6-dichloro-5-formylpyridin-2-yl)carbamate

<Reaction Scheme 1-2>

After dissolving diisopropylamine (87 mL, 0.62 mol) in tetrahydrofuran (1.5 L), n-butyllithium (321 mL, solution in 1.6M hexane, 0.51 mol) was slowly added at -78°C. After stirring the reaction solution at 0°C for 1 hour and 30 minutes, tert-butyl (4,6-dichloropyridin-2-yl)carbamate (54 g, 0.21 mol) dissolved in tetrahydrofuran (500 mL) was added to -78 It was added slowly at °C. After stirring the reaction solution at -78°C for 30 minutes, N,N-dimethylformamide (48 mL, 0.62 mol) was slowly added at -78°C. The reaction solution was stirred at -78°C for 30 minutes, the reaction was terminated with a supersaturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography under a solution of hexane/ethyl acetate = 30/1. The title compound (45 g, 76%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.39 (s, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 1.53 (s, 9H)

MS (ESI ⁺ ): m/z 292 [M+H] ⁺ .

(Step 3) Preparation of tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl)carbamate

<Scheme 1-3>

After dissolving tert-butyl (4,6-dichloro-5-formylpyridin-2-yl)carbamate (45 g, 0.16 mol) in tetrahydrofuran (1.5 L), diisopropylethylamine at 0°C (122 mL, 0.70 mol) was added, followed by hydroxylammonium chloride (43 g, 0.62 mol). The reaction solution was stirred at room temperature for 48 hours, and then extracted with ethyl acetate and water. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Trichloroacetonitrile (500 mL, 4.99 mol) was added to the obtained residue, followed by stirring at 100°C for 12 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by column chromatography under a solution of hexane/ethyl acetate = 20/1. The title compound (42.7 g, 95%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.42 (s, 1H), 1.53 (s, 9H)

MS (ESI ⁺ ): m/z 289 [M+H] ⁺ .

Preparation Example 2: Synthesis of tert-butyl (4-chloro-5-cyano-6-(1H-imidazol-1-yl)pyridin-2-yl)carbamate

An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.

<Reaction Scheme 2>

(Step 1) Preparation of tert-butyl (4-chloro-5-cyano-6-(1H-imidazol-1-yl)pyridin-2-yl)carbamate

Sodium hydride (NaH, 2.8 g, 69.40 mmol) was dissolved in acetonitrile (100 mL) and then imidazole (2.8 g, 41.60 mmol) was slowly added at room temperature. After the reaction solution was stirred at room temperature for 30 minutes, tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl)carbamate (10 g, 34.70 mmol) was slowly added. The reaction solution was stirred at 50° C. for 12 hours, cooled to room temperature, and further imidazole (2.8 g, 41.60 mmol) was slowly added. After stirring the reaction solution at room temperature for 30 minutes, further tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl) carbamate (10 g, 34.70 mmol) was gradually added, and the reaction solution was The mixture was stirred at 50°C for 12 hours. After cooling the reaction solution to room temperature, cooled water (200 mL) was added and crystallized using ethyl acetate. The title compound (4.6 g, 42%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.53 (s, 1H), 8.46-8.45 (t, 1H), 8.25 (s, 1H), 7.91-7.90 (s, 1H), 7.24-7.23 (m, 1H) ), 1.59 (s, 9H)

MS (ESI ⁺ ): m/z 320 [M+H] ⁺ .

Preparation Example 3: Synthesis of 6-amino-2,4-dichloronicotinonitrile

An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.

<Reaction Scheme 3>

(Step 1) Preparation of 4,6-dichloro-5-iodopyridin-2-amine

<Reaction Scheme 3-1>

2-Amino-4,6-dichloropyridine (20 g, 122.7 mmol) was added to 200 ml of dimethylformamide, followed by stirring at room temperature for 10 minutes. N-iodo succinimide (33 g, 147.2 mmol) was added, followed by stirring at 75° C. for 3 hours. After cooling to room temperature, 100 ml of water and 200 ml of an aqueous sodium thiosulfate solution were added. The mixture was stirred at room temperature for 1 hour, filtered under reduced pressure, and washed with water. The obtained residue was dried at 50° C. to obtain 29 g (yield: 82%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.55 (s, 1H), 4.66 (brs, 2H)

MS (ESI ⁺ ): m/z 290 [M+H] ⁺ .

(Step 2) Preparation of 6-amino-2,4-dichloronicotinonitrile

<Reaction Scheme 3-2>

The compound (29 g, 0.10 mol) prepared in step 1) and copper cyanide (10.8 g, 0.12 mol) were added to 145 ml of dimethylformamide, followed by stirring at 130° C. for 2 hours. After cooling to room temperature, the reaction product was diluted with 150 ml of ethyl acetate and filtered through a pad of Celite. At this time, Celite was washed with 150 ml of dimethylformamide: ethyl acetate = 1:1 (volume ratio). The filtrate was diluted with ethyl acetate and aqueous ammonia, and the organic layer was extracted. The separated organic layer was washed twice with an aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure. 60 ml of ethanol was added to the obtained residue, stirred at room temperature for 30 minutes, and then filtered to obtain 12.5 g of the title compound (yield: 66%).

¹ H NMR (300 MHz, DMSO-d6) δ 7.81 (brs, 2H), 6.61 (s, 1H)

MS (ESI ⁺ ): m/z 189 [M+H] ⁺ .

Preparation Example 4: Synthesis of 6-amino-4-chloro-2-(1H-imidazol-1-yl)nicotinonitrile

An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.

<Reaction Scheme 4>

(Step 1) Preparation of 6-amino-4-chloro-2-(1H-imidazol-1-yl)nicotinonitrile

Sodium hydride (1.28 g, 31.92 mmol) was added to 60 ml of acetonitrile at 0°C, and imidazole (1.63 g, 23.93 mmol) was slowly added to the reaction solution, followed by stirring at room temperature for 10 minutes. The compound (3.00 g, 15.96 mmol) prepared in step 2) was added to the reaction solution, followed by stirring at room temperature for 23 hours. When the reaction was completed, ice water was slowly added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was washed with water and filtered under reduced pressure to obtain 3.0 g (yield: 86%) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 8.25 (t, 1H), 7.74-7.71 (m, 3H), 7.12 (t, 1H), 6.68 (s, 1H)

MS (ESI ⁺ ): m/z 220 [M+H] ⁺ .

Example 1: (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Preparation of Tinonitrile

As an A2AR antagonist, (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Tinonitrile was prepared.

<Reaction Scheme 5>

(Step 1) Preparation of (R)-1-(3-bromo-5-methoxyphenyl)-3-methoxypyrrolidine

<Reaction Scheme 5-1>

After dissolving 1,3-dibromo-5-methoxybenzene (9 g, 33.80 mmol) in toluene (200 mL), (R)-3-methoxypyrrolidine hydrochloride (5.6 g, 40.60 mmol), 2 ,2'-bis(diphenylphosphino)-1,1'-binapthyl (BINAP, 655 mg, 1.02 mmol), cesium carbonate (Cs ₂ CO ₃ , 38.6 g, 118.40 mmol) in a sealed tube (sealed tube) ) Was added. After degassing the reaction solution, Pd(OAc) ₂ (78 mg, 0.34 mmol) was added, followed by stirring at 100° C. for 12 hours.

After cooling to room temperature, celite was filtered using ethyl acetate, and extracted several times with ethyl acetate and water. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by column chromatography under a solution of hexane/ethyl acetate = 10/1. The title compound (7.1 g, 74%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.40 (m, 1H), 6.33 (m, 1H), 6.00 (m, 1H), 4.10-4.07 (m, 1H), 3.77 (s, 3H), 3.46- 3.28 (m, 7H), 2.16-2.07 (m, 2H).

MS (ESI ⁺ ): m/z 287 [M+H] ⁺ .

(Step 2) (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Phenyl) pyrrolidine preparation

<Reaction Scheme 5-2>

After dissolving (R)-1-(3-bromo-5-methoxyphenyl)-3-methoxypyrrolidine (7.1 g, 24.90 mmol) synthesized in (Step 1) in dioxane (200 mL) , 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (9.7 g, 37.30 mmol) , Potassium acetate (KOAc, 7.6 g, 75.00 mmol) was added to a sealed tube. After degassing the reaction solution, Pd(dppf)Cl ₂ (915 mg, 1.25 mmol) was added, followed by stirring at 90°C for 12 hours.

After cooling the reaction solution to room temperature, the filtrate filtered through celite using ethyl acetate was extracted several times with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by column chromatography under hexane/ethyl acetate = 0-20% solution. The title compound (7.6 g, 91%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.70-6.67 (m, 2H), 6.23-6.22 (m, 1H), 4.11-4.05 (m, 1H), 3.83 (s, 3H), 3.53-3.32 (m , 7H), 2.13-2.10 (m, 2H), 1.35 (s, 12H).

MS (ESI ⁺ ): m/z 334 [M+H] ⁺ .

(Step 3) Tert-butyl (R)-(5-cyano-6-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidine-1-) Preparation of yl)phenyl)pyridin-2-yl)carbamate

<Reaction Scheme 5-3>

Tert-butyl (4-chloro-5-cyano-6-(1H-imidazol-1-yl)pyridin-2-yl)carbamate (4 g, 12.50 mmol) synthesized in Preparation Example 2 and ( (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) synthesized in Step 2) -Yl)phenyl)pyrrolidine (8.3 g, 25.00 mmol) and cesium fluoride (CsF, 3.9 g, 25.00 mmol) were dissolved in acetonitrile/water = 3/1 (60/20 mL) and added to a sealed tube. . After degassing the reaction solution, Pd(PPh ₃ ) ₂ Cl ₂ (912 mg, 1.25 mmol) was added, followed by stirring at 100° C. for 5 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography using hexane/ethyl acetate = 30-70% solvent to give the title compound (3.9 g, 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (t, 1H), 8.14 (brs, 1H), 8.13 (s, 1H), 7.89-7.88 (t, 1H), 7.23-7.22 (t, 1H), 6.44-6.42 (t, 1H), 6.37-6.36 (t, 1H), 6.22-6.21 (t, 1H), 4.14-4.12 (m, 1H), 3.86 (s, 3H), 3.55-3.41 (m, 4H) ), 3.38 (s, 3H), 2.19-2.14 (m, 2H), 1.56 (s, 9H).

MS (ESI ⁺ ): m/z 491 [M+H] ⁺ .

(Step 4) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Preparation of Tinonitrile

<Reaction Scheme 5-4>

Tert-butyl (R)-(5-cyano-6-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrroli) synthesized in (Step 3) above After dissolving din-1-yl)phenyl)pyridin-2-yl)carbamate (3.9 g, 7.89 mmol) in dichloromethane (200 mL), trifluoroacetic acid (TFA, 27 mL, 0.3 M) was added. I did. The reaction solution was stirred at room temperature for 12 hours, extracted using a supersaturated aqueous sodium hydrogen carbonate solution and a mixed solution of dichloromethane:methanol = 4:1, and the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using dichloromethane/methanol = 0-5% solution. The resulting residue was crystallized with diethyl ether to give the title compound (2.8 g, 93%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 7.73-7.72 (t, 1H), 7.46 (brs, 2H), 7.11-7.10 (t, 1H), 6.56 (s, 1H) ), 6.38 (m, 1H), 6.33 (m, 1H), 6.19-6.18 (m, 1H), 4.10-4.09 (m, 1H), 3.78 (s, 3H), 3.47-3.24 (m, 7H), 2.10-2.04 (m, 2H).

MS (ESI ⁺ ): m/z 391 [M+H] ⁺ .

Examples 2 to 36

In the same manner as in Example 1, but instead of 1,3-dibromo-5-methoxybenzene and (R)-3-methoxypyrrolidine hydrochloride in (Step 1) of Example 1, various 1,3 -Using the dibromobenzene derivative and the amine derivative, the compounds of Examples 2 to 36 shown in Table 1 were prepared.

Example 37: Preparation of 6-amino-4-(3-(cyclopentyloxy)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile

<Reaction Scheme 6>

(Step 1) Preparation of 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

<Reaction Scheme 6-1>

After dissolving 3-bromo-5-methoxyphenol (5.3 g, 25.50 mmol) in dioxane (100 mL), 4,4,4',4',5,5,5',5'-octamethyl -2,2'-Bi(1,3,2-dioxaborolane) (10 g, 38.30 mmol), potassium acetate (KOAc, 7.8 g, 76.50 mmol) were added to a sealed tube. After degassing the reaction solution, Pd(dppf)Cl ₂ (986 mg, 1.30 mmol) was added, followed by stirring at 90°C for 12 hours.

After cooling the reaction solution to room temperature, the filtrate filtered through celite using ethyl acetate was extracted several times with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography under hexane/ethyl acetate = 0-25% solution. The title compound (6.4 g, Quant.) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.93-6.92 (d, 1H), 6.87-6.86 (d, 1H), 6.54-6.52 (t, 1H), 4.86 (s, 1H), 3.81 (s, 3H) ), 1.35 (s, 12H).

MS (ESI ⁺ ): m/z 251 [M+H] ⁺ .

(Step 2) Tert-butyl (5-cyano-4-(3-hydroxy-5-methoxyphenyl)-6-(1H-imidazol-1-yl)pyridin-2-yl)carbamate Produce

<Reaction Scheme 6-2>

Tert-butyl (4-chloro-5-cyano-6-(1H-imidazol-1-yl)pyridin-2-yl)carbamate (500 mg, 1.56 mmol) synthesized in Preparation Example 2 and ( 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (783 mg, 3.13 mmol) synthesized in Step 1), Cesium fluoride (485 mg, 3.13 mmol) was dissolved in acetonitrile/water = 3/1 (30/10 mL) and added to a sealed tube. After degassing the reaction solution, Pd(PPh ₃ ) ₂ Cl ₂ (112 mg, 0.16 mmol) was added, followed by stirring at 100° C. for 12 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified by column chromatography using hexane/ethyl acetate = 15-70% solvent to give the title compound (250 mg, 39%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.67 (br, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.67-7.62 (m, 2H), 7.27-7.26 (m, 1H), 6.92-6.90 (m, 1H), 6.66-6.62 (m, 1H), 3.86 (s, 3H), 1.56 (s, 9H).

MS (ESI ⁺ ): m/z 408 [M+H] ⁺ .

(Step 3) tert-butyl (5-cyano-4-(3-(cyclopentyloxy)-5-methoxyphenyl)-6-(1H-imidazol-1-yl)pyridin-2-yl)car Preparation of Bamate

<Reaction Scheme 6-3>

Tert-butyl (5-cyano-4-(3-hydroxy-5-methoxyphenyl)-6-(1H-imidazol-1-yl)pyridin-2-yl) synthesized in (Step 2) above Carbamate (120 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (DMF, 2 mL) and sodium hydride (NaH, 35 mg, 0.89 mmol) was added. After stirring at room temperature for 30 minutes, bromocyclopentane (0.08 mL, 0.74 mmol) was added to the reaction solution, followed by stirring at 50° C. for 12 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified by column chromatography with a solution of hexane/ethyl acetate = 15-70% to obtain the title compound (58 mg, 41%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 8.34 (br, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.23 (s, 1H), 6.73-6.72 ( m, 2H), 6.58-6.56 (m, 1H), 4.82 (m, 1H), 3.86 (s, 3H), 1.97-1.79 (m, 6H), 1.67-1.62 (m, 2H), 1.57 (s, 9H).

MS (ESI ⁺ ): m/z 476 [M+H] ⁺ .

(Step 4) Preparation of 6-amino-4-(3-(cyclopentyloxy)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile

<Reaction Scheme 6-4>

Tert-butyl (5-cyano-4-(3-(cyclopentyloxy)-5-methoxyphenyl)-6-(1H-imidazol-1-yl)pyridin-2 synthesized in (Step 3) above -Yl)carbamate (55 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (TFA, 0.4 mL, 0.3 M) was added. The reaction solution was stirred at room temperature for 2 hours, extracted using a supersaturated aqueous sodium hydrogen carbonate solution and a mixed solution of dichloromethane:methanol = 4:1, and the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using dichloromethane/methanol = 0-5% solution. The resulting residue was crystallized with diethyl ether to give the title compound (18 mg, 41%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 7.74 (s, 1H), 7.49 (brs, 2H), 7.11 (s, 1H), 6.71-6.70 (m, 2H), 6.60-6.59 (t, 1H), 6.56 (s, 1H), 4.88 (m, 1H), 3.79 (s, 3H), 1.96-1.92 (m, 2H), 1.75-1.60 (m, 6H).

MS (ESI ⁺ ): m/z 376 [M+H] ⁺ .

Example 38

Conducted in the same manner as in Example 37, but using (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate instead of bromocyclopentane in (Step 3) of Example 37, the implementation shown in Table 2 below. The compound of Example 38 was obtained.

Example 39: N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)azetidine- Preparation of 3-yl)-1-methylcyclopropane-1-carboxamide

<Reaction Scheme 7>

(Step 1) Preparation of tert-butyl 3-(1-methylcyclopropane-1-carboxamido)azetidine-1-carboxylate

<Reaction Scheme 7-1>

1-methylcyclopropane-1-carboxylic acid (0.62 mL, 6.20 mmol), HATU (2.4 g, 6.20 mmol), and diisopropylethylamine (DIPEA, 1.6 mL, 9.30 mmol) were dissolved in dichloromethane. After stirring at room temperature for 30 minutes, tert-butyl 3-aminoazetidine-1-carboxylate (1 mL, 6.20 mmol) was added to the reaction solution, followed by stirring at room temperature for 2 hours.

The reaction solution was extracted with dichloromethane and water, and the separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified using column chromatography in a solution of hexane/ethyl acetate = 0-70% to give the title compound (1.1 g, 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.07-6.05 (br, 1H), 4.67-4.59 (m, 1H), 4.29-4.23 (t, 2H), 3.76-3.71 (q, 2H), 1.45 (s , 9H), 1.35 (s, 3H), 1.20-1.19 (m, 2H), 0.61-0.60 (m, 2H).

MS (ESI ⁺ ): m/z 255 [M+H] ⁺ .

(Step 2) Preparation of N-(azetidin-3-yl)-1-methylcyclopropane-1-carboxamide

<Reaction Scheme 7-2>

The tert-butyl 3-(1-methylcyclopropane-1-carboxamido)azetidine-1-carboxylate (1.1 g, 4.32 mmol) synthesized in (Step 1) was dissolved in dichloromethane and trifluoro Acetic acid (TFA, 14 mL, 0.3 M) was added.

The reaction solution was stirred at room temperature for 12 hours, neutralized with aqueous ammonia, and distilled under reduced pressure. The next step was carried out with the obtained compound (666 mg, Quant.) without further purification steps.

¹ H NMR (300 MHz, MeOD) δ 4.78-4.68 (m, 1H), 4.50-4.15 (m, 4H), 1.33 (s, 3H), 1.12-1.08 (m, 2H), 0.66-0.62 (m, 2H).

(Step 3) Preparation of N-(1-(3-bromo-5-methoxyphenyl)azetidin-3-yl)-1-methylcyclopropane-1-carboxamide

<Reaction Scheme 7-3>

After dissolving 1,3-dibromo-5-methoxybenzene (1.2 g, 4.32 mmol) in toluene (30 mL), N-(azetidin-3-yl)-1 synthesized in (Step 2) above -Methylcyclopropane-1-carboxamide (666 mg, 4.32 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binapthyl (BINAP, 83 mg, 0.13 mmol), carbonic acid Cesium (Cs ₂ CO ₃ , 3.5 g, 10.80 mmol) was added to a sealed tube. After degassing the reaction solution, Pd(OAc) ₂ (9 mg, 0.04 mmol) was added, followed by stirring at 100°C for 12 hours.

After cooling to room temperature, celite was filtered using ethyl acetate, and extracted several times with ethyl acetate and water. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography under a solution of hexane/ethyl acetate = 0-50%. The title compound (208 mg, 15%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.49-6.47 (t, 1H), 6.22-6.21 (t, 1H), 6.13-6.11 (br, 1H), 5.89-5.88 (t, 1H), 4.85-4.78 (m, 1H), 4.25-4.19 (t, 2H), 3.76 (s, 3H), 3.66-3.62 (m, 2H), 1.35 (s, 3H), 1.23-1.20 (m, 2H), 0.64-0.60 (m, 2H).

(Step 4) N-(1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine- Preparation of 3-yl)-1-methylcyclopropane-1-carboxamide

<Reaction Scheme 7-4>

N-(1-(3-bromo-5-methoxyphenyl)azetidin-3-yl)-1-methylcyclopropane-1-carboxamide synthesized in (Step 3) (190 mg, 0.56 mmol ) In dioxane (7 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxa Bororane) (218 mg, 0.84 mmol) and potassium acetate (KOAc, 170 mg, 1.68 mmol) were added to a sealed tube. After degassing the reaction solution, Pd(dppf)Cl ₂ (22 mg, 0.03 mmol) was added, followed by stirring at 90°C for 12 hours.

After cooling the reaction solution to room temperature, the filtrate filtered through celite using ethyl acetate was extracted several times with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography under a solution of hexane/ethyl acetate = 0-55%. The title compound (197 mg, 91%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.79-6.78 (m, 1H), 6.56-6.55 (m, 1H), 6.13-6.11 (m, 2H), 4.84-4.81 (m, 1H), 4.28-4.23 (t, 2H), 3.82 (s, 3H), 3.67-3.62 (q, 2H), 1.56 (s, 3H), 1.35 (s, 12H), 1.22-1.20 (t, 2H), 0.62-0.59 (m , 2H).

(Step 5) Tert-butyl (5-cyano-6-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-(1-methylcyclopropane-1-carboxa) Preparation of mido)azetidin-1-yl)phenyl)pyridin-2-yl)carbamate

<Reaction Scheme 7-5>

Tert-butyl (4-chloro-5-cyano-6-(1H-imidazol-1-yl)pyridin-2-yl)carbamate (108 mg, 0.34 mmol) synthesized in Preparation Example 2 and ( N-(1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ase synthesized in Step 4) Tidin-3-yl)-1-methylcyclopropane-1-carboxamide (195 mg, 0.51 mmol), cesium fluoride (CsF, 105 mg, 0.67 mmol) acetonitrile/water = 3/1 (6/2 mL) and added to a sealed tube. After degassing the reaction solution, Pd(PPh ₃ ) ₂ Cl ₂ (24 mg, 0.03 mmol) was added, followed by stirring at 100° C. for 12 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified by column chromatography using hexane/ethyl acetate = 0-100% solvent to obtain the title compound (68 mg, 37%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.23 (s, 1H), 6.56 (m, 1H), 6.25 (m, 1H), 6.10 (m, 1H), 4.85 (m, 1H), 4.30 (m, 2H), 3.85 (s, 3H), 3.80 (m, 2H), 1.56 (s, 9H), 1.37 (s, 3H ), 1.19 (m, 2H), 0.63 (m, 2H).

(Step 6) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)azetidine- Preparation of 3-yl)-1-methylcyclopropane-1-carboxamide

<Reaction Scheme 7-6>

Tert-butyl (5-cyano-6-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-(1-methylcyclopropane-) synthesized in (Step 5) above- 1-carboxamido)azetidin-1-yl)phenyl)pyridin-2-yl)carbamate (60 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), followed by trifluoroacetic acid (TFA, 0.4 mL, 0.3 M) was added. The reaction solution was stirred at room temperature for 12 hours, extracted using a supersaturated aqueous sodium hydrogen carbonate solution and a mixed solution of dichloromethane:methanol = 4:1, and the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using dichloromethane/methanol = 0-10% solution. The resulting residue was crystallized with diethyl ether to give the title compound (19 mg, 39%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ δ 8.24 (t, 1H), 7.72-7.71 (t, 1H), 7.45 (br, 2H), 7.11-7.10 (t, 1H), 6.52 (s, 1H), 6.39 (s, 1H), 6.33 (m, 2H), 6.01-5.97 (t, 1H), 4.26-4.24 (m, 2H), 3.95 (m, 1H), 3.74 (s, 3H), 3.24 -3.02 (m, 2H), 1.25 (s, 3H), 1.01-0.99 (m, 2H), 0.66-0.64 (m, 2H).

MS (ESI ⁺ ): m/z 444 [M+H] ⁺ .

Examples 40-43

In the same manner as in Example 39, but various carboxylate derivatives in place of tert-butyl 3-aminoazetidine-1-carboxylate and 1-methylcyclopropane-1-carboxylate in (Step 1) of Example 39 Using, to obtain the compounds of Examples 40 to 43 shown in Table 3 below.

Example 44: Preparation of 6-amino-2,4-di(1H-pyrazol-1-yl)nicotinonitrile

<Reaction Scheme 8>

(Step 1) Preparation of tert-butyl (5-cyano-4,6-di(1H-pyrazol-1-yl)pyridin-2-yl) carbamate

<Reaction Scheme 8-1>

Sodium hydride (NaH, 100 mg, 2.48 mmol) was dissolved in acetonitrile (4 mL), and then pyrazole (128 mg, 1.88 mmol) was slowly added at 0°C. After stirring at 0°C for 30 minutes, tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl)carbamate (360 mg, 1.24 mmol) was slowly added. The reaction solution was stirred at 50° C. for 12 hours, the reaction solution was cooled to room temperature, ice water was added, and the obtained solid was filtered and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the title compound (80 mg, 18%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.89 (s, 2H), 7.51 (brs, 1H, NH), 6.60 ( s, 1H), 6.54 (s, 1H), 1.57 (s, 9H)

MS (ESI ⁺ ): m/z 352 [M+H] ⁺ .

(Step 2) Preparation of 6-amino-2,4-di(1H-pyrazol-1-yl)nicotinonitrile

<Reaction Scheme 8-2>

Tert-butyl (R)-(5-cyano-6-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypy) in (Step 4) of Example 1 Rolidin-1-yl)phenyl)pyridin-2-yl)carbamate instead of tert-butyl (5-cyano-4,6-di(1H-pyrazol-1-yl)pyridin-2-yl)car Using bamate, the title compound (26 mg, 74%) was obtained.

¹ H NMR (300 MHz, DMSO-d6) δ 8.40 (dd, 2H), 7.89 (s, 2H), 7.60 (brs, 2H, NH ₂ ), 6.72 (s, 1H), 6.63 (dd, 2H).

MS (ESI ⁺ ): m/z 252 [M+H] ⁺ .

Examples 45-47

Various amines were used instead of the imidazole of Preparation Example 2, and (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-) in (Step 3) of Example 1 Using various borate derivatives instead of tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine, as shown in Table 4 below in the same manner as (Step 3) and (Step 4). The compounds of Examples 45 to 47 were obtained.

Examples 48-62

Various amines were used instead of the imidazole of Preparation Example 2, and (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-) in (Step 3) of Example 1 Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine or 3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetra) Examples 48 to 62 shown in Table 5 below in the same manner as in (Step 3) and (Step 4) using methyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine To obtain a compound of

Example 63: (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2H-1,2,3-triazole Synthesis of -2-yl)nicotinonitrile

<Reaction Scheme 9>

(Step 1) Preparation of 6-amino-4-chloro-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile

<Reaction Scheme 9-1>

Sodium hydride (0.43 g, 10.64 mmol) was added to 20 ml of acetonitrile at 0 °C, and 1,2,3-triazole (0.46 ml, 7.98 mmol) was slowly added to the reaction solution, followed by stirring at room temperature for 10 minutes. . The compound (1.00 g, 5.32 mmol) prepared in step 2) was added to the reaction solution, followed by stirring at 90° C. for 4 hours. Upon completion of the reaction, after cooling to room temperature, ice water was slowly added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was washed with water and dichloromethane and filtered under reduced pressure to obtain 0.55 g (yield: 47%) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 6.61 (s, 1H)

MS (ESI ⁺ ): m/z 221 [M+H] ⁺ .

(Step 2) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2H-1,2,3-triazole Preparation of -2-yl)nicotinonitrile

<Reaction Scheme 9-2>

6-amino-4-chloro-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile (70 mg, 0.317 mmol, [Intermediate 1]), (R)-3-methoxy -1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (159 mg, 0.476 mmol, [Intermediate 1]), bis(triphenylphosphine)palladium(II) dichloride (33 mg, 0.048 mmol) and potassium carbonate (110 mg, 0.793 mmol) were added to 1.4 ml of acetonitrile: water = 3: 1 (volume ratio), and the mixture was refluxed at 100° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered through a pad of Celite. The filtrate was diluted with ethyl acetate and water, and the organic layer was extracted. The separated organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography, and then recrystallized with EtOH to give 20 mg (yield: 16%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 6.61 (s, 1H), 6.40-6.38 (m, 2H), 6.20-6.18 (m, 1H), 5.21 (brs, 2H), 4.11-4.10 (m, 1H), 3.84 (s, 3H), 3.53-3.39 (m, 4H), 3.37 (s, 3H), 2.17-2.10 (m, 2H).

MS (ESI ⁺ ): m/z 392 [M+H] ⁺ .

Examples 64 to 66

In (Step 2) of Example 63 (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro) Ran-2-yl)phenyl)pyrrolidine was used instead of various borate derivatives to obtain the compounds of Examples 63 to 65 shown in [Table 6] in the same manner as in Example 63.

Example 67: Preparation of 6-amino-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile

<Reaction Scheme 10>

(Step 1) Preparation of tert-butyl (4-chloro-5-cyano-6-(5-methylfuran-2-yl)pyridin-2-yl)carbamate

<Reaction Scheme 10-1>

Tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl) carbamate (3.0 g, 10.41 mmol) synthesized in Preparation Example 1 was added to ethylene glycol dimethyl ether/water = 3/2 (120 /80 mL) was dissolved in a mixed solution. 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (2.5 mL, 12.50 mmol) and cesium carbonate (Cs ₂ CO ₃ , 10.2 g, 31.23 mmol) was added to the reaction solution. The reaction solution was degassed, and Pd(dppf)Cl ₂ (380 mg, 0.52 mmol) was added, followed by stirring at 80° C. for 2 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified using a mixed solution of ethyl acetate/hexane = 0-5% to give the title compound (1.1 g, 32%).

^OneH NMR (300 MHz, CDCl₃)δ8.01 (s, 1H), 7.51 (br, 1H), 7.40-7.39 (d, 1H), 6.21-6.20 (m, 1H), 2.45 (s, 3H), 1.53 (s, 9H).

MS (ESI ⁺ ): m/z 334 [M+H] ⁺ .

(Step 2) Tert-butyl (5-cyano-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-6-(5-methylfuran-2-yl)pyridin-2 -I) Preparation of carbamate

<Reaction Scheme 10-2>

Tert-butyl (4-chloro-5-cyano-6-(5-methylfuran-2-yl) pyridin-2-yl) carbamate (100 mg, 0.30 mmol) synthesized in (Step 1) above It was dissolved in a mixed solution of acetonitrile/water = 3/1 (3/1 mL). 1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (110 mg, 0.36 mmol) Cesium perfluoride (CsF, 114 mg, 0.75 mmol) was added to the reaction solution. The reaction solution was degassed, and Pd(PPh ₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) was added, followed by stirring at 80° C. for 4 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified using a mixed solution of ethyl acetate/hexane = 0-10% to give the title compound (95 mg, 67%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.50 (br, 1H), 7.46-7.44 (d, 1H), 6.39-6.38 (d, 1H), 6.37-6.36 (d, 1H), 6.20-6.18 (t, 1H), 3.84 (s, 3H), 3.35-3.31 (m, 4H), 2.46 (s, 3H), 2.03-1.99 (m, 4H), 1.52 (s, 9H).

MS (ESI ⁺ ): m/z 475 [M+H] ⁺ .

(Step 3) Preparation of 6-amino-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile

<Reaction Scheme 10-3>

Tert-butyl (5-cyano-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-6-(5-methylfuran-2-yl) synthesized in (Step 2) above )Pyridin-2-yl)carbamate (95 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (TFA, 0.4 mL, 6.00 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, extracted using a supersaturated aqueous sodium hydrogen carbonate solution and a mixed solution of dichloromethane:methanol = 4:1, and the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using dichloromethane/methanol = 0-3% solution. The resulting residue was crystallized with diethyl ether to give the title compound (50 mg, 67%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.21-7.20 (d, 1H), 7.10 (brs, 2H), 6.40 (s, 1H), 6.33 (m, 1H), 6.31 (m, 1H), 6.30 (s, 1H), 6.15-6.14 (m, 1H), 3.77 (s, 3H), 3.31 (s, 3H), 3.28-3.24 (m, 4H), 2.37 (s, 3H), 1.99-1.94 ( m, 4H).

MS (ESI+): m/z 375 [M+H]+.

Examples 68-73

In (Step 2) of Example 67 (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro) Ran-2-yl)phenyl)pyrrolidine was used instead of various borate derivatives to obtain the compounds of Examples 68 to 73 shown in [Table 7] in the same manner as in Example 67.

Example 74: 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)nico Preparation of Tinonitrile

<Reaction Scheme 11>

(Step 1) Preparation of tert-butyl (4-chloro-5-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamate

<Reaction Scheme 11-1>

Tert-butyl (4,6-dichloro-5-cyanopyridin-2-yl) carbamate (288 mg, 1.00 mmol) synthesized in Preparation Example 1 was added to ethylene glycol dimethyl ether/water = 3/2 (20 /13 mL) was dissolved in a mixed solution. 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (263 mg, 1.20 mmol) and cesium carbonate ( Cs ₂ CO ₃ , 978 mg, 3.00 mmol) was added to the reaction solution. The reaction solution was degassed, and Pd(dppf)Cl ₂ (37 mg, 0.05 mmol) was added, followed by stirring at 80° C. for 12 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified using a mixed solution of hexane/ethyl acetate = 15-60% to give the title compound (133 mg, 40%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.42 (br, 1H), 3.99 (s, 3H), 1.55 (9H).

MS (ESI ⁺ ): m/z 334 [M+H] ⁺ .

(Step 2) Tert-butyl (5-cyano-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-6-(1-methyl-1H-pyrazole- Preparation of 4-yl)pyridin-2-yl)carbamate

<Reaction Scheme 11-2>

Tert-butyl (4-chloro-5-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamate synthesized in (Step 1) (130 mg, 0.39 mmol) was dissolved in a mixed solution of acetonitrile/water = 3/1 (6/2 mL). 3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (260 mg, 0.78 mmol) and cesium fluoride (CsF, 121 mg, 0.78 mmol) were added to the reaction solution. The reaction solution was degassed, and Pd(PPh ₃ ) ₂ Cl ₂ (28 mg, 0.04 mmol) was added, followed by stirring at 100° C. for 5 hours.

After cooling the reaction solution to room temperature, it was extracted several times with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was purified using a mixed solution of hexane/ethyl acetate = 15-60% to give the title compound (113 mg, 57%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 7.39 (br, 1H), 6.43-6.42 (t, 1H), 6.37 (t, 1H), 6.20-6.19 (t, 1H), 4.14-4.10 ( m, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 3.55-3.38 (m, 7H), 2.18-2.12 (m, 2H), 1.54 (9H).

MS (ESI ⁺ ): m/z 505 [M+H] ⁺ .

(Step 3) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)nico Preparation of Tinonitrile

<Reaction Scheme 11-3>

Tert-butyl (5-cyano-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-6-(1-methyl-1H) synthesized in (Step 2) above -Pyrazol-4-yl)pyridin-2-yl)carbamate (110 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (TFA, 0.7 mL, 0.3 M) was added. I did. The reaction solution was stirred at room temperature for 12 hours, extracted using a supersaturated aqueous sodium hydrogen carbonate solution and a mixed solution of dichloromethane:methanol = 4:1, and the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using dichloromethane/methanol = 0-5% solution. The resulting residue was crystallized with diethyl ether to give the title compound (64 mg, 73%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 8.06-8.05 (d, 1H), 6.97 (brs, 2H), 6.37 (s, 1H), 6.31 (m, 1H), 6.26 (m, 1H), 6.16 (m, 1H), 4.09-4.08 (m, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.47-3.35 (m, 4H), 3.27 (s, 3H), 2.07-2.04 (m, 2H).

MS (ESI+): m/z 405 [M+H]+.

Examples 75-81

In (Step 1) of Example 74, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Using boronic acid/borate derivatives, compounds of Examples 75 to 81 shown in the following [Table 8] were obtained in the same manner as in Example 73.

Example 82: (R)-6-amino-5-fluoro-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidine-1- 1) Preparation of phenyl) nicotinonitrile

<Reaction Scheme 12>

(Step 1) Preparation of 2,6-dichloro-5-fluoro-4-iodonicotinonitrile

<Reaction Scheme 12-1>

Diisopropyl amine (22 mL, 157 mmol) was added to 200 mL of tetrahydrofuran. After cooling to -78°C, n-butyllithium (2.5 M in Hex, 63 mL, 157 mmol) was added dropwise to the reaction solution while maintaining the temperature. The mixture was stirred at -30°C for 30 minutes.

2,6-dichloro-5-fluoronicotinonitrile (10 g, 52.4 mmol) was dissolved in 200 mL of tetrahydrofuran, and then iodine (I ₂ , 26.5 g, 104.7 mmol) was added. After cooling the reaction solution to -78 °C, the prepared LDA solution was slowly added dropwise while maintaining the temperature. The reaction solution was stirred at room temperature for 12 hours. Extracted with 400 mL of ethyl acetate and washed twice with 500 mL of saturated aqueous sodium thiosulfate solution. After drying over anhydrous magnesium sulfate and distilling under reduced pressure, a crude compound (18 g, 100%) was obtained.

MS (ESI ⁺ ): m/z 315.8 [M+H] ⁺ .

(Step 2) Preparation of 6-(benzylhydrylamino)-2-chloro-5-fluoro-4-iodonicotinonitrile

<Reaction Scheme 12-2>

2,6-dichloro-5-fluoro-4-iodonicotinonitrile (18 g, 56.8 mmol) synthesized in (Step 1) was dissolved in 180 mL of acetonitrile, and then aminodiphenylmethane (19.5 mL, 113.6). mmol) was added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was extracted with 400 mL of ethyl acetate and washed twice with 200 mL of distilled water. The organic layer was concentrated under reduced pressure and purified with a column ethyl acetate:hexane = 1:15 mixed solution to obtain the target compound (7.8 g, 30%).

¹ H NMR (300 MHz, DMSO) δ 9.08 (Br, 1H), 7.36-7.26 (m, 10H), 6.43 (Br, 1H)

(Step 3) (R)-6-(benzylhydrylamino)-2-chloro-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl) Preparation of Nicotinonitrile

<Reaction Scheme 12-3>

6-(Benzylhydrylamino)-2-chloro-5-fluoro-4-iodonicotinonitrile (250 mg, 0.54 mmol) synthesized in (Step 2) was added to 5 mL of 80% aq.dioxane. Added. (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pi Rollidine (270 mg, 0.81 mmol), 1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (44 mg, 0.05 mmol), potassium triphosphate (343 mg, 1.61 mmol) was added and then nitrogen It was degassed for 10 minutes using. After heating the reaction solution to reflux for 4 hours, the reaction solution was purified by preparative thin film chromatography under the condition of ethyl acetate:hexane = 1:3 to obtain the target compound (130 mg, 44%).

¹ H NMR (300 MHz, DMSO) δ 9.00-8.98 (d, 1H), 7.42-7.27 (m, 10H), 6.53-6.51 (d, 1H), 6.32 (s, 1H), 6.18 (s, 1H) , 6.17 (s, 1H), 4.09-4.07 (m, 1H), 3.76 (s, 3H), 3.46-3.24 (m, 7H), 2.07-2.04 (m, 2H)

MS (ESI+): m/z data [M+H]+.

(Step 4) (R)-6-(Benzylhydrylamino)-5-fluoro-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypy) Preparation of rolidin-1-yl)phenyl)nicotinonitrile

<Reaction Scheme 12-4>

(R)-6-(benzylhydrylamino)-2-chloro-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidine-1-) synthesized in (Step 3) above Il)phenyl)nicotinonitrile (130 mg, 0.24 mmol) was dissolved in 2.6 mL of dimethylformamide. Potassium carbonate (66 mg, 0.48 mmol) and imidazole (24 mg, 0.36 mmol) were added to the reaction solution, followed by stirring at 90°C for 12 hours. The reaction solution was purified by preparative thin-layer chromatography under the condition of ethyl acetate:hexane 1:1 to obtain the target compound (60 mg, 43%).

¹ H NMR (300 MHz, DMSO) δ 8.99-8.96 (d, 1H), 8.20 (s, 1H), 7.69 (s, 1H), 7.45-7.26 (m, 10H), 7.11 (s, 1H), 6.58 (d, 1H), 6.38 (s, 1H), 6.31 (s, 1H), 6.20 (s, 1H), 4.10-4.09 (m, 1H), 3.77 (s, 3H), 3.48-3.18 (m, 7H) ), 2.08-2.05 (m, 2H)

(Step 5) (R)-6-amino-5-fluoro-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidine-1- 1) Preparation of phenyl) nicotinonitrile

<Reaction Scheme 12-5>

(R)-6-(benzylhydrylamino)-5-fluoro-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(synthesized in (Step 4) above) After dissolving 60 mg of 3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile in 0.54 ml of trifluoroacetic acid (9v/w), 60 μL of trifluoromethanesulfonic acid was added. The reaction solution was stirred at 25° C. for 1 hour and then neutralized with a sodium bicarbonate. 5.3 mg of the target compound was obtained under purification in ethyl acetate solvent by preparative thin layer chromatography.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.39 (s, 1H), 7.19 (s,1H), 6.51 (s, 1H), 6.26 (m, 1H), 6.17 (m, 2H) 5.00 (brs, 2H), 4.16-4.11 (m, 1H), 3.84 (s, 3H), 3.54-3.36 (m, 7H), 2.19-2.14 (m, 2H).

MS (ESI+): m/z 409 [M+H]+.

Examples 83-87

In (Step 3) of Example 82 (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro) In the same manner as in Example 82, various borate derivatives were used instead of lan-2-yl)phenyl)pyrrolidine, and various amine/borate derivatives were used instead of imidazole in (Step 4), as shown in Table 9 below. The compounds of Examples 83 to 87 were obtained.

Experimental Example 1: In vitro cAMP measurement test

In each of the compounds prepared in Examples 1 to 87, inhibitory activity against cAMP production in HEK293-A2AR cells was measured. The activity was measured using the LACNE ^TM cAMP 384 Kit developed by PerkinElmer. This evaluation method was performed by using the Alexa Fluor 647-labeled cAMP antibody (Alexa Fluor 647-anti cAMP) and the Europium-conjugated streptavidin antibody (Eu-W8044 labeled streptavidin) to produce biotin-labeled cAMP and HEK293-A2AR cells. This is a method of measuring the activity of cells for cAMP production by measuring the competitive binding of cAMP with a fluorescence resonance energy transfer (FRET) signal. The cultured cell lines were prepared in 2.5×10 ³ cells/20 μl, placed in a 384 well plate, and cultured in EMEM containing 10% FBS for 24 hours. After removing the culture medium, HBSS was carried out in a solution of pH 7.4 containing 5 mM HEPES, 0.1% BSA, and 30 μM Rolipram. In the state that cAMP production was increased by 1 nM of Adenosine, the compound to be evaluated was subjected to stepwise dilution at a set concentration (eg, 5,000 to 0.32 nM, 1/5 dilution). As a control without a compound, only a solvent (1% DMSO) was added to measure cAMP production inhibitory activity. The 50% activity inhibition value (IC ₅₀ ) for cAMP production of the compound was calculated using GraphPad Prism software. The results are shown in Table 10 below.

Claims (11)

Compounds of the following formula 1, optical isomers, solvates, or pharmaceutically acceptable salts thereof: <Formula 1>

In Formula 1, X is H or halogen; A and B are each independently C _6-12 aryl or C _2-14 heteroaryl, wherein aryl and heteroaryl are each independently halogen, -R ¹ , -CHR ¹ R ² , -CN, -OR ¹ ,- SR ¹ , -S(=O) _m R ¹ , C _1-6 alkylsulfonylamino, -C(=O)NR ¹ R ² , -R ¹ OR ² , -R ¹ OCR ² , -NR ¹ R ² , -NR ¹ C(=O)R ² , -NR ¹ S(=O) _m R ² , -N(R ¹ ) _m OR ² , C _3-20 cycloalkyl, and C _2-20 heterocycloalkyl. May be substituted with one or more substituents selected from the group consisting of, wherein m is an integer from 0 to 3, and R ¹ and R ² are each independently H, halogen, CH ₂ F, CF ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl; When the above substituents are more than one, they are the same or different from each other, and two adjacent substituents may be optionally bonded to form a fused ring; Among the substituents of A and B, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl and C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl and C among R ¹ and R ² Each _2-14 heteroaryl is independently halogen, -CN, -OH, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkylsulfonylamino, NQ ¹ C( =O)Q ² (wherein Q ¹ and Q ² are each independently H, halogen, -CF ₃ , C _1-6 alkyl, C _2-6 alkenyl, or C _3-20 cycloalkyl, C _2-20 Heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl), -CH ₂ F, -CF ₃ , C _2-20 may be substituted with one or more substituents selected from the group consisting of heterocycloalkyl; If the each independently a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl optionally substituted by the substituents, may form a fused or spiro derivatives each other ; The C _2-14 heteroaryl or C _2-20 heterocycloalkyl each independently includes 1 to 3 heteroatoms selected from the group consisting of N, O and S. The compound of claim 1, wherein the C _2-20 heterocycloalkyl comprises 1 to 3 heteroatoms selected from N, O and S. The compound of claim 2, wherein the C _2-20 heterocycloalkyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. The method of claim 1, wherein B is C _6-12 aryl or C _2-14 hetero substituted with at least one substituent selected from the group consisting of halogen, -CN, C _1-6 alkyl, and C _1-6 alkoxy. The compound that is aryl. The compound of claim 1, wherein B is selected from the group consisting of substituted or unsubstituted pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, and phenyl. The method of claim 1, wherein B is C _6-12 substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, -CF ₃ , C _1-6 alkyl, and C _1-6 alkoxy. The compound that is aryl. The method of claim 1, Wherein A is C _6-12 aryl or C _2-14 heteroaryl, wherein C _6-12 aryl or C _2-14 heteroaryl are each independently C _3-20 cycloalkyl, C _2-20 heterocycloalkyl,- OR ¹ , and -SR ¹ , wherein R ¹ is C _3-20 cycloalkyl or C _2-20 heterocycloalkyl; Additionally, -OCF ₃ , -R ¹ , -OR ¹ , -SR ¹ (where R ¹ is C _1-6 alkyl or C _2-6 alkenyl) may be substituted with one substituent selected from the group consisting of There is; Here, C _3-20 cycloalkyl and C _2-20 heterocycloalkyl are each independently halogen, -CN, -OH, C _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkylsulfonylamino, NQ ¹ C(=O)Q ² (wherein Q ¹ and Q ² are each independently H, halogen, -CF ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _3-20 cycloalkyl, C _2-20 heterocycloalkyl, C _6-12 aryl or C _2-14 heteroaryl), -CH ₂ F, -CF ₃ , C _3-20 cycloalkyl, C _2-20 It can be optionally substituted with one or more substituents selected from the group consisting of heterocycloalkyl, in the substituents each independently represent a C _3-20 cycloalkyl or C _2-20 heterocycloalkyl C _3-20 cycloalkyl or C _2-20 When heterocycloalkyl is substituted, it may be fused with each other or form a spiro derivative; Wherein B is C _6-12 aryl or C _2-14 heteroaryl, wherein C _6-12 aryl or C _2-14 heteroaryl are each independently H, halogen, -R ¹ , -CHR ¹ R ² , -CN , -OH, -OCF ₃ , C _1-6 alkyl, C _1-6 alkoxy, and -SR ¹ may be substituted with one or more substituents selected from the group consisting of, where m is an integer from 0 to 3, and R ¹ and R ² are each independently H, halogen, -CF ₃ , C _1-6 alkyl, or C _2-6 alkenyl. The method of claim 1, The compound represented by Formula 1 is a compound selected from the group consisting of compounds of the following 1) to 62): 1) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile ; 2) (S)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile ; 3) (R)-6-amino-4-(3-(3-ethoxypyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ; 4) (S)-6-amino-4-(3-(3-ethoxypyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ; 5) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-isopropoxypyrrolidin-1-yl)-5-methoxyphenyl)nico Tinonitrile; 6) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)nicotinonitrile; 7) 6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 8) 6-amino-4-(3-(3,3-difluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ; 9) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile; 10) 6-amino-4-(3-(3,3-dimethylpyrrolidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 11) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(5-azaspiro[2.4]heptan-5-yl)phenyl)nicotinonitrile; 12) 6-Amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- Day) phenyl) nicotinonitrile; 13) 6-amino-4-(3-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-5-methoxyphenyl)-2-(1H-imidazole-1- I) nicotinonitrile; 14) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)phenyl)nico Tinonitrile; 15) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(2-oxa-7-azaspiro[4.4]nonan-7-yl)phenyl)nico Tinonitrile; 16) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(piperidin-1-yl)phenyl)nicotinonitrile; 17) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methylpiperidin-1-yl)phenyl)nicotinonitrile; 18) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(4-methylpiperidin-1-yl)phenyl)nicotinonitrile; 19) 6-amino-4-(3-(3-fluoropepyridin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 20) 6-amino-4-(3-(3,3-difluoropiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile ; 21) 6-amino-4-(3-(4-fluoropiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 22) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypiperidin-1-yl)phenyl)nicotinonitrile; 23) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(4-methoxypiperidin-1-yl)phenyl)nicotinonitrile; 24) 6-amino-4-(3-(3,5-dimethylpiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 25) 6-amino-4-(3-((3R,5S)-3,5-dimethylpiperidin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl ) Nicotinonitrile; 26) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)nico Tinonitrile; 27) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(4-methylpiperazin-1-yl)phenyl)nicotinonitrile; 28) 6-amino-4-(3-(4-(2-hydroxyethyl)piperazin-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotino Nitrile; 29) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-morpholinophenyl)nicotinonitrile; 30) 6-amino-4-(3-(azepan-1-yl)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 31) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-methoxypyrrolidin-1-yl)-5-methylphenyl)nicotinonitrile; 32) 6-amino-4-(3-ethyl-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 33) 6-amino-2-(1H-imidazol-1-yl)-4-(3-isopropyl-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile; 34) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-methoxypyrrolidin-1-yl)-5-(trifluoromethoxy)phenyl)nicotinonitrile ; 35) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(3-methoxypiperidin-1-yl)-5-(trifluoromethoxy)phenyl)nicotinonitrile ; 36) 6-amino-2-(1H-imidazol-1-yl)-4-(3-(4-methoxypiperidin-1-yl)-5-(trifluoromethoxy)phenyl)nicotinonitrile ; 37) 6-amino-4-(3-(cyclopentyloxy)-5-methoxyphenyl)-2-(1H-imidazol-1-yl)nicotinonitrile; 38) (R)-6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-((tetrahydrofuran-3-yl)oxy)phenyl)nicotinonitrile ; 39) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)azetidine-3- Yl)-1-methylcyclopropane-1-carboxamide; 40) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)azetidine-3- One) cyclopentanecarboxamide; 41) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)-1-methylcyclopropane-1-carboxamide; 42) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)cyclopentanecarboxamide; 43) N-(1-(3-(6-amino-3-cyano-2-(1H-imidazol-1-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)cyclohexanecarboxamide; 44) 6-amino-2,4-di(1H-pyrazol-1-yl)nicotinonitrile; 45) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(4-methyl-1H -Pyrazol-1-yl)nicotinonitrile; 46) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(4-methyl-1H -Imidazol-1-yl)nicotinonitrile; 47) 6-amino-4-(3-methoxy-5-morpholinophenyl)-2-(4-methyl-1H-pyrazol-1-yl)nicotinonitrile; 48) 6-amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Tinonitrile; 49) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-pyrazol-1-yl)nicotinonitrile; 50) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(3-methyl-1H-pyrazol-1-yl)nicotinonitrile ; 51) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(4-methyl-1H-pyrazol-1-yl)nicotinonitrile ; 52) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(3-(trifluoromethyl)-1H-pyrazole-1- I) nicotinonitrile; 53) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-1,2,3-triazol-1-yl)nico Tinonitrile; 54) 6-amino-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile; 55) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(4-methyl-1H-imidazol-1-yl)nicotinonitrile ; 56) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2-methyl-1H-imidazol-1-yl)nicotinonitrile ; 57) 6-amino-2-(2,4-dimethyl-1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nico Tinonitrile; 58) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-1,2,4-triazole-1 -Yl)nicotinonitrile; 59) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methyl-1H-1,2,4- Triazol-1-yl)nicotinonitrile; 60) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(3-methyl-1H-1,2,4- Triazol-1-yl)nicotinonitrile; 61) (R)-6-amino-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-(3-methoxy-5-(3-methoxypy) Rolidin-1-yl)phenyl)nicotinonitrile; 62) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(4-methyl-2H-1,2,3- Triazol-2-yl)nicotinonitrile; 63) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2H-1,2,3-triazole-2 -Yl)nicotinonitrile; 64) 6-amino-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile; 65) (R)-6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(2H-1,2,3-triazole- 2-yl)nicotinonitrile; 66) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(2H-1,2 ,3-triazol-2-yl)nicotinonitrile; 67) 6-amino-4-(3-methoxy-5-(pyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile; 68) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile ; 69) (S)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile ; 70) (R)-6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(5-methylfuran-2-yl)nicotino Nitrile; 71) (S)-6-amino-4-(3-(3-fluoropyrrolidin-1-yl)-5-methoxyphenyl)-2-(5-methylfuran-2-yl)nicotino Nitrile; 72) 6-amino-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-(5-methylfuran- 2-yl)nicotinonitrile; 73) N-(1-(3-(6-amino-3-cyano-2-(5-methylfuran-2-yl)pyridin-4-yl)-5-methoxyphenyl)pyrrolidine-3 -Yl)-1-methylcyclopropane-1-carboxamide; 74) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinonitrile ; 75) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2-yl)nicotinonitrile; 76) 6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylthiophen-2-yl)nicotinonitrile; 77) 6-amino-2-(3-cyanophenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile; 78) 6-amino-2-(3-fluorophenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile; 79) 6-amino-2-(4-fluorophenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile; 80) (R)-6-amino-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(oxazol-2-yl)nicotinonitrile; 81) (R)-6-amino-2-(3-cyano-2-methylphenyl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)nicotinonitrile ; 82) (R)-6-amino-5-fluoro-2-(1H-imidazol-1-yl)-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl) Phenyl)nicotinonitrile; 83) (R)-6-amino-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(1H-1,2,3 -Triazol-1-yl)nicotinonitrile; 84) (R)-6-amino-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(2H-1,2,3 -Triazol-2-yl)nicotinonitrile; 85) (R)-6-amino-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-2-(5-methylfuran-2- I) nicotinonitrile; 86) (R)-6-amino-2-(3-cyano-2-methylphenyl)-5-fluoro-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl) Phenyl)nicotinonitrile; 87) 6-amino-5-fluoro-4-(3-methoxy-5-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)phenyl)-2-( 5-methylfuran-2-yl)nicotinonitrile. A pharmaceutical composition for preventing or treating cancer or inflammatory disease, comprising the compound according to any one of claims 1 to 8 as an active ingredient. The method of claim 9, The cancer is lung cancer, stomach cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, germ cell cancer, bone cancer, liver cancer, Thyroid cancer, skin cancer, neoplasms of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and a pharmaceutical composition that is one or more selected from the group consisting of virus-related cancer. The method of claim 9, The inflammatory disease is at least one selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, transplant versus host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin-dependent diabetes.