KR20220162116A - Novel compounds inhibiting the binding between AIMP2-DX2 and KRAS and their uses - Google Patents

Abstract

The present invention relates to a novel compound having an activity of inhibiting the binding between AIMP2-DX2 and KRAS and uses thereof. The compounds according to the present invention are useful for preventing or treating diseases caused by KRAS mutation or overexpression, such as cancer.

Description

Novel compounds inhibiting the binding between AIMP2-DX2 and KRAS and their uses

The present invention relates to a novel compound having an activity of inhibiting the binding between AIMP2-DX2 and KRAS, and its use for preventing or treating diseases caused by KRAS mutation or overexpression, such as cancer.

AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is one of the proteins involved in the formation of an aminoacyl-tRNA synthetase (ARS) complex (Multi-tRNA synthetase complex: MSC). In addition to its function for MSC formation, AIMP2 functions as a powerful tumor suppressor through various mechanisms.

In Korean Patent Publication No. 2006-0058014 (published on May 29, 2006), AIMP2-DX2 (ARS-interacting multifunctional protein 2-Exon 2 deleted), a variant in which AIMP2 is deficient in exon 2, is used in lung cancer, liver cancer, and breast cancer. , It is specifically expressed in cancer tissues such as skin cancer, renal cancer, and osteosarcoma, and AIMP2-DX2 competitively binds to the target protein of AIMP2 to prevent AIMP2 from exerting a cancer suppression effect, causing cancer, Therefore, it has been reported that suppressing the production of AIMP2-DX2 can prevent or treat cancer.

KRAS is well known as the most frequently altered oncogene in cancer cells. In addition, it affects the decrease in the survival rate of cancer patients and is a factor that makes it difficult to prescribe through early diagnosis. Although KRAS is an important target for cancer treatment, studies on the regulation of intracellular levels of KRAS protein in cancer cells are not well understood.

When mutations occur in proto-oncogenes such as KRAS, normal cells may progress to malignancy. In particular, KRAS mutations can be found at a high level in patients with pancreatic cancer, colon cancer, lung cancer, and the like. According to a previous study, AIMP2-DX2, an oncogenic variant of AIMP2, binds to mutated KRAS and stabilizes KRAS, thus promoting the differentiation and growth of tumor cells due to mutated KRAS (Korean Patent Publication No. 2018-0015847 ( Publication date: 2018.02.14)). Therefore, inhibition of the interaction between AIMP2-DX2 and KRAS could be an important strategy for cancer treatment.

One object of the present invention is to provide a novel compound useful as a binding inhibitor between AIMP2-DX2 and KRAS, an isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a novel compound useful as a combination inhibitor of AIMP2-DX2 and KRAS, pharmaceuticals for preventing or treating diseases caused by KRAS mutation or overexpression, such as cancer, including isomers thereof or pharmaceutically acceptable salts thereof. to provide a composition.

In order to achieve the above object, the present invention provides a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

X and Y are each independently C or N;

R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO _2- NH ₂ , -OC _1-6 alkyl -OC _1-6 alkyl, -O-CO-5-6 membered heteroaryl, -O-SO _2- C _6-10 aryl, or -O-CH ₂ -C _6-10 aryl, wherein the C _{1- 6} alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, and 0-CH ₂ -C _6-10 aryl are each independently unsubstituted or may be substituted with 1 to 3 halogens or C _1-6 alkyl;

R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;

or R ₁ and R ₂ together with the benzene ring to which they are attached may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;

R ₃ is C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5 -6-membered heteroaryl, 5-6-membered heterocyclyl or -C _1-6 alkyl-5-6-membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 Alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and -C _1-6 alkyl- 5-6 membered heterocyclyls are each independently unsubstituted or 1 to 4 halogen, CN, -COOH, C _1-6 alkyl, -CO-C _1-6 alkyl or -COO-C _1-6 alkyl may be substituted with;

R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or - 5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5- 10-membered heteroaryl, 5-10-membered heterocyclyl, and -5-6-membered heteroaryl-5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, or -NH-CO-C _1-6 alkyl;

The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. .

In addition, the present invention provides a pharmaceutical product for preventing or treating a disease caused by KRAS mutation or overexpression, such as cancer, including the compound of Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. composition is provided.

Since the compound of Formula 1, its isomer or its pharmaceutically acceptable salt of the present invention inhibits the binding between AIMP2-DX2 and KRAS and has the effect of reducing the intracellular level of KRAS, mutation or overexpression of KRAS is the cause It can be usefully used for the prevention or treatment of diseases such as cancer.

1 is a graph showing the results of evaluation of the inhibitory effect of AIMP2-DX2 and KRAS binding by (a) Compound 44 and (b) Compound 48 according to the present invention by measuring luciferase activity.

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

In the present invention, the term "halogen" means F, Cl, Br or I unless otherwise specified.

The term “C _1-6 alkyl” refers to a linear or branched, saturated hydrocarbon residue having 1 to 6 carbon atoms. Specifically, C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1- methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. In one embodiment, an alkyl group may be substituted with one or more substituents, such as 1 to 3 halogen or C _1-6 alkyl.

The term “C _1-6 alkoxy” means an alkyl of the formula —OC _1-6 alkyl, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , n-pentoxy, isopentoxy, tert-pentoxy, sec-pentoxy, neopentoxy, hexyloxy, and the like. In one embodiment, an alkoxy group may be substituted with one or more substituents, such as 1 to 3 halogen or C _1-6 alkyl.

The term "cycloalkyl" refers to a hydrocarbon 3 to 8 membered monocyclic or 7 to 14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring is to some extent may have unsaturation. A cycloalkyl group may be optionally substituted with one or more substituents. In one embodiment of the present invention, C _3-8 cycloalkyl refers to a monocyclic ring having 3 to 8 carbon atoms. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctyl, and the like. Not limited.

The term "aryl" refers to a hydrocarbon monocyclic or bicyclic aromatic ring. That is, aryl in this specification may include phenyl, naphthyl, etc., and biaryl unless otherwise defined. In one embodiment of the present invention, C _6-10 aryl refers to an aromatic ring having 6 to 10 carbon atoms. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of the aryl group may be substituted with a substituent.

The term “heteroaryl” refers to an aromatic 5- to 10-membered monocyclic or bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. That is, heteroaryl is a 5-membered or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, or a bicyclic ring in which the heteroaryl ring is fused to a benzene ring or another heteroaryl ring. refers to the ring. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted with a substituent. Examples of monocyclic heteroaryls include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl , oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and similar groups, but are not limited thereto. Examples of bicyclic heteroaryls include indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzooxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztria zolyl, quinolinyl, isoquinolinyl, quinoxalinyl, purinyl, furopyridinyl, and similar groups, but are not limited thereto.

The term "heterocyclyl" denotes a saturated or partially unsaturated carbocyclic ring of 5 to 10 ring atoms containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from N, O and S. In one embodiment, the heterocyclyl may be a 5- or 6-membered aliphatic heterocycle, or a bicyclic ring in which the heterocyclyl ring is fused to a benzene ring or another heterocyclyl ring. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocyclyl group may be substituted with a substituent. For example, heterocyclyl is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, dioxane Solyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranil, piperazinil, morpholinil, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanil, diazepa Nil, homopiperazinyl, oxazepanil, indolyl, isoindolyl, dihydroindolyl, dioxoisoindolinyl, dihydrofuryl, dihydroimidazolinyl, dihydrooxazolyl, dihydrobenzodioxy yl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolyl, or benzodioxanil.

The term "substitution" refers to the replacement of a hydrogen atom in a molecular structure with a substituent such that the valence on the designated atom is not exceeded and the compound chemically stable from such substitution. For example, "group A is substituted with substituent B" means that a hydrogen atom bonded to an atom such as carbon constituting the backbone of group A is replaced with substituent B, so that group A and substituent B form a covalent bond. can do.

The present invention provides a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

X and Y are each independently C or N;

R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , -OC _1-6 alkyl -OC _1-6 alkyl, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, or -O-CH ₂ -C _6-10 aryl, wherein the C _{1- 6} alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, and 0-CH ₂ -C _6-10 aryl are each independently unsubstituted or may be substituted with 1 to 3 halogens or C _1-6 alkyl;

R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;

or R ₁ and R ₂ together with the benzene ring to which they are attached may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;

R ₃ is C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5 -6-membered heteroaryl, 5-6-membered heterocyclyl or -C _1-6 alkyl-5-6-membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 Alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and -C _1-6 alkyl- 5-6 membered heterocyclyls are each independently unsubstituted or 1 to 4 halogen, CN, -COOH, C _1-6 alkyl, -CO-C _1-6 alkyl or -COO-C _1-6 alkyl may be substituted with;

R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or - 5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5- 10-membered heteroaryl, 5-10-membered heterocyclyl, and -5-6-membered heteroaryl-5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, or -NH-CO-C _1-6 alkyl;

The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. .

또는

일 수 있다.In one embodiment, in the compound of Formula 1, R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , -O-CH ₂ -O-CH ₃ , -O-CO-furanyl, -O-SO ₂ -phenyl, or -O-CH ₂ -phenyl, wherein said C _1-6 alkyl; C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , -O-CH ₂ -O-CH ₃ , -O-CO-furanyl, -O- SO ₂ -phenyl and -O-CH ₂ -phenyl may each independently be unsubstituted or substituted with 1 to 3 halogens or C _1-6 alkyl. For example, methoxyoxy (-OCH ₃ ) may be substituted with 1 to 3 halogens to form -OCF ₃ or -OCF ₂ H; The -O-CO-furanyl, -O-SO ₂ -phenyl and -O-CH ₂ -phenyl are

or

can be

In one embodiment, R ₂ in the compound of Formula 1 may be hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens. Specifically, R ₂ may be H, -CH ₃ , -C ₂ H ₅ , or -CF ₃ , but is not limited thereto.

또는

형태의 고리를 형성할 수 있다.In addition, as an embodiment, in the compound of Formula 1, R ₁ and R ₂ together with the benzene ring to which they are attached, benzodioxole, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring can form For example, in the compound of Formula 2, R ₁ and R ₂ together with the benzene ring to which they are attached,

or

A ring can be formed.

사이클로프로필,

또는

일 수 있고, 이에 한정되는 것은 아니다. 예컨대,

및

에서 N은 HCl과 염을 형성할 수 있다.In one embodiment, in the compound of Formula 1, R ₃ is C _1-6 alkyl, C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, pyra zolyl, tetrahydropyranyl, piperidinyl or morpholinoethyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, phenyl, benzyl. Pyridinyl, pyrimidinyl, pyrazolyl, tetrahydropyranyl, piperidinyl and morpholinoethyl are each independently selected from 1 to 4 halogen, CN, -COOH, C _1-6 alkyl, - CO-C _1-6 alkyl or -COO-C _1-6 alkyl. Specifically, R ₃ is, for example, ethyl;

cyclopropyl,

or

It may be, but is not limited thereto. for example,

and

N can form a salt with HCl.

또는

이고, 이때 상기 C_1-6 알킬, -CO-C_1-6 알킬, 페닐, 나프틸, -CO-페닐, 퓨라닐, 옥사졸릴, 티아졸릴, 피리디닐, 피라지닐, 벤조퓨라닐, 퀴녹살리닐 및 디하이드로벤조디옥시닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, -NH₂, -NO₂, -COOH, C_1-6 알킬 또는 C_1-6 알콕시로 치환될 수 있다. 구체적으로, 상기 R₄는 예컨대

또는

일 수 있고, 이에 한정되는 것은 아니다.As an embodiment, in the compound of Formula 1, R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, phenyl, naphthyl, -CO-phenyl, furanyl, oxazolyl, isoxazolyl, thia zolyl, pyridinyl, pyrazinyl, benzofuranil, quinoxalinyl, dihydrobenzodioxinyl,

or

Wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, phenyl, naphthyl, -CO-phenyl, furanyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, benzofuranyl, quinoxali Nyl and dihydrobenzodioxinyl may each independently be unsubstituted or substituted with 1 to 4 halogens, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl or C _1-6 alkoxy . Specifically, the R ₄ is, for example

or

It may be, but is not limited thereto.

In another embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 2 below:

[Formula 2]

In the above formula,

R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, or -O- CH ₂ -C _6-10 aryl, wherein the C _1-6 alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, and O -CH ₂ -C _6-10 aryl may each independently be unsubstituted or substituted with 1 to 3 halogens or C _1-6 alkyl;

R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;

or R ₁ and R ₂ together with the benzene ring to which they are attached may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;

R ₃ is C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5-6 membered heteroaryl; Or a 5-6 membered heterocyclyl, wherein the C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 6 membered heterocyclyl. may be substituted with 4 halogens, C _1-6 alkyl, or -COO-C _1-6 alkyl; R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or - 5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5- 10-membered heteroaryl, 5-10-membered heterocyclyl, and -5-6-membered heteroaryl-5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, or -NH-CO-C _1-6 alkyl;

The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. .

또는

일 수 있다.In one embodiment, in the compound of Formula 2, R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -O-CO-furanyl, -O-SO ₂ -phenyl, or -O-CH ₂ -phenyl, wherein the C _1-6 alkyl, C _1-6 alkoxy, -O-CO-furanyl, -O-SO ₂ -phenyl and -O-CH ₂ -phenyl are each independently may be unsubstituted or substituted with 1 to 3 halogens or C _1-6 alkyl. For example, methoxyoxy (-OCH ₃ ) may be substituted with 1 to 3 halogens to form -OCF ₃ or -OCF ₂ H; The -O-CO-furanyl, -O-SO ₂ -phenyl and -O-CH ₂ -phenyl are

or

can be

In one embodiment, R ₂ in the compound of Formula 2 may be hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens. Specifically, R ₂ may be H, -CH ₃ , -C ₂ H ₅ , or -CF ₃ , but is not limited thereto.

또는

형태의 고리를 형성할 수 있다.In addition, as an embodiment, in the compound of Formula 2, R ₁ and R ₂ together with the benzene ring to which they are attached, benzodioxole, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring can form For example, in the compound of Formula 2, R ₁ and R ₂ together with the benzene ring to which they are attached,

or

A ring can be formed.

또는

일 수 있고, 이에 한정되는 것은 아니다.In one embodiment, in the compound of Formula 2, R ₃ is C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrazolyl, tetrahydropyranyl or piperidinyl. , wherein the above C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, phenyl, benzyl. Pyridinyl, pyrazolyl, tetrahydropyranyl and piperidinyl may each independently be unsubstituted or substituted with 1 to 4 halogen, C _1-6 alkyl, or -COO-C _1-6 alkyl. Specifically, the R ₃ is

or

It may be, but is not limited thereto.

또는

이고, 이때 상기 C_1-6 알킬, -CO-C_1-6 알킬, 페닐, 나프틸, -CO-페닐, 퓨라닐, 옥사졸릴, 티아졸릴, 피라지닐, 벤조퓨라닐, 퀴녹살리닐, 디하이드로벤조디옥시닐,

및

은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, -NH₂, -NO₂, -COOH, C_1-6 알킬 또는 C_1-6 알콕시로 치환될 수 있다. 구체적으로, 상기 R₄는 예컨대

또는

일 수 있고, 이에 한정되는 것은 아니다.In one embodiment, in the compound of Formula 2, R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, phenyl, naphthyl, -CO-phenyl, furanyl, oxazolyl, isoxazolyl, thia zolyl, pyrazinyl, benzofuranil, quinoxalinyl, dihydrobenzodioxinyl,

or

, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, phenyl, naphthyl, -CO-phenyl, furanyl, oxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxalinyl, di hydrobenzodioxinyl,

and

may each independently be unsubstituted or substituted with 1 to 4 halogens, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl or C _1-6 alkoxy. Specifically, the R ₄ is, for example

or

It may be, but is not limited thereto.

Specific examples of the compound of Formula 2 according to the present invention are as follows, but are not limited thereto:

(1) N- (2-fluorophenyl) -N -((5-phenylthiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(2) N- (2-fluorophenyl) -N -((5-phenylthiophen-2-yl)methyl)furan-2-carboxamide:

(3) N- (2-fluorophenyl) -N -((5-(m-tolyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(4) N- (2-fluorophenyl) -N -((5-(m-tolyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(5) N- cyclopentyl- N- ((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(6) N- cyclohexyl- N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(7) N- ((5-(4-fluorophenyl)thiophen-2-yl)methyl) -N- phenylfuran-2-carboxamide;

(8) N- (2-fluorophenyl) -N- ((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(9) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)oxazole-4-carboxamide;

(10) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-4-carboxamide;

(11) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-2-carboxamide;

(12) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

(13) N- ((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(14) N -((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;

(15) N- benzyl- N- ((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(16) N- ((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)furan-2-carboxamide;

(17) N- ((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)furan-2-carboxamide;

(18) N- ((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(19) N- ((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(20) N- ((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;

(21) N -((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;

(22) N- (3-fluorophenyl) -N -((5-(4-methyl-3-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;

(23) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(24) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(25) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(26) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(27) N- (3-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;

(28) N -benzyl- N- ((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(29) N- (2-fluorophenyl) -N -((5-(4-hydroxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(30) N- (2-fluorophenyl) -N -((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(31) N -((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(32) N- (3-fluorophenyl) -N -((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(33) N -((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;

(34) N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl) -N -phenylfuran-2-carboxamide;

(35) N- (2-fluorophenyl) -N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(36) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(37) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;

(38) 4-amino- N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;

(39) 4-((3-fluorophenyl)((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)carbamoyl)benzoic acid;

(40) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

(41) N- (2-fluorophenyl)-5-methoxy- N- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide ;

(42) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-2-naphthamide;

(43) N- (2-fluorophenyl) -N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(44) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(45) N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl) -N -phenylquinoxaline-2-carboxamide;

(46) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoline-2-carboxamide;

(47) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide;

(48) N- (3-fluorophenyl) -N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(49) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(50) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

(51) 6-chloro- N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

(52) 5-chloro- N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

(53) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(54) N- (4-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(55) N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl) -N- (pyridin-2-yl)furan-2-carboxamide;

(56) N -benzyl- N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(57) N- (2,4-difluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(58) N- (3,4-difluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(59) N -((5-(4-ethoxyphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)furan-2-carboxamide;

(60) N -((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(61) N -((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;

(62) N- (2-fluorophenyl) -N -((5-(4-propoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(63) N- (2-fluorophenyl) -N -((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(64) N- (3-fluorophenyl) -N -((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(65) N- (2-fluorophenyl) -N -((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(66) N- (3-fluorophenyl) -N -((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(67) N -((5-(4-(difluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(68) N -((5-(4-(difluoromethoxy)-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide ;

(69) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(70) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(71) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)oxazole-5-carboxyl mid;

(72) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)isoxazole-5-carb copy mid;

(73) N- (2-fluorophenyl)-5-nitro- N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide ;

(74) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide ;

(75) 6-chloro- N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) thiophen-2-yl) methyl) pyrazine-2 -carboxamide;

(76) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(77) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(78) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;

(79) N- (3-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;

(80) N- (4-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;

(81) 4-(5-(( N- (3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl furan-2-carboxylate;

(82) 4-(5-(( N- (3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl benzenesulfonate;

(83) N -((5-(4-(benzyloxy)phenyl)thiophen-2-yl)methyl) -N- (3-chlorophenyl)pentanamide;

(84) N- (3-chlorophenyl) -N -((5-(4-((4-methylbenzyl)oxy)phenyl)thiophen-2-yl)methyl)pentanamide;

(85) N -((5-(benzo[d][1,3]dioxol-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2- carboxamide;

(86) N -((5-(benzo[ d ]oxazol-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(87) N -((5-(benzofuran-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(88) N -((5-(benzofuran-5-yl)thiophen-2-yl)methyl) -N- (4-fluorophenyl)quinoxaline-2-carboxamide;

(89) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-morpholinopyrazine-2-carboxa mid;

(90) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperazine-1- 1) pyrazine-2-carboxamide;

(91) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperidin-1 -yl)pyrazine-2-carboxamide;

(92) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-6-carboxamide;

(93) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide ;

(94) N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) thiophen-2-yl) methyl) benzofuran-2-carboxyl mid;

(95) N -((5-(2,3-dihydrobenzofuran-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide ;

(96) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)acetamide;

(97) 4-acetamido- N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;

(98) N- (2-fluorophenyl) -N -((5-(2-methyl-1,3-dioxoisoidolin-5-yl)thiophen-2-yl)methyl)quinoxaline-2 -carboxamide;

(99) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-2,3-dihydro benzo[b][1,4]dioxine-2-carboxamide;

(100) N- (3-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(101) N- (4-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(102) N- (2-bromophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

(103) N -((5-(4-fluorophenyl)thiophen-2-yl)methyl) -N- (o-tolyl)furan-2-carboxamide;

(104) N- (2-fluorophenyl)-5-methoxy- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)benzofuran -2-carboxamide;

(105) N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) thiophen-2-yl) methyl) -5-nitrofuran-2 -carboxamide;

(106) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-nitrobenzofuran-2-carboxamide ;

(107) N- (2-fluorophenyl)-5-methoxy- N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxyl mid;

(108) N- cyclobutyl- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(109) N -cyclopentyl- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(110) N -cyclohexyl- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(111) N- (cyclohexylmethyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(112) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

(113) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (tetrahydro-2H-pyran-4-yl)quinoxaline -2-carboxamide;

(114) tert -butyl 4-( N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamido)piperidine -1-carboxylate;

(115) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (piperidin-4-yl)quinoxaline-2-car copy mid;

(116) N -((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl 1)quinoxaline-2-carboxamide;

(117) N -((5-(3-ethyl-4-fluorophenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl 1)quinoxaline-2-carboxamide;

(118) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (pyrazin-2-yl)quinoxaline-2-carboxyl mid;

(119) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (pyrimidin-5-yl)quinoxaline-2-car copy mid; and

(120) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (1H-pyrazol-4-yl)quinoxalin-2 -Carboxamides.

In one embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 3 below:

[Formula 3]

In the above formula,

R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , or -OC _1-6 alkyl-OC _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxy each independently may be unsubstituted or substituted with 1 to 3 halogens;

R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;

R ₃ is C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, or -C _1-6 alkyl-5-6 membered hetero cyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and -C _1-6 alkyl-5-6 each membered heterocyclyl may be independently unsubstituted or substituted with 1 to 4 halogens, CN, -COOH, C _1-6 alkyl, or -CO-C _1-6 alkyl;

R ₄ is 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or -5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the above 5-10 membered heteroaryl, 5-10 membered heterocyclyl Cyclyl and -5-6 membered heteroaryl-5-6 membered heterocyclyl may each independently be unsubstituted or substituted with 1 to 4 halogen or C _1-6 alkyl;

The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. .

As an embodiment, in the compound of Formula 3, R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , or -O-CH ₂ -O-CH ₃ , wherein the C _1-6 alkyl and C _1-6 alkoxy each independently may be unsubstituted or substituted with 1 to 3 halogens. . For example, methoxyoxy (-OCH ₃ ) may be substituted with 1 to 3 halogens to form -OCF ₃ or -OCF ₂ H.

In one embodiment, in the compound of Formula 3, R ₂ may be hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens. Specifically, R ₂ may be H, -CH ₃ , -C ₂ H ₅ , or -CF ₃ , but is not limited thereto.

또는

이고, 이에 한정되는 것은 아니다.In one embodiment, in the compound of Formula 3, R ₃ is C _1-6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl, or morpholinoethyl, wherein the C _1-6 alkyl, cyclopropyl, Phenyl, pyridinyl, pyrimidinyl and morpholinoethyl are each independently unsubstituted or substituted with 1 to 4 halogen, CN, -COOH, C _1-6 alkyl or -CO-C _1-6 alkyl. can Specifically, the R ₃ is, for example, ethyl, cyclopropyl,

or

and is not limited thereto.

및

에서 N은 HCl과 염을 형성할 수 있다.for example,

and

N can form a salt with HCl.

또는

이고, 이때 상기 피리디닐, 피라지닐, 퀴녹살리닐, 디하이드로벤조디옥시닐,

및

은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 C_1-6 알킬로 치환될 수 있는 것일 수 있다. 구체적으로, 상기 R₄는 예컨대

또는

이고, 이에 한정되는 것은 아니다.In one embodiment, in the compound of Formula 3, R ₄ is pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl,

or

Wherein the pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl,

and

Each may be independently unsubstituted, or may be substituted with 1 to 4 halogen or C _1-6 alkyl. Specifically, the R ₄ is, for example

or

and is not limited thereto.

Specific examples of the compound of Formula 3 according to the present invention are as follows, but are not limited thereto:

(121) N -((2-(4-fluoro-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(122) N -((2-(4-chloro-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(123) N- (2-fluorophenyl) -N -((2-(4-methoxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(124) N -((2-(4-(difluoromethoxy)phenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(125) N -((2-(4-(difluoromethoxy)-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide ;

(126) 6-chloro- N - (2-fluorophenyl) - N - ((2- (4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) pyrazine-2-carboxamide ;

(127) N- (2-fluorophenyl)-6-morpholino- N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)pyrazine-2-carb copy mid;

(128) N - (2-fluorophenyl) - N - ((2- (3-methyl-4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) quinoxaline-2-carboxyl mid;

(129) N- (2-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(130) N- (4-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(131) N- (3-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(132) N - (4-fluorophenyl) - N - ((2- (3-methyl-4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) quinoxaline-2-carboxyl mid;

(133) N- (pyridin-2-yl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(134) N- (pyridin-3-yl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(135) N -ethyl- N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(136) N- (2-fluorophenyl) -N -((2-(4-(trifluoromethoxy)piperidin-1-yl)thiazol-5-yl)methyl)quinoxaline-2- carboxamide;

(137) N- (pyridin-3-yl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(138) 3-( N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamido)pyridin-1-ium chloride;

(139) N - (2-fluorophenyl) - N - ((2- (4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) -2,3-dihydrobenzo [b] [1,4]dioxin-2-carboxamide;

(140) N- (4-fluorophenyl) -N -((2-(4-(methoxymethoxy)-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide ;

(141) N- (4-fluorophenyl) -N -((2-(4-hydroxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(142) N -((2-(4-methoxyphenyl)thiazol-5-yl)methyl) -N- (3-methylpyridin-2-yl)quinoxaline-2-carboxamide;

(143) N -((2-(4-methoxyphenyl)thiazol-5-yl)methyl) -N- (pyrimidin-2-yl)quinoxaline-2-carboxamide;

(144) N- (2-fluorophenyl) -N -((2-(4-methoxyphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

(145) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N -cyclopropylquinoxaline-2-carboxamide;

(146) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)picolinamide;

(147) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N- (4-cyanophenyl)quinoxaline-2-carboxamide;

(148) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N- (2-morpholinoethyl)quinoxaline-2-carboxamide;

(149) 4-(N-((2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide)benzoic acid;

(150) N -((2-(4-(aminomethyl)phenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(151) N -((2-(4-carbamoylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(152) N -((2-(4-carbamoyl-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;

(153) N- (2-fluorophenyl) -N -((2-(4-sulfomoylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; and

(154) N- (3-acetylphenyl) -N -((2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide.

In one embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 4 below:

[Formula 4]

In the above formula,

R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, or C _1-6 alkoxy, wherein the C _1-6 alkyl and C _1-6 alkoxy are each independently unsubstituted, or 1 to 3 may be substituted with halogen;

R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;

R ₃ is C _6-10 aryl or 5-6 membered heteroaryl, wherein the C _6-10 aryl and 5-6 membered heteroaryl are each independently unsubstituted, or 1 to 4 halogen or C _1-6 may be substituted with alkyl;

R ₄ is a 5-10 membered heteroaryl, wherein each of the 5-10 membered heteroaryls is independently unsubstituted or may be substituted with 1 to 4 halogen or C _1-6 alkyl;

The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S.

이고, 이에 한정되는 것은 아니다.In one embodiment, in the compound of Formula 4, R ₃ is phenyl or pyridinyl, wherein the phenyl and pyridinyl are each independently unsubstituted or substituted with 1 to 4 halogens or C _1-6 alkyl have. Specifically, the R ₃ is, for example

and is not limited thereto.

이고, 이에 한정되는 것은 아니다.In one embodiment, in the compound of Formula 4, R ₄ is pyrazinyl or quinoxalinyl, wherein the pyrazinyl and quinoxalinyl are each independently unsubstituted, or 1 to 4 halogen or C _1-6 alkyl can be replaced with Specifically, the R ₄ is, for example

and is not limited thereto.

Specific examples of the compound of Formula 4 according to the present invention are as follows, but are not limited thereto:

(155) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2 -carboxamide;

(156) N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) -1,3,4-thiadiazol-2-yl) methyl ) quinoxaline-2-carboxamide; and

(157) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline- 2-Carboxamide.

The present invention includes pharmaceutically acceptable salts of the compound of Formula 1 above.

The pharmaceutically acceptable salt should have low toxicity to humans and should not have any adverse effect on the biological activity and physicochemical properties of the parent compound. For example, the pharmaceutically acceptable salt may be an acid addition salt formed with a pharmaceutically acceptable free acid.

An inorganic acid or an organic acid may be used as the free acid. In this case, the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc., and the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene sul phonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound of Formula 1 in an aqueous solution of excess acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile It can be.

In addition, the pharmaceutically acceptable salt may be an alkali metal salt (sodium salt, etc.) or an alkaline earth metal salt (potassium salt, etc.).

The alkali metal salt or alkaline earth metal salt may be obtained, for example, by dissolving the compound of Formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. .

In addition, the compounds of the present invention may have chiral carbon centers and thus may exist in the form of R or S isomers, racemates, individual enantiomers or mixtures, individual diastereomers or mixtures, all such stereoisomers and mixtures thereof may fall within the scope of this invention.

In addition, the compound of the present invention may include a hydrate and a solvate of the compound of Formula 1 above. The hydrates and solvates can be prepared using known methods, and are preferably non-toxic and water-soluble. Particularly, preferably, the hydrate and the solvate may be a combination of 1 to 5 molecules of water and an alcoholic solvent (particularly, ethanol, etc.), respectively.

In addition, the present invention provides a method for preparing the compound of Formula 1.

Specifically, the compound of Formula 1 may be prepared by the method shown in the following reaction schemes, but is not limited to being prepared by this method. In particular, those skilled in the art will fully understand that the compound represented by Chemical Formula 1 of the present invention can be prepared by various methods using well-known techniques in the art.

The following reaction schemes show the preparation methods of representative compounds according to the present invention step by step, and various compounds of the present invention may be prepared by changing the reagents and solvents used in the following preparation steps or by changing the reaction order.

General procedure

The compound of the present invention is obtained by combining aryl bromide, aryl boronic acid, or aryl boronic acid pinacol ester with heteroaryl carboxaldehyde through a Suzuki coupling reaction (step b) followed by reductive amination (step c) followed by N -acylation (step c).

[Scheme 1]

Reagents and conditions: (a) MOM-Cl, DIPEA, DCM, room temperature at 0°C for 12 hours; (b) Pd(dppf)Cl ₂ .CH ₂ Cl ₂ , Na ₂ CO ₃ , 1,4-dioxane:H ₂ O (9:1), 95° C., 12 hours; (c) i) corresponding amine (R ₁ -NH ₂ ), catalyst (cat.) acetic acid, DCM, ii) NaBH ₃ CN, MeOH, room temperature, 12 hours; (d) corresponding acyl chloride (R ₂ COCl), triethylamine, CH ₂ Cl ₂ , 0° C. to room temperature, 12 hours

Step a: MOM protection

Prior to performing the Suzuki coupling reaction of step b, starting materials having phenolic hydroxyl groups are MOM-Cl (Chloromethyl methyl ether: chloromethyl methyl ether), DIPEA ( N , N -diisopropylethylamine) and DCM (CH ₂ Cl ₂ ) was added and stirred for 12 hours while slowly raising the temperature from 0° C. to room temperature to form methoxymethyl (MOM) ether to protect the phenolic hydroxyl group.

Step b: Suzuki Coupling

Degassed aryl bromide (1.0 equiv.) and boronic acid/ester (1.1 equiv.) solution in 1,4-dioxane:H ₂ O (9:1) mixture. To this was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.05 eq.). Na ₂ CO ₃ (2.5 eq) was added to the reaction mixture and heated at 95 °C. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a celite wash with ethyl acetate (EtOAc). The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography.

Step c: Reductive Amination

Aryl amine (2.0 equiv.) and a catalytic amount of acetic acid were added to a solution of the aldehyde of CH ₂ Cl ₂ (1.0 equiv.). The reaction mixture was stirred at room temperature until imine was completely formed while observing by TLC. Excess methanol (MeOH) was evaporated and the residue was redissolved in tetrahydrofuran (THF). 1.0M NaCNBH ₃ in THF (1.1 equiv.) was added to the reaction mixture and stirred for 12 hours. After completion of the reaction, the solvent was removed in vacuo. The residue was redissolved in ethyl acetate (EtOAc), washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography.

Step d: N -Acylation (N-acylation)

Acyl chloride/sulfonyl chloride ( _2.0 equiv.) was added to a solution of secondary amine (1.0 equiv.) and triethylamine (3.0 equiv.) in CH ₂ Cl 2 at 0°C. Added slowly. The reaction mixture was slowly warmed to room temperature while stirring for 12 hours. After completion of the reaction, the reaction mixture was diluted with CH ₂ Cl ₂ , washed with brine, dried over MgSO ₄ and evaporated in vacuo to give crude crude product. The residue was purified by flash column chromatography.

The target compounds produced in the above reaction scheme can be separated and purified using a conventional method, for example, tube chromatography, recrystallization, or the like.

Since the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof has an excellent effect of inhibiting KRAS activity or expression, the compound or a pharmaceutical composition containing the same can prevent diseases caused by KRAS mutation or overexpression, such as cancer. Or it can be usefully used for treatment. Specifically, the compound according to the present invention or a pharmaceutical composition containing the same can be usefully used as a target anticancer agent for various cancers, and can be used as an anticancer agent capable of overcoming drug resistance or radiation resistance by combination therapy with existing anticancer agents or immunotherapeutic agents. can

As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administration of a compound or pharmaceutical composition according to the present invention, and "treatment" refers to a compound according to the present invention. Or any action that improves or beneficially changes the symptoms of the disease by administration of the pharmaceutical composition.

The present invention provides a use of the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating a disease caused by KRAS mutation or overexpression, such as cancer.

The present invention provides a use of the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for inhibiting the activity or expression of KRAS.

The present invention provides a use of the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a drug for preventing or treating a disease caused by KRAS mutation or overexpression, such as cancer.

The present invention provides a use of the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a drug for inhibiting KRAS activity or expression. In addition, the present invention provides a method for preventing or treating a disease caused by KRAS mutation or overexpression, such as cancer, comprising administering the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof do.

In addition, the present invention provides a method for inhibiting the activity or expression of KRAS, comprising administering the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need of the activity or expression inhibition of KRAS do.

A disease caused by the KRAS mutation or overexpression may be cancer. "Cancer", a disease to be prevented and treated by the composition of the present invention, is classified as a disease in which normal tissue cells proliferate indefinitely for some reason and continue to grow rapidly regardless of the living phenomenon of the living body or the state of surrounding tissues. "Cancer" includes, but is not limited to, dysplasia, hyperplasia, solid tumors, and hematopoietic stem cell carcinoma, and includes various cancer types known in the art. Other cancers may include, but are not limited to, cancers of the following organs or organs: brain, heart, lungs, stomach, large intestine, genitourinary tract, liver, bone, nervous system, gynecology, blood, skin, breast, and adrenal glands. It doesn't work. Other types of cancer include gliomas (schwannoma, glioblastoma, astrocytoma), neuroblastoma, pheochromocytoma, paraganglioma, meningioma, adrenocortical cancer, medulloblastoma, rhabdomyosarcoma, renal cancer, various types of vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine fibroids, salivary gland cancer, choroid plexus cancer, breast cancer, pancreatic cancer, colon cancer, colorectal cancer and megakaryocyte leukemia; and sarcomas such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, fibrosarcoma or angiosarcoma, and melanoma including skin cancer.

In one embodiment, the cancer preventable or treatable by the compound or pharmaceutical composition according to the present invention is carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor ( neuroendocrine tumor), mesothelioma, schwanoma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoidmalignancy, squamous cell cancer, epithelial squamous cell cancer, lung cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, lung squamous carcinoma ( squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer , glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, Rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer (kidney and renal cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer ( testicular cancer), esophageal cancer, biliary tract cancer, colorectal cancer, and head and neck cancer.

The pharmaceutical composition of the present invention can inhibit the activity or expression of KRAS. As used herein, the term "inhibition" refers to inhibiting any step of gene transcription, mRNA processing, translation, translocation, and maturation, or inhibiting protein-protein binding, protein activation, or signal transduction therethrough. .

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is one commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. In addition to the above components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like may be further included.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage is the patient's condition and weight, the degree of disease , Depending on the drug form, administration route and time, it can be appropriately selected by a person skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concomitantly used drugs, and other factors well known in the medical field.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs, and in general, body weight 0.001 to 150 mg per 1 kg, preferably 0.01 to 100 mg may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.

In addition, the present invention provides a method for preventing, controlling or treating cancer comprising administering the pharmaceutical composition to a subject. In the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, means a mammal such as a human or non-human primate, mouse, dog, cat, horse, and cow. .

Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention by way of example, and the scope of the present invention is not limited by these examples.

[Example]

Example 1. N -(2-fluorophenyl)- N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 44)

[Scheme 2]

Reagents and conditions: a) 4-methoxy-3-methylphenylboronic acid, K ₃ PO ₄ , Pd(dppf)Cl ₂ .CH ₂ Cl ₂ , 1,4-dioxane (1,4-dioxane):H ₂ O (4:1) mixture, refluxed for 8 hours; b) 2-fluoroaniline, NaCNBH ₃ , acetic acid, DCM, methanol (MeOH) at room temperature for 8 hours; c) 2-quinoxaloyl chloride, TEA, DCM, room temperature at 0°C for 8 hours.

Step 1: Synthesis of 5-(4-methoxy-3-methylphenyl)thiophene-2-carboxaldehyde

Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.05 eq.) was dissolved in degassed 5-bromothiophene-2- in 1,4-dioxane:H ₂ O (4:1). Carboxaldehyde (5-bromothiophene-2-carboxaldehyde) (1 equiv.), 4-methoxy-3-methylphenylboronic acid (1.2 equiv.), and K ₃ PO ₄ (2 equiv.) ) was added to the solution. The reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc) and filtered through celite. The filtrate was washed with brine, dried over MgSO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-5% EtOAc in hexanes) gave the title compound as a yellow solid (70% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.85 (s, 1H), 7.70 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J = 4.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 2.26 (s, 3H).

Step 2: 2-Fluoro- N Synthesis of -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)aniline

Acetic acid (2 equiv.) was mixed with 5-(4-methoxy-3-methylphenyl)thiophene-2-carboxaldehyde (1 equiv.) and 2-fluoroaniline (0.83 equiv.) in DCM. equivalent) and stirred at room temperature while observing by TLC until imine was completely formed. DCM and acetic acid were then removed by evaporation. The reaction mixture was redissolved in methanol (MeOH). NaCNBH ₃ (3 equivalents) was added to the reaction mixture at 0° C. and stirred at room temperature for 8 hours. Solvent was removed in vacuo. The residue was redissolved in ethyl acetate (EtOAc), washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. Purification by flash column chromatography (silica gel, 0-5% EtOAc in hexanes) gave the title compound as a white solid (65% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.35 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.03-6.96 (m, 3H), 6.94 (d, J = 3.6 Hz, 1H) , 6.80 (d, J = 8.0 Hz, 2H), 6.66 (q, J = 6.8 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 4.34 (br, 1H), 3.84 (s, 3H) , 2.23 (s, 3H).

Step 3: N -(2-fluorophenyl)- N Synthesis of -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 44)

_{2 -} Fluoro-N-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)aniline (1 equiv.) and triethylamine (2 Eq.) 2-quinoxaloyl chloride (1.5 eq.) was added slowly at 0° C. in an argon environment to a solution of 2-quinoxaloyl chloride. The reaction mixture was slowly warmed to room temperature while stirring for 8 hours. The reaction mixture was diluted with CH ₂ Cl ₂ , washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated in vacuo. Purification by FCC (silica gel, 0-25% ethyl acetate in hexanes (EtOAc)) gave the title compound as a yellow solid (80% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.23 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.72-7.60 (m, 3H), 7.36 (d, J = 7.2 Hz, 1H) , 7.35 (s, 1H), 7.14–7.08 (m, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 3.6 Hz, 1H), 6.95–6.90 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.57 (d, J = 14.8 Hz, 1H), 4.95 (d, J = 14.8 Hz, 1H), 3.81 ( s, 3H), 2.22 (s, 3H).

Example 2. N -(2-fluorophenyl)- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 78)

[Scheme 3]

Reagents and conditions: a) 5-formyl-2-thiopheneboronic acid, K ₃ PO ₄ , Pd(dppf)Cl ₂ .CH ₂ Cl ₂ , 1,4-dioxane (1,4-dioxane):H ₂ O (4:1) mixture, refluxed for 8 hours; b) 2-fluoroaniline, NaCNBH ₃ , acetic acid, DCM, methanol (MeOH) at room temperature for 8 hours; c) 2-quinoxaloyl chloride, TEA, DCM, room temperature at 0°C for 8 hours.

Step 1: Synthesis of 5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophene-2-carboxaldehyde

Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.05 equiv.) was added to degassed 5-bromo-2-tri in 1,4-dioxane:H ₂ O (4:1). Fluoromethoxytoluene (5-bromo-2-trifluoromethoxytoluene) (1 equiv.), 5-formyl-2-thiopheneboronic acid (1.2 equiv.) and K ₃ PO ₄ (2 equiv.) ) was added to the solution. The reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc) and filtered through celite. The filtrate was washed with brine, dried over MgSO ₄ and concentrated in vacuo. Purification by flash column chromatography gave the title compound (70%).

Step 2: 2-Fluoro- N Synthesis of -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)aniline

After reacting under the above reagents and reaction conditions, the title compound was obtained as a yellow liquid (80% yield) by purification using silica gel column chromatography (hexane:EtOAc = 60:1).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.43 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 2.9 Hz , 1H), 7.01 (dd, J = 12.9, 5.7 Hz, 3H), 6.79 (t, J = 8.2 Hz, 1H), 6.71 - 6.65 (m, 1H), 4.55 (s, 2H), 4.40 (s, 1H), 2.34 (s, 3H).

Step 3: N -(2-fluorophenyl)- N Synthesis of -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 78)

After reacting under the above reagents and reaction conditions, the title compound was obtained as a yellow solid (90% yield) by purification using silica gel column chromatography (hexane:EtOAc = 4:1).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 (s, 1H), 8.03 (d, J = 6.7 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.67 (s, 2H), 7.45 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.18 (d, J = 6.5 Hz, 2H), 7.08 (d, J = 2.0 Hz, 2H), 6.96 (d, J = 7.1 Hz, 2H) , 6.89 (d, J = 1.8 Hz, 1H), 5.55 (d, J = 14.5 Hz, 1H), 4.99 (d, J = 14.9 Hz, 1H), 2.33 (s, 3H).

Example 3. N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 112)

[Scheme 4]

Reagents and conditions: (a) 5-bromo-2-trifluoromethoxytoluene, 5-formyl-2-thiophenboronic acid, PdCl ₂ (PPh ₃ ) ₂ , Na ₂ CO ₃ , 1,2-dimethoxy Toxyethane:EtOH:H ₂ O (2:1:1), rt, 18 h; (b) HONH ₂ HCl, 12 M HCl, zinc dust, EtOH, rt, 2 h; (c) 2-quinoxalinecarboxylic acid, TiCl ₄ , pyridine, 80° C., 6 h.

Step 1: Synthesis of 5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophene-2-carbaldehyde

5-bromo-2-trifluoromethoxytoluene (2.0 g, 7.84 mmol) in DME:EtOH:H O (4:2:2.5) (30 mL), 5-formyl-2-thiophenboronic acid (1.59 g, 10.20 mmol), and to a degassed solution of anhydrous Na2CO3 (2.49 g, 23.53 mmol) was added Pd(dppf)Cl ₂ CH ₂ Cl ₂ (0.27 g, 0.39 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mass was diluted with H ₂ O and extracted with EtOAc. The organic layers were combined and washed with H ₂ O and brine. Dried over MgSO ₄ , filtered and concentrated under vacuum. Purification by flash column chromatography (silica gel, 0-5% EtOAc in hexanes) gave the title compound as a yellow solid (1.99 g, 89%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.89 (s, 1H), 7.74 (d, J = 3.9 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 8.5, 1.8 Hz, 1H) , 7.37 (d, J = 3.9 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 2.37 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 182.92, 152.75, 148.59, 142.95, 137.51, 132.13, 131.75, 129.70, 125.32, 124.63, 121.64, 121.63, 16.40.

Step 2: Synthesis of (5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methanamine

To a solution of 5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-carbaldehyde (140.0 mg, 0.49 mmol) in ethanol (2 mL) was added hydroxylammonium chloride (40.8 mg, 0.59 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Hydrochloric acid (12 M, 163.3 uL) and zinc dust (80 mg, 1.23 mmol) were then slowly added to the solution and the mixture was stirred at room temperature for 15 minutes. A solution of ammonia (30%, 140 uL) and sodium hydroxide (6 M, 300 uL) was added dropwise to the resulting slurry, and the mixture was stirred at room temperature for 15 minutes. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The solvent was removed in vacuo to give the title compound as a brown liquid (27.8 mg, 20%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.43 (s, 1H), 7.39 (dd, J = 8.4, 1.8 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 6.88 (d, J = 3.3 Hz, 1H), 4.06 (s, 2H), 2.34 (s, 3H), 1.75 (s, 2H).

Step 3: N Synthesis of -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 112)

To a solution of (5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methanamine (10.5 mg, 0.04 mmol) in pyridine (3 mL) at room temperature under an argon atmosphere, 2- Quinoxaloyl chloride (12.7 mg, 0.07 mmol) was added. The reaction mixture was stirred for 15 minutes while slowly rising to 80 °C. A solution of titanium(IV) chloride in DCM (14%, 110 uL) was then added dropwise to the reaction mixture and stirred at 80° C. for 6 hours. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with H ₂ O and brine. Dried over MgSO ₄ and concentrated under vacuum. Purification by flash column chromatography (silica gel, 0-30% EtOAc in hexanes) gave the title compound as a yellow solid (15.0 mg, 91%).

¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.59 (s, 1H), 9.25 (br, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.13 (dd, J = 8.1, 1.1 Hz, 1H), 8.02 - 7.90 (m, 2H), 7.62 (d, J = 1.3 Hz, 1H), 7.55 (dd, J = 8.5, 1.9 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 4.90 (s, 2H), 2.34 (s, 3H); ¹³ C NMR (100 MHz, Acetone- D 6) δ 163.96, 147.60, 144.85, 144.63, 143.29, 142.66, 141.07, 134.39, 132.57, 132.43, 131.90, 130.46, 130.25, 129.38 , 120.59, 38.60, 16.04.

Compounds 1 to 120 shown in Table 1 below were prepared using the same method as in Examples 1 to 3.

Example 4. N -(2-fluorophenyl)- N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide (Compound 129)

[Scheme 5]

Step 1: Synthesis of 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde

General Process A (Suzuki Coupling)

Degassed aryl bromide (1.0 equiv.) and boronic acid/ester (1.1 equiv.) solution in 1,4-dioxane:H ₂ O (9:1) mixture. To this was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.05 eq.). Na ₂ CO ₃ (2.5 eq) was added to the reaction mixture and heated at 95 °C. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a celite wash with ethyl acetate (EtOAc). The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography.

2-bromo-5-carboxaldehyde and [4-(Trifluoromethoxy)phenyl]boronic acid according to General Procedure A was reacted to give the title compound. Purification by flash column chromatography (silica gel, 0-5% EtOAc in hexanes) gave the title compound 35i as a yellow solid (70% yield).

^1H NMR (CDCl ₃ , 400 MHz) δ 10.06 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H)

Step 2: 2-Fluoro- N Synthesis of -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)aniline

General Process B (Reductive Amination)

Aryl amine (2.0 equiv.) and a catalytic amount of acetic acid were added to a solution of the aldehyde of CH ₂ Cl ₂ (1.0 equiv.). The reaction mixture was stirred at room temperature until imine was completely formed while observing by TLC. Excess methanol (MeOH) was evaporated and the residue was redissolved in tetrahydrofuran (THF). 1.0M NaCNBH ₃ in THF (1.1 equiv.) was added to the reaction mixture and stirred for 12 hours. After completion of the reaction, the solvent was removed in vacuo. The residue was redissolved in ethyl acetate (EtOAc), washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography.

The title compound was prepared according to General Procedure B from 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde prepared in Step 1. Purification by flash column chromatography (silica gel, 0-5% EtOAc in hexanes) gave the title compound 36p as a pale yellow solid (0.15 g, 80% yield).

^1H NMR (CDCl ₃ , 400 MHz) δ 7.93 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.00 (t, J = 8.6 Hz) , 2H), 6.78 (t, J = 8.2 Hz, 1H), 6.70 (q, J = 6.8 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.37 (s, 1H)

Step 3: N -(2-fluorophenyl)- N Synthesis of -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide (Compound 129)

General process C ( N -acylation; N -acylation)

Acyl chloride/sulfonyl chloride ( _2.0 equiv.) was added to a solution of secondary amine (1.0 equiv.) and triethylamine (3.0 equiv.) in CH ₂ Cl 2 at 0°C. Added slowly. The reaction mixture was slowly warmed to room temperature while stirring for 12 hours. After completion of the reaction, the reaction mixture was diluted with CH ₂ Cl ₂ , washed with brine, dried over MgSO ₄ and evaporated in vacuo to give crude crude product. The residue was purified by flash column chromatography.

The title compound was prepared according to General Procedure C from 2-fluoro- N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)aniline prepared in Step 2. Purification by flash column chromatography (silica gel, 0-30% EtOAc in hexanes) gave the title compound 37ae as a light brown solid (40.0 mg, 28% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.24 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.77 -7.73 (m, 1H) , 7.66 (d, J = 3.2 Hz, 2H), 7.59 (s, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.19 (q, J = 6.7 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 8.4 Hz, 2H), 5.48 (d, J = 14.4 Hz, 1H), 5.13 (d, J = 15.3 Hz, 1H)

According to the method of Example 4, compounds 121 to 154 shown in Table 2 below were prepared using various bromotiazole derivatives and boronic acid derivatives.

Example 5. N -(2-fluorophenyl)- N -((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2-carboxamide (Compound 157)

[Scheme 6]

Reagents and Conditions: (a) Corresponding boronic acid/ester, Pd(OAc) ₂ , xantphos, N -methyl morpholine, toluene:H ₂ O (2: 1), room temperature, 7 hours; (b) NaBH ₄ , MeOH, 0° C., 1 hour; (c) Dess-Martin periodinane, CH ₂ Cl ₂ , room temperature, 12 hours; (d) i) 2-fluoroaniline, cat. acetic acid, MeOH, ii) 1.0 M NaBH ₃ CN in THF, THF, room temperature, 12 hours; (e) 2-quinoxaloyl chloride, triethylamine, CH ₂ Cl ₂ , 0°C to room temperature, 12 hours.

Step 1: Synthesis of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate (12)

The round bottom flask was charged with ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate, (4-(trifluoro) Lomethoxy)phenyl)boronic acid ((4-(trifluoromethoxy)phenyl)boronic acid), Pd(OAc) ₂ and xantphos were loaded. After adding a solution of N -methyl morpholine in toluene , water (H ₂ O) was added. The reaction mixture was vigorously stirred at room temperature for 7 hours. After the reaction was complete, the residue was redissolved in ethyl acetate (EtOAc), and the organic layer was washed with water (H ₂ O) and brine, dried over MgSO ₄ and evaporated under reduced pressure. Purification by flash column chromatography (silica gel, 0-10% EtOAc in hexanes) gave the title compound as a white solid (0.52 g, 77% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.08 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 4.55 (q, J = 7.2 Hz, 2H), 1.49 (t , J = 7.2 Hz, 3H)

Step 2: Synthesis of 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxaldehyde (14)

To a solution of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate in anhydrous MeOH was carefully added NaBH ₄ at 0 °C and the reaction mixture was then cooled to 0 °C. It was stirred for 1 hour at °C. After the reaction was complete, excess MeOH was evaporated, and the reaction was quenched by slow addition of water at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. To a solution of alcohol in anhydrous DCM was added Dess-Martin periodinane and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction was diluted with DCM and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-15% EtOAc in hexanes) to give the title compound as a white solid (0.26 g, 88% yield).

^1H NMR (CDCl ₃ , 400 MHz) δ 10.25 (s, 1H), 8.13 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H)

Step 3: 2-Fluoro- N Synthesis of -((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)aniline (15)

The title compound was synthesized according to the general procedure B of Example 4 above. Purification by flash column chromatography (silica gel, 0-15% EtOAc in hexanes) gave the title compound as a white solid (0.12 g, 57% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.96 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.05-6.96 (m, 2H), 6.78-6.70 (m, 2H), 4.87 (d, J = 6.4 Hz, 2H), 4.78 (s, 1H)

Step 4: N -(2-fluorophenyl)- N Synthesis of -((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2-carboxamide (16) (Compound 157)

The title compound was synthesized according to general procedure C of Example 4 above. Purification by flash column chromatography (silica gel, 0-30% EtOAc in hexanes) gave the title compound as a white solid (24.0 mg, 19% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.28 (s, 1H), 8.07 (s, merged, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.78 (t, J = 7.6 Hz, 1H) , 7.70–7.64 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.29–7.27 (merged, 1H), 7.20 (q, J = 6.8 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 9.4 Hz, 1H), 5.64 (d, J = 14.0 Hz, 1H), 5.44 (d, J = 15.2 Hz, 1H)

It is used in the method of Example 5, but in step 1 of Example 5, ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate and (4-(trifluoromethoxy)phenyl) Compounds 155 to 157 shown in Table 3 below were prepared using various bromotiadiazole derivatives and boronic acid derivatives as starting materials instead of boronic acid.

Preparation of intermediates

In synthesizing some compounds, intermediates for Suzuki coupling reaction were prepared by the following method.

[Scheme 7]

Reagents and Conditions: (a) Corresponding aryl bromide, Pd(dppf)Cl ₂ .CH ₂ Cl ₂ , 1,4-dioxane:H ₂ O, 95° C., 12 hour; (b) i) 2-fluoroaniline, cat. acetic acid, MeOH, ii) 1.0M NaBH ₃ CN in tetrahydrofuran (THF), tetrahydrofuran (THF) ), room temperature, 12 hours; (c) 2-quinoxaloyl chloride, triethylamine, CH ₂ Cl ₂ , 0° C. to room temperature, 12 hours; (d) propargyl amine, HATU, DIPEA, DMF, room temperature, 24 hours; (e) (PhSe) ₂ , selectfluor, H ₂ O, CH ₃ CN, room temperature, 12 hours; (f) ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate, Pd(OAc) ₂ , Zant Phosphorus (xantphos), N -methyl morpholine ( N -methyl morpholine), toluene:H ₂ O (2:1), room temperature, 7 hours; (g) NaBH ₄ , MeOH, 0° C., 1 hour; (h) Dess-Martin periodinane, CH ₂ Cl ₂ , room temperature, 12 hours.

[Production Example]

Preparation Example 1. Ethyl 5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazole-2-carboxylate (18)

RBF was ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate), (4- (trifluoromethoxy )phenyl)boronic acid ((4-(trifluoromethoxy)phenyl)boronic acid), Pd(OAc) ₂ and xantphos. A solution of N -methyl morpholine in toluene was added and then water (H ₂ O) was added . The reaction mixture was vigorously stirred at room temperature for 7 hours. After the reaction was complete, the residue was redissolved in ethyl acetate (EtOAc), and the organic layer was washed with water (H ₂ O) and brine, dried over MgSO ₄ and evaporated under reduced pressure. Purification by flash column chromatography (silica gel, 0-10% EtOAc in hexanes) gave the title compound as a white solid (0.65 g, 84% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.86 (s, merged, 1H), 7.82 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.53 (q, J = 7.3 Hz, 2H) , 3.91 (s, 3H), 2.28 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H)

Production Example 2. 5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)methanol (19)

To a solution of the ester (1.0 equiv) in anhydrous methanol (MeOH) (5.0 mL) was carefully added NaBH ₄ (2.0 equiv) at 0 °C under an argon atmosphere and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, excess methanol (MeOH) was evaporated and the reaction mass was quenched at 0 °C by the slow addition of water and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-50% EtOAc in hexanes) gave the title compound as a white solid (0.58 g, 100% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.76 (d, J = 6.8 Hz, 1H), 7.75 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.09 (d, J = 6.4 Hz , 2H), 3.89 (s, 3H), 2.78 (t, J = 6.4 Hz, 1H), 2.27 (s, 3H)

[Experimental example]

To discover protein-protein interaction (PPI) inhibitors for the oncogenic interaction between KRAS and AIMP2-DX2, a compound library was screened using a NanoBiT-based screening system.

In this experimental example, the following materials and equipment were used.

Compound library (1,697 various compound libraries provided by Dongguk University) and 1,102 commercial compound libraries (Selleckchem)

· RPMI + 10mM HEPES Medium (Hyclone)

Fetal bovine serum (Hyclone)

· Penicillin/Streptomycin (Hyclone)

· Trypsin (Hyclone)

· Turboffect (Thermo)

Dimethyl Sulphoxide (DMSO) (Sigma)

· Nano-Glo Live Cell Assay System Kit (Promega)

Plasmid Midi-prep Kit (Qiagen)

· Cell culture dish 100 x 15mm (Nunc)

White flat bottom 96-well plates (Corning)

· CH0-K1 cell line (ATCC)

· Glomax Microplate Reader Discover (Promega)

· Countess II FL Automated Cell Counter (Thermo)

Trypan blue hair dye 0.4% (Invitrogen)

· LgBiT-AIMP2-DX2 (Biocon): AIMP2-DX2 capable of co-expressing LgBiT

· SmBiT-KRAS (Biocon): KRAS that can express SmBiT together

LgBiT-PRKAR2A (Biocon): PRKAR2A capable of co-expressing LgBiT

SmBiT-PRKACA (Biocon): PRKACA that can express SmBiT together

Experimental Example 1. Protocol

First, 2x10 ⁶ CH0-K1 cells were seeded in a 100x15 mm cell culture dish and cultured for 24 hours, and LgBiT-AIMP2-DX2 and SmBiT-KRAS were transfected into the cells.

Transfection

A 1.5 mL Eppendorf tube was prepared and 4 μg each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added thereto. After adding 600 μL of preheated serum-free RPMI medium to the tube containing the plasmid, the mixture was mixed by vortexing for 5 seconds. 16 μL of Turbofect was then added to the tube, mixed by vortexing for 5 seconds, and left for 15 minutes. While the reaction tube was left standing, the culture medium was removed from the culture dish, and then 6 mL of new cell culture medium was added. After 15 minutes, the reaction mixture was added to the cell culture dish, mixed gently, and incubated in a CO ₂ incubator for 4 hours. After 4 hours, the medium was replaced with fresh cell culture medium. After 24 hours, the cells were removed from the culture dish and resuspended in 10 mL of RPMI growth medium. After adding 10 μL of trypan blue dye 0.4% to 10 μL of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a flat-bottomed white 96-well plate. After culturing for 24 hours, the cell culture medium was removed, and 100 µL of serum-free RPMI medium supplemented with the compound (3 µM) was added to the cell plate, followed by culturing for 4 hours. After 4 hours, Nanoluciferase activity was measured at an integration time of 0.4 seconds/well using the Glomax Discover Microplate Reader as follows.

Preparing for the Nano-Glo Live Cell assay

The Nano-Glo ^® LCS dilution buffer was thawed and allowed to equilibrate to room temperature before use. 4 μg each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo ^® Live Cell reagent was prepared by combining 1.25 volumes of Nano-Glo ^® Live Cell substrate and 23.75 volumes of Nano-Glo ^® LCS dilution buffer and mixing well by vortexing. (Since long-term storage or exposure to light may cause loss of reagent activity, new Nano-Glo ^® Live Cell reagents were prepared for each experiment, and the reagent preparation procedure was performed under dark conditions.) Nano-Glo ^® Live Cell reagents Mix well by vortexing. After adding 25 μL of the prepared Nano-Glo ^® Live Cell reagent to all wells, the cells were incubated in a humidified incubator at 37° C. and 5% CO ₂ for 10 minutes.

Experimental Example 2. Confirmation of selectivity

In order to confirm the selective inhibition of the binding between KRAS and AIMP2-DX2, the following experiment was performed. First, 2x10 ⁶ CH0-K1 cells were seeded in a 100x15 mm cell culture dish, and 24 hours later, LgBiT-PRKAR2A and SmBiT-PRKACA were transfected into the cells.

transfection

A 1.5 mL Eppendorf tube was prepared and 4 μg each of LgBiT-PRKAR2A and SmBiT-PRKACA were added. After adding 600 μL of preheated serum-free RPMI medium to the tube containing the plasmid, the mixture was mixed by vortexing for 5 seconds. 16 μL of Turbofect was then added to the tube, mixed by vortexing for 5 seconds, and left for 15 minutes. While the reaction tube was left standing, the medium was removed from the culture dish, and then 6 mL of new cell culture medium was added. After 15 minutes, the reaction mixture was added to the cell culture dish, mixed gently, and incubated in a CO ₂ incubator for 4 hours. After 4 hours, the medium was exchanged with fresh cell culture medium. After 24 hours, the cells were removed from the culture dish and suspended in 10 mL of RPMI growth medium. After adding 10 μL of trypan blue dye 0.4% to 10 μL of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a white flat bottom 96-well plate. After 24 hours, the cell culture medium was removed, and 100 µL of serum-free RPMI medium supplemented with the compound (3 µM) was added to the cell plate, followed by culturing for 4 hours. After 4 hours, nanoluciferase activity was measured at a measurement time of 0.4 seconds/well using a Glomax Discover Microplate Reader as follows.

Preparing for the Nano-Glo Live Cell assay

The Nano-Glo ^® LCS dilution buffer was thawed and allowed to equilibrate to room temperature before use. 4 μg each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo ^® Live Cell reagent was prepared by combining 1.25 volumes of Nano-Glo ^® Live Cell substrate and 23.75 volumes of Nano-Glo ^® LCS dilution buffer and mixing well by vortexing. (Since long-term storage or exposure to light may cause loss of reagent activity, new Nano-Glo ^® Live Cell reagents were prepared for each experiment, and the reagent preparation procedure was performed under dark conditions.) Nano-Glo ^® Live Cell reagents Mix well by vortexing. After adding 25 μL of the prepared Nano-Glo ^® Live Cell reagent to all wells, the cells were incubated in a humidified incubator at 37° C. and 5% CO ₂ for 10 minutes.

Experimental Example 3: Confirmation of dose dependence

In order to confirm the dose-dependent inhibition of the binding between KRAS and AIMP2-DX2, the following experiment was performed. First, 2x10 ⁶ CH0-K1 cells were seeded in a 100x15 mm cell culture dish, and 24 hours later, LgBiT-AIMP2-DX2 and SmBiT-KRAS, or LgBiT-PRKAR2A and SmBiT-PRKACA were transfected into the cells.

transfection

A 1.5 mL Eppendorf tube was prepared and 4 μg each of Lg-BiT-AIMP2-DX2 and SmBiT-KRAS or LgBiT-PRKAR2A and SmBiT-PRKACA were added. After adding 600 μL of preheated serum-free RPMI medium to the tube containing the plasmid, the mixture was mixed by vortexing for 5 seconds. 16 μL of Turbofect was then added to the tube, mixed by vortexing for 5 seconds, and left for 15 minutes. While the reaction tube was left standing, the medium was removed from the culture dish, and then 6 mL of new cell culture medium was added. After 15 minutes, the reaction mixture was added to the cell culture dish, mixed gently, and incubated in a CO ₂ incubator for 4 hours. After 4 hours, the medium was exchanged with fresh cell culture medium. After 24 hours, the cells were removed from the culture dish and suspended in 10 mL of RPMI growth medium. After adding 10 μL of trypan blue dye 0.4% to 10 μL of the cell suspension, the number of cells was measured using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a white flat bottom 96-well plate. After 24 hours, the cell culture medium was removed, and 100 µL of serum-free RPMI medium supplemented with three-fold serially diluted compounds (0.003-10, 50 µM) was added to the cell plate, followed by culturing for 4 hours. After 4 hours, nanoluciferase activity was measured at a measurement time of 0.4 seconds/well using a Glomax Discover Microplate Reader as follows.

Preparing for the Nano-Glo Live Cell assay

The Nano-Glo ^® LCS dilution buffer was thawed and allowed to equilibrate to room temperature before use. 4 μg each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo ^® Live Cell reagent was prepared by combining 1.25 volumes of Nano-Glo ^® Live Cell substrate and 23.75 volumes of Nano-Glo ^® LCS dilution buffer and mixing well by vortexing. (Since long-term storage or exposure to light may cause loss of reagent activity, new Nano-Glo ^® Live Cell reagents were prepared for each experiment, and the reagent preparation procedure was performed under dark conditions.) Nano-Glo ^® Live Cell reagents Mix well by vortexing. After adding 25 μL of the prepared Nano-Glo ^® Live Cell reagent to all wells, the cells were incubated in a humidified incubator at 37° C. and 5% CO ₂ for 10 minutes.

The experimental results are shown in Table 4 below.

In Table 4, the inhibition rate (%) represents the inhibition rate of the compound of the present invention on the binding between AIMP2-DX2 and KRAS at a single concentration (3uM). IC ₅₀ is a measurement of the concentration of the compound of the present invention capable of inhibiting the binding of AIMP2-DX2 and KRAS by 50% through a concentration-dependent experiment, and the compound of the present invention does not affect other binding through inhibition of the binding of PRKACA-PRKAR2A It shows that only the binding of AIMP2-DX2-KRAS can be specifically inhibited.

Figure 1 shows the results of evaluating the inhibitory effect of AIMP2-DX2 and KRAS binding by (a) Compound 44 and (b) Compound 48 according to the present invention by measuring luciferase activity. Both compound 44 and compound 48 exhibited effective inhibitory activity against the binding of AIMP2-DX2 and KRAS. In particular, compound 44 showed a binding inhibition rate of 86.46% for the binding between AIMP2-DX2 and KRAS at a single concentration of 3uM, In light of the fact that the 50% inhibitory concentration (IC ₅₀ ) of the AIMP2-DX2-KRAS binding was measured to be 0.308uM through concentration experiments thereafter, and the IC ₅₀ was not measured (ND) for PRKACA-PRKAR2 in the experimental concentration range, It can be confirmed that compound 44 is a compound that specifically inhibits only the binding between AIMP2-DX2 and KRAS.

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.

Claims (15)

A compound of Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof:
[Formula 1]

In the above formula,
X and Y are each independently C or N;
R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , -OC _1-6 alkyl -OC _1-6 alkyl, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, or -O-CH ₂ -C _6-10 aryl, wherein the C _{1- 6} alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, and O-CH ₂ -C _6-10 aryl are each independently unsubstituted or may be substituted with 1 to 3 halogens or C _1-6 alkyl;
R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;
or R ₁ and R ₂ together with the benzene ring to which they are attached may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;
R ₃ is C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5 -6-membered heteroaryl, 5-6-membered heterocyclyl or -C _1-6 alkyl-5-6-membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 Alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and -C _1-6 alkyl- 5-6 membered heterocyclyls are each independently unsubstituted or 1 to 4 halogen, CN, -COOH, C _1-6 alkyl, -CO-C _1-6 alkyl or -COO-C _1-6 alkyl may be substituted with;
R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or - 5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5- 10-membered heteroaryl, 5-10-membered heterocyclyl, and -5-6-membered heteroaryl-5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, or -NH-CO-C _1-6 alkyl;
The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. . According to claim 1,
A compound in which the compound of Formula 1 is a compound of Formula 2 below, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 2]

In the above formula,
R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, or -O- CH ₂ -C _6-10 aryl, wherein the C _1-6 alkyl, C _1-6 alkoxy, -O-CO-5-6 membered heteroaryl, -O-SO ₂ -C _6-10 aryl, and O -CH ₂ -C _6-10 aryl may each independently be unsubstituted or substituted with 1 to 3 halogens or C _1-6 alkyl, R ₂ is hydrogen, C _1-6 alkyl, or 1 to 3 C _1-6 alkyl substituted with two halogens;
or R ₁ and R ₂ together with the benzene ring to which they are attached may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;
R ₃ is C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, C _6-10 aryl, -C _1-6 alkyl-C _6-10 aryl, 5-6 membered heteroaryl; Or a 5-6 membered heterocyclyl, wherein the C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 6 membered heterocyclyl. may be substituted with 4 halogens, C _1-6 alkyl, or -COO-C _1-6 alkyl; R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or - 5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, C _6-10 aryl, -CO-C _6-10 aryl, 5- 10-membered heteroaryl, 5-10-membered heterocyclyl, and -5-6-membered heteroaryl-5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, or -NH-CO-C _1-6 alkyl;
The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. . According to claim 2,
R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -O-CO-furanyl, -O-SO ₂ -phenyl, or -O-CH ₂ -phenyl, wherein C _1-6 alkyl, C _1-6 alkoxy, -O-CO-furanyl, -O-SO ₂ -phenyl and -O-CH ₂ -phenyl are each independently unsubstituted, or 1 to 3 halogen or It may be substituted with C _1-6 alkyl;
R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;
or R ₁ and R ₂ together with the benzene ring to which they are attached may form a benzodioxole, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring;
R ₃ is C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrazolyl, tetrahydropyranyl or piperidinyl, wherein said C _3-8 cycloalkyl; -CH ₂ -C _3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrazolyl, tetrahydropyranyl and piperidinyl are each independently unsubstituted or 1 to 4 halogen, C _1-6 alkyl, or -COO-C _1-6 alkyl;
R ₄ is C _1-6 alkyl, -CO-C _1-6 alkyl, phenyl, naphthyl, -CO-phenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxaly Nil, dihydrobenzodioxinyl,

or

, wherein the C _1-6 alkyl, -CO-C _1-6 alkyl, phenyl, naphthyl, -CO-phenyl, furanyl, oxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxalinyl, di hydrobenzodioxinyl,

and

are each independently unsubstituted or may be substituted with 1 to 4 halogens, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl or C _1-6 alkoxy, an isomer thereof or a compound thereof A pharmaceutically acceptable salt. According to claim 2 or 3,
Any one compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1) N- (2-fluorophenyl) -N -((5-phenylthiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(2) N- (2-fluorophenyl) -N -((5-phenylthiophen-2-yl)methyl)furan-2-carboxamide:
(3) N- (2-fluorophenyl) -N -((5-(m-tolyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(4) N- (2-fluorophenyl) -N -((5-(m-tolyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(5) N- cyclopentyl- N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(6) N- cyclohexyl- N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(7) N -((5-(4-fluorophenyl)thiophen-2-yl)methyl) -N- phenylfuran-2-carboxamide;
(8) N- (2-fluorophenyl) -N- ((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(9) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)oxazole-4-carboxamide;
(10) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-4-carboxamide;
(11) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-2-carboxamide;
(12) N- (2-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;
(13) N -((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(14) N -((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;
(15) N- benzyl- N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(16) N -((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)furan-2-carboxamide;
(17) N -((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)furan-2-carboxamide;
(18) N -((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(19) N -((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(20) N -((5-(4-chlorophenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;
(21) N -((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;
(22) N- (3-fluorophenyl) -N -((5-(4-methyl-3-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;
(23) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(24) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(25) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(26) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(27) N- (3-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;
(28) N- benzyl- N -((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(29) N- (2-fluorophenyl) -N -((5-(4-hydroxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(30) N- (2-fluorophenyl) -N -((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(31) N -((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(32) N- (3-fluorophenyl) -N -((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(33) N -((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;
(34) N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl) -N -phenylfuran-2-carboxamide;
(35) N- (2-fluorophenyl) -N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(36) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(37) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;
(38) 4-amino- N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;
(39) 4-((3-fluorophenyl)((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)carbamoyl)benzoic acid;
(40) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;
(41) N- (2-fluorophenyl)-5-methoxy- N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide ;
(42) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-2-naphthamide;
(43) N- (2-fluorophenyl) -N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(44) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(45) N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl) -N -phenylquinoxaline-2-carboxamide;
(46) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoline-2-carboxamide;
(47) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide;
(48) N- (3-fluorophenyl) -N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(49) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(50) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;
(51) 6-chloro- N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;
(52) 5-chloro- N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;
(53) N- (3-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(54) N- (4-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(55) N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl) -N- (pyridin-2-yl)furan-2-carboxamide;
(56) N- benzyl- N -((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(57) N- (2,4-difluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(58) N- (3,4-difluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(59) N -((5-(4-ethoxyphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)furan-2-carboxamide;
(60) N -((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(61) N -((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl) -N- (3-fluorophenyl)quinoxaline-2-carboxamide;
(62) N- (2-fluorophenyl) -N -((5-(4-propoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(63) N- (2-fluorophenyl) -N -((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(64) N- (3-fluorophenyl) -N -((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(65) N- (2-fluorophenyl) -N -((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(66) N- (3-fluorophenyl) -N -((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(67) N -((5-(4-(difluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(68) N -((5-(4-(difluoromethoxy)-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide ;
(69) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(70) N- (3-fluorophenyl) -N- ((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(71) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)oxazole-5-carboxyl mid;
(72) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)isoxazole-5-carb copy mid;
(73) N- (2-fluorophenyl)-5-nitro- N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide ;
(74) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide ;
(75) 6-chloro- N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) thiophen-2-yl) methyl) pyrazine-2 -carboxamide;
(76) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(77) N- (3-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(78) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;
(79) N- (3-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;
(80) N- (4-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl mid;
(81) 4-(5-(( N- (3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl furan-2-carboxylate;
(82) 4-(5-(( N- (3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl benzenesulfonate;
(83) N -((5-(4-(benzyloxy)phenyl)thiophen-2-yl)methyl) -N- (3-chlorophenyl)pentanamide;
(84) N- (3-chlorophenyl) -N -((5-(4-((4-methylbenzyl)oxy)phenyl)thiophen-2-yl)methyl)pentanamide;
(85) N -((5-(benzo[d][1,3]dioxol-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2- carboxamide;
(86) N -((5-(benzo[ d ]oxazol-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(87) N -((5-(benzofuran-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(88) N -((5-(benzofuran-5-yl)thiophen-2-yl)methyl) -N- (4-fluorophenyl)quinoxaline-2-carboxamide;
(89) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-morpholinopyrazine-2-carboxa mid;
(90) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperazine-1- 1) pyrazine-2-carboxamide;
(91) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperidin-1 -yl)pyrazine-2-carboxamide;
(92) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-6-carboxamide;
(93) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide ;
(94) N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) thiophen-2-yl) methyl) benzofuran-2-carboxyl mid;
(95) N -((5-(2,3-dihydrobenzofuran-5-yl)thiophen-2-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide ;
(96) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)acetamide;
(97) 4-acetamido- N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;
(98) N- (2-fluorophenyl) -N -((5-(2-methyl-1,3-dioxoisoidolin-5-yl)thiophen-2-yl)methyl)quinoxaline-2 -carboxamide;
(99) N- (2-fluorophenyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-2,3-dihydro benzo[b][1,4]dioxine-2-carboxamide;
(100) N- (3-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(101) N- (4-fluorophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(102) N- (2-bromophenyl) -N -((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;
(103) N -((5-(4-fluorophenyl)thiophen-2-yl)methyl) -N- (o-tolyl)furan-2-carboxamide;
(104) N- (2-fluorophenyl)-5-methoxy- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)benzofuran -2-carboxamide;
(105) N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) thiophen-2-yl) methyl) -5-nitrofuran-2 -carboxamide;
(106) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-nitrobenzofuran-2-carboxamide ;
(107) N- (2-fluorophenyl)-5-methoxy- N -((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxyl mid;
(108) N- cyclobutyl- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(109) N- cyclopentyl- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(110) N -cyclohexyl- N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(111) N- (cyclohexylmethyl) -N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(112) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;
(113) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (tetrahydro-2H-pyran-4-yl)quinoxaline -2-carboxamide;
(114) tert -butyl 4-( N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamido)piperidine -1-carboxylate;
(115) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (piperidin-4-yl)quinoxaline-2-car copy mid;
(116) N -((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl 1)quinoxaline-2-carboxamide;
(117) N -((5-(3-ethyl-4-fluorophenyl)thiophen-2-yl)methyl) -N- (2-fluorophenyl 1)quinoxaline-2-carboxamide;
(118) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (pyrazin-2-yl)quinoxaline-2-carboxyl mid;
(119) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (pyrimidin-5-yl)quinoxaline-2-car copy mid; and
(120) N -((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl) -N- (1H-pyrazol-4-yl)quinoxalin-2 -Carboxamides. According to claim 1,
A compound in which the compound of Formula 1 is a compound of Formula 3, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 3]

In the above formula,
R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-NH ₂ , -CO-NH ₂ , -SO ₂ -NH ₂ , or -OC _1-6 alkyl-OC _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxy each independently may be unsubstituted or substituted with 1 to 3 halogens;
R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;
R ₃ is C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, or -C _1-6 alkyl-5-6 membered hetero cyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and -C _1-6 alkyl-5-6 each membered heterocyclyl may be independently unsubstituted or substituted with 1 to 4 halogens, CN, -COOH, C _1-6 alkyl, or -CO-C _1-6 alkyl;
R ₄ is 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or -5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the above 5-10 membered heteroaryl, 5-10 membered heterocyclyl Cyclyl and -5-6 membered heteroaryl-5-6 membered heterocyclyl may each independently be unsubstituted or substituted with 1 to 4 halogen or C _1-6 alkyl;
The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. . According to claim 5,
R ₃ is C _1-6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl, or morpholinoethyl, wherein the C _1-6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl and morpholino each noethyl may be independently unsubstituted or substituted with 1 to 4 halogens, CN, -COOH, C _1-6 alkyl or -CO-C _1-6 alkyl;
R ₄ is pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl;

or

Wherein the pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl,

and

are each independently unsubstituted, or a compound that may be substituted with 1 to 4 halogens or C _1-6 alkyl, an isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 5 or 6,
Any one compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(121) N -((2-(4-fluoro-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(122) N -((2-(4-chloro-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(123) N- (2-fluorophenyl) -N -((2-(4-methoxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(124) N -((2-(4-(difluoromethoxy)phenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(125) N -((2-(4-(difluoromethoxy)-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide ;
(126) 6-chloro- N- (2-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)pyrazine-2-carboxamide ;
(127) N- (2-fluorophenyl)-6-morpholino- N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)pyrazine-2-carb copy mid;
(128) N - (2-fluorophenyl) - N - ((2- (3-methyl-4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) quinoxaline-2-carboxyl mid;
(129) N- (2-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(130) N- (4-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(131) N- (3-fluorophenyl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(132) N- (4-fluorophenyl) -N - ((2- (3-methyl-4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) quinoxaline-2-carboxyl mid;
(133) N- (pyridin-2-yl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(134) N- (pyridin-3-yl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(135) N- ethyl- N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(136) N- (2-fluorophenyl) -N -((2-(4-(trifluoromethoxy)piperidin-1-yl)thiazol-5-yl)methyl)quinoxaline-2- carboxamide;
(137) N- (pyridin-3-yl) -N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(138) 3-( N -((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamido)pyridin-1-ium chloride;
(139) N - (2-fluorophenyl) - N - ((2- (4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) -2,3-dihydrobenzo [b] [1,4]dioxin-2-carboxamide;
(140) N- (4-fluorophenyl) -N -((2-(4-(methoxymethoxy)-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide ;
(141) N- (4-fluorophenyl) -N -((2-(4-hydroxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(142) N -((2-(4-methoxyphenyl)thiazol-5-yl)methyl) -N- (3-methylpyridin-2-yl)quinoxaline-2-carboxamide;
(143) N -((2-(4-methoxyphenyl)thiazol-5-yl)methyl) -N- (pyrimidin-2-yl)quinoxaline-2-carboxamide;
(144) N- (2-fluorophenyl)-N-((2-(4-methoxyphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;
(145) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N -cyclopropylquinoxaline-2-carboxamide;
(146) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)picolinamide;
(147) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N- (4-cyanophenyl)quinoxaline-2-carboxamide;
(148) N -((2-(4-chlorophenyl)thiazol-5-yl)methyl) -N- (2-morpholinoethyl)quinoxaline-2-carboxamide;
(149) 4-( N -((2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide)benzoic acid;
(150) N -((2-(4-(aminomethyl)phenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(151) N -((2-(4-carbamoylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(152) N -((2-(4-carbamoyl-3-methylphenyl)thiazol-5-yl)methyl) -N- (2-fluorophenyl)quinoxaline-2-carboxamide;
(153) N- (2-fluorophenyl) -N -((2-(4-sulfomoylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; and
(154) N- (3-acetylphenyl) -N -((2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide. According to claim 1,
A compound in which the compound of Formula 1 is a compound of Formula 4, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 4]

In the above formula,
R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkyl, or C _1-6 alkoxy, wherein the C _1-6 alkyl and C _1-6 alkoxy are each independently unsubstituted, or 1 to 3 may be substituted with halogen;
R ₂ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with 1 to 3 halogens;
R ₃ is C _6-10 aryl or 5-6 membered heteroaryl, wherein the C _6-10 aryl and 5-6 membered heteroaryl are each independently unsubstituted, or 1 to 4 halogen or C _1-6 may be substituted with alkyl;
R ₄ is a 5-10 membered heteroaryl, wherein each of the 5-10 membered heteroaryls is independently unsubstituted or may be substituted with 1 to 4 halogen or C _1-6 alkyl;
The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S. According to claim 8,
R ₃ is phenyl or pyridinyl, wherein the phenyl and pyridinyl may each independently be unsubstituted or substituted with 1 to 4 halogen or C _1-6 alkyl;
R ₄ is pyrazinyl or quinoxalinyl, wherein the pyrazinyl and quinoxalinyl are independently unsubstituted or may be substituted with 1 to 4 halogens or C _1-6 alkyl, isomers thereof or a pharmaceutically acceptable salt thereof. The method of claim 8 or 9,
Any one compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(155) N- (2-fluorophenyl) -N -((5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2 -carboxamide;
(156) N - (2-fluorophenyl) - N - ((5- (3-methyl-4- (trifluoromethoxy) phenyl) -1,3,4-thiadiazol-2-yl) methyl ) quinoxaline-2-carboxamide; and
(157) N- (2-fluorophenyl) -N -((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline- 2-Carboxamide. For preventing or treating diseases caused by KRAS mutation or overexpression, comprising the compound according to any one of claims 1 to 10, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier pharmaceutical composition. According to claim 11,
A pharmaceutical composition wherein a disease caused by KRAS mutation or overexpression is cancer. According to claim 11 or 12,
The cancer is carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor, mesothelioma, schwanoma, meningioma ), adenocarcinoma, melanoma, leukemia, lymphoidmalignancy, squamous cell cancer, epithelial squamous cell cancer, lung cancer, Small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, liver cell hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer, ovarian cancer ( ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer endometrial or uterine carcinoma, salivary gland carcinoma, kidney and renal cancer, prostate cancer te cancer), vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer ), any one selected from the group consisting of biliary tract, colorectal cancer and head and neck cancer, a pharmaceutical composition. A method for preventing or treating a disease caused by KRAS mutation or overexpression, comprising administering the compound according to any one of claims 1 to 10, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject. Use of a compound according to any one of claims 1 to 10, an isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating a disease caused by KRAS mutation or overexpression.

Images