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WO2022249113A1 - Novel compound inhibiting binding between aimp2-dx2 and kras, and use thereof - Google Patents

Novel compound inhibiting binding between aimp2-dx2 and kras, and use thereof Download PDF

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Publication number
WO2022249113A1
WO2022249113A1 PCT/IB2022/054935 IB2022054935W WO2022249113A1 WO 2022249113 A1 WO2022249113 A1 WO 2022249113A1 IB 2022054935 W IB2022054935 W IB 2022054935W WO 2022249113 A1 WO2022249113 A1 WO 2022249113A1
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Prior art keywords
methyl
carboxamide
fluorophenyl
thiophen
quinoxaline
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PCT/IB2022/054935
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French (fr)
Korean (ko)
Inventor
이경
김성훈
김민경
김대규
이관식
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Zymedi Co Ltd
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Zymedi Co Ltd
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Priority to KR1020227021003A priority Critical patent/KR102870330B1/en
Publication of WO2022249113A1 publication Critical patent/WO2022249113A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel compounds inhibiting the binding between AIMP2-DX2 and KRAS, and use thereof ⁇ Novel compounds inhibit the binding between AIMP2-DX2 and KRAS, and use thereof ⁇
  • 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 a disease 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 the aminoacyl-tRNA synthetase (ARS) complex (Mult i_tRNA synthetase complex: MSC). In addition to its function for MSC formation, AIMP2 functions as a potent tumor suppressor through various mechanisms.
  • ARS aminoacyl-tRNA synthetase
  • MSC aminoacyl-tRNA synthetase complex
  • AIMP2 functions as a potent tumor suppressor through various mechanisms.
  • a I MP2-DX2 (ARS- interacting mult i functional protein 2- Exon 2 deleted), a variant in which AIMP2 has exon 2 deletion, is It is specifically expressed in cancer tissues such as lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, and osteosarcoma, and AIMP2-DX2 competitively binds to AIMP2's target protein to prevent AIMP2 from exerting its anticancer action, causing cancer. 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.
  • 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 2022/249113 ?01/162022/054935 ⁇ , normal cells can progress to malignancy. Mutations can be found in high levels in patients with pancreatic cancer, colon cancer, and lung cancer. According to previous studies The oncogenic variant, Sa Thing-u, was mutated binds to stabilize 1(1 and thus mutated Promote the differentiation and growth of tumor cells due to (Korean Patent Publication No. 2018-0015847 (published date: 2018.02.14)). therefore, Inhibition may be an important strategy in the treatment of cancer.
  • the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
  • X and are each independently 0 or ; 2022/249113 ?01/162022/054935
  • 3 ⁇ 4 is hydrogen, halogen, hydride 2, -0-(: 1-6 alkyl-0-(: 1-6 alkyl, -0-(:0-5-6 membered heteroaryl, -0-Xia 2 -(: 6-10 aryl, or -0 - (3 ⁇ 4- (: 6-1 () aryl, wherein - 6 alkyl, - 6 alkoxy , -0- (: 0-5-6 membered heteroaryl, -0- 50 2 -0 6-10 aryl, and 0-01 ⁇ 2-(: 6-1 () aryl each independently may be unsubstituted or substituted with 1 to 3 halogens or 01-6 alkyl;
  • 3 ⁇ 4 is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or 3 ⁇ 4 and 3 ⁇ 4, together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;
  • 3 ⁇ 4 is 01-6 alkyl, 0 3-8 cycloalkyl, Alkyl- 3 ⁇ 4- 8 cycloalkyl, 06-10 aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl heterocyclyl, wherein the above 0 1-6 alkyl, 0 3-8 cycloalkyl, -0 1-6 alkyl-3 ⁇ 4- 8 cycloalkyl, 0 6-10 aryl, -01-6 alkyl-(: 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and - - 6 alkyl- 5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, ⁇ - ⁇ (3 ⁇ 4, may be substituted with 0 1-6 alkyl, -(1)-inalkyl or -000-01-6alkyl; Myo 4 is -6 alkyl, -(1)-
  • the present invention provides a pharmaceutical preparation for preventing or treating diseases caused by 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 2022/249113 ?01/162022/054935 provides.
  • Figure 1 is (3) compound 44 and 0)) compound 48 according to the present invention It is a graph showing the results of evaluating the inhibitory effect of binding by measuring luciferase activity.
  • halogen means 01, or I unless otherwise specified.
  • '' - 6 alkyl means a linear or branched, saturated hydrocarbon residue having 1 to 6 carbon atoms.
  • 01-6 alkyl is methyl, ethyl, 11-propyl, isopropyl, 11-butyl, isobutyl, -Pentyl, isopentyl, neopentyl, pentyl, 1-methylbutyl, 11-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. Including but not limited to these.
  • an alkyl group may be substituted with one or more substituents, such as 1 to 3 halogen or 01-6 alkyl.
  • '' -6 alkoxy means an alkyl in the formula - ⁇ (:, for example, methoxy, ethoxy, 11-propoxy, isopropoxy, 11-butoxy, isobutoxy, ⁇ butoxy, 11 -Pentoxy, isopentoxy, including, but not limited to, neopentoxy, hexyloxy, and the like.
  • an alkoxy group may be substituted with one or more substituents, such as 1 to 3 halogen or 0 1-6 alkyl.
  • 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, In this case, the non-aromatic ring may have some degree of unsaturation.
  • the cycloalkyl group may be optionally substituted with one or more substituents.
  • 0 3-8 cycloalkyl is a monocyclic group having 3 to 8 carbon atoms.
  • 0 1 2 3 or 4 atoms of each ring of a cycloalkyl group may be substituted with a substituent.
  • cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclo but is not limited to hexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctyl, and the like.
  • Hydrocarbon refers to a 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 Aryl refers to an aromatic ring containing 6 to 10 carbon atoms.
  • heteroaryl 01 ra03 1) refers to an aromatic 5- to 10-membered monocyclic or bicyclic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. That is, heteroaryl is a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, or a bicyclic ring in which the heteroaryl ring is fused to a benzene ring or another heteroaryl ring. refers to 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 is not limited thereto.
  • bicyclic heteroaryls include indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzooxazolyl, 2022/249113 ?01/162022/054935 benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, purinyl, puropyridinyl and similar groups may be mentioned, but is not limited thereto.
  • Terms represents 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 0 and £.
  • the heterocyclyl may be a 5-membered or 6-membered aliphatic heterocycle, or a bicyclic ring in which the heterocyclyl ring is fused to a benzene ring or another heterocyclyl ring.
  • 0, 1, 2, 3, or 4 atoms of each ring of a heterocyclyl group may be substituted with a substituent.
  • heterocyclyl is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, dioxane Solyl, Piperidinyl, Tetrahydropyranyl, Tetrahydrothiopyranyl, Piperazinil, Morpholinil, Thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, Azefanil, Diazepa Nil, Homopiperazinyl, Oxazepanil, Indolyl, Isoindolyl, Dihydroindolyl, Dioxoisoindolinyl, Dihydrofuryl, Dihydroimidazolinyl, Dihydrooxazolyl, Dihydrobenzodioxy nyl
  • substitution refers to the replacement of a hydrogen atom in a molecular structure with a substituent such that the valency (>3163 ⁇ 4:6) on the designated atom is not exceeded and the compound is chemically stable from such substitution.
  • group show is substituted with substituent 8 means that a hydrogen atom bonded to an atom such as carbon constituting the backbone of group show is replaced with a substituent moiety, and group show and substituent 8 form a covalent bond.
  • the present invention provides a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:
  • X and are each independently 0 or ;
  • 3 ⁇ 4 is hydrogen, halogen, hydride ⁇ 2 , -0- ⁇ - 6 alkyl- 0- - 6 alkyl, -0-(: 0-5-6 membered heteroaryl, uh-, aryl, or -0 - (3 ⁇ 4-(: 6-1() aryl, wherein the above -6 alkyl, -6 alkoxy, -0-(: 0-5-6 membered heteroaryl, -0- 50 2 -0 6-10 aryl, and 0-01 ⁇ 2-(: 6-1( ) each aryl can be independently unsubstituted or substituted with 1 to 3 halogen or 01-6 alkyl,
  • 3 ⁇ 4 is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or 3 ⁇ 4 and 3 ⁇ 4, together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;
  • 3 ⁇ 4 is 01-6 alkyl, 0 3-8 cycloalkyl, -6 alkyl- 3 ⁇ 4- 8 cycloalkyl, 0 6-10 aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl , 5-6 membered heterocyclyl or Heterocyclyl, wherein the above 0 1-6 Alkyl, 0 3-8 Cycloalkyl, -0 1-6 Alkyl- 3 ⁇ 4- 8 Cycloalkyl, 0 6-10 Aryl, -01-6 Alkyl- (: 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and - - 6 alkyl-5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, ⁇ - ⁇ (3 ⁇ 4, may be substituted with 0 1-6 alkyl, -(1)-inalkyl or -000-01-6alkyl; seed 4 is -6 alkyl,
  • a methoxy group (-0 to 3 ) may be substituted with 1 to 3 halogens to be in the - ⁇ or - form;
  • the above -0- (1)-furanyl, -0-x 2 -phenyl and -0-to 2 -phenyl are for example
  • 3 ⁇ 4 in the compound of Formula 1 may be hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens. Specifically, the 3 ⁇ 4 is - Yes, but is not limited thereto.
  • 3 ⁇ 4 and 3 ⁇ 4 in the compound of Formula 1, together with the benzene ring to which they are attached, form a benzodioxol, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring can For example, 3 ⁇ 4 and 3 ⁇ 4 in the compound of Formula 2, together with the benzene ring to which they are attached, It can form a ring shape.
  • 3 ⁇ 4 is -6 alkyl, 3 ⁇ 4- 8 cycloalkyl, -01 ⁇ 2 3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, 2022/249113 1 ⁇ (:1 ⁇ 2022/054935 tetrahydropyranyl, piperidinyl or morpholinoethyl, wherein the above 01-6alkyl, 0 3-8 cycloalkyl, _01 ⁇ 2_(: 3-8 cycloalkyl, Phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, tetrahydropyranyl, piperidinyl and morpholinoethyl are each independently unsubstituted or 1 to 4 halogen, ⁇ _(:0(3 ⁇ 4, - 6 alkyl, - ⁇ units , can form As an embodiment
  • the compound of Formula 1 may be a compound of Formula 2 below: 2022/249113 ?01/162022/054935
  • 3 ⁇ 4 is hydrogen, halogen, hydroxy, -6 alkyl, -6 alkoxy, _0 to (1) -5-6 membered heteroaryl, -0-502_06-10 aryl, or -0 1 ⁇ 2-06-10 aryl,
  • the 01-6 alkyl, 01-6 alkoxy, _ 0 - 0) -5-6 membered heteroaryl, -0-502-06-10 aryl, and 0- ⁇ 2-06-10 aryl are each independently substituted or may be substituted with 1 to 3 halogens or 01-6 alkyl,
  • 3 ⁇ 4 is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or 3 ⁇ 4 and , together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;
  • Cat 3 is 0 3 -8 cycloalkyl, -01-6 alkyl- 3 ⁇ 4- 8 cycloalkyl, 06-10 aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl, or 5- 6-membered heterocyclyl, wherein the 3 ⁇ 4- 8 cycloalkyl, aryl, 5-6-membered heteroaryl and 5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, 01-6 alkyl , or -000-01-6 alkyl;
  • Key 4 is -6 alkyl, -(1)-internal alkyl,
  • 3 ⁇ 4 is hydrogen, halogen, hydroxy, 0 1-6 alkyl, -6 alkoxy, -0 -(1) -furanyl, -0-30 2 -phenyl, or -0- (:3 ⁇ 4-phenyl, wherein the above 0 1 - 2022/249113 1 ⁇ (:1 ⁇ 2022/054935
  • 6 alkyl , 01-6 alkoxy , -0- (1)-furanyl , _0-x 2 -phenyl and -0- (3 ⁇ 4-phenyl are each independently unsubstituted, or with 1 to 3 halogen or 01-6 alkyl can be substituted.
  • methoxyoxy (-0(:3 ⁇ 4) may be substituted with 1 to 3 halogens to form - ⁇ or -0CF 2 H;
  • the -0- (: 0 -furanyl, -0-x 2 -phenyl and -0- (3 ⁇ 4-phenyl are, for example have.
  • 3 ⁇ 4 in the compound of Formula 2 may be hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens. Specifically, the 3 ⁇ 4 is - Yes, but is not limited thereto.
  • 3 ⁇ 4 and 3 ⁇ 4 in the compound of Formula 2 together with the benzene ring to which they are attached, form a benzodioxol, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring can For example, in the compound of Formula 2, 3 ⁇ 4 and 2 are together with the benzene ring to which they are attached. It can form a ring shape.
  • parent 3 is 03-8 cycloalkyl, _ (]3 ⁇ 4-03-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrazolyl, tetrahydropyranyl or piperidinyl, , wherein the above 3 ⁇ 4- 8 cycloalkyl, _01 ⁇ 2_ (: 3-8 cycloalkyl, phenyl, benzyl.
  • Pyridinyl , pyrazolyl , tetrahydropyranyl and piperidinyl are each independently unsubstituted or represented by 1 to 4 halogen, 01-6 alkyl, or -000-01-6 alkyl.
  • Cat 4 is 01-6 alkyl-00-01-6 alkyl, phenyl, naphthyl, -(1)-phenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyra Zinyl, Benzofuranil, Quinoxalinil, Dihydrobenzodioxinyl, , wherein the 0 1-6 alkyl, -(1)- -6 alkyl, phenyl, naphthyl, -(1)-phenyl, furanyl, oxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxalinyl, dihydrobenzo deoxinyl, Each may be independently unsubstituted or substituted with 1 to 4 halogens, - 2 , _ ⁇ 2 , -0 ⁇ , 0 1-6
  • the compound of Formula 1 may be a compound of Formula 3 below:
  • 3 ⁇ 4 is hydrogen, halogen , hydroxy , -6 alkyl , -6 alkoxy ,(:1-6 alkyl- 2 , _(:0-50 2 2 , or alkyl within -alkyl, wherein the above 01- 6 alkyl and 01-6 alkoxy each independently may be unsubstituted or substituted with 1 to 3 halogen; parent 2 is hydrogen, 01-6 alkyl, or 01-6 alkyl substituted with 1 to 3 halogens; Symptom 3 is 01-6 alkyl, 0 3-8 cycloalkyl, 06-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, or - - 6 alkyl-5-6 membered heterocyclyl; wherein the 0 1-6 alkyl, 3 ⁇ 4- 8 cyclo 5-6 membered heteroaryl , 5-6 membered heterocyclyl and -0 1-6 2022/249113 ?01/162022/054935 alkyl-5-6 member
  • 3 ⁇ 4 is hydrogen, halogen, hydroxy, 01-6 alkyl, 01-6 alkoxy, 01-6 alkyl 3 ⁇ 4, -(1)-e2, -302 _ 1 ⁇ 3 ⁇ 4 , or -0-03 ⁇ 4-0-03 ⁇ 4, wherein the 01-6alkyl and 01-6alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens.
  • methoxyoxy (-0(:3 ⁇ 4) may be substituted with 1 to 3 halogens to be in the form of -00 or - «.
  • 3 ⁇ 4 may be hydrogen, -6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens.
  • 3 ⁇ 4 is - , and is not limited thereto.
  • 3 ⁇ 4 is -6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl, or morpholinoethyl, wherein the 01-6 alkyl, cyclopropyl, phenyl, pyridinyl , pyrimidinyl and morpholinoethyl may each independently be unsubstituted or substituted with 1 to 4 halogens, ⁇ _(:0(3 ⁇ 4, -6 alkyl or -00-01-6 alkyl.
  • the 3 ⁇ 4 is, for example, ethyl, 2022/249113 1 ⁇ (:1 ⁇ 2022/054935
  • 3 ⁇ 4 is pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl, Wherein the pyridinyl
  • the grave 4 is, for example and is not limited thereto.
  • Specific examples of the compound represented by Formula 3 according to the present invention are as follows, but are not limited thereto:
  • the compound of Formula 1 may be a compound of Formula 4 below:
  • 3 ⁇ 4 is hydrogen, halogen , hydroxy , 0 1-6 alkyl , or 0 1-6 alkoxy, wherein the 0 1-6 alkyl and 0 1-6 alkoxy are each independently unsubstituted, or with 1 to 3 halogen can be substituted;
  • 3 ⁇ 4 is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens;
  • Cat 3 is 0 6-10 aryl or 5-6 membered heteroaryl, wherein the 0 6-10 aryl and 5-6 membered heteroaryl are each independently unsubstituted, or 1 to 4 halogen or 01-6 alkyl may be substituted with;
  • parent 4 is a 5-10 membered heteroaryl, wherein each of the 5-10 membered heteroaryls may be independently unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl; 2022/249113 ?01/162022/054935
  • the heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £.
  • 3 ⁇ 4 in the compound of Formula 4 is phenyl or pyridinyl, wherein the phenyl and pyridinyl may each independently be unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl.
  • the 3 ⁇ 4 is for example and is not limited thereto.
  • 3 ⁇ 4 is pyrazinyl or quinoxalinyl, wherein the pyrazinyl and quinoxalinyl are each independently unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl It can be.
  • the grave 4 is, for example and is not limited thereto.
  • Specific examples of the compound represented by Formula 4 according to the present invention are as follows, but are not limited thereto:
  • 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.
  • the pharmaceutically acceptable salt may be an acid addition salt formed by a pharmaceutically acceptable free acid ( ⁇ 66%).
  • An inorganic acid or an organic acid may be used as the free acid, wherein the inorganic acid is 2022/249113 ?01/162022/054935 Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc.
  • organic acids may be acetic acid, methanesulfonic acid, ethanesulfonic acid, I) -toluenesulfonic acid, fumaric acid, maleic acid, malic acid ronic 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 excess acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile It can be.
  • 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. .
  • the compounds of the present invention may have a chiral carbon center and thus may exist in the form of myo or £ isomers, racemates, individual enantiomers or mixtures, individual diastereomers or mixtures, all such stereoisomers. and mixtures thereof may fall within the scope of this invention.
  • 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, each of the hydrate and the solvate may be a combination of 1 to 5 molecules of water and an alcoholic solvent (eg, ethanol).
  • the present invention provides a preparation method for the compound of Formula 1.
  • 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.
  • the compound represented by Formula 1 of the present invention can be prepared by a person skilled in the art by various methods using known techniques well known in the art. 2022/249113 ?01/162022/054935 You will understand.
  • 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 sequence.
  • Step a MOM protection Prior to carrying out the Suzuki coupling reaction of step b, the starting material with phenolic hydroxyl groups is MOM-CKChloromethyl methyl ether: Chloromethyl methyl ether) , DIPEA ( ⁇ diisopropylethylamine) and DCM (CH 2 C1 2 ) were added and methoxymethyl (M0M) ether was formed by stirring for 12 hours while slowly raising the temperature from 0 ° C to room temperature to form phenol The acidic hydroxyl group was protected.
  • Step b Suzuki Coupling
  • Step 0 Reductive Amination (Mo6(!11(:1: 1 6 1 ⁇ 2 1 18011) 2022/249113 ?01/162022/054935
  • Aryl amine (2.0 equiv) and a catalytic amount of acetic acid were added to a solution of the aldehyde of C3 ⁇ 4C1 2 (1.0 equiv).
  • the reaction mixture was stirred at room temperature while observing through TLC until imine was completely formed.
  • Excess methanol (MeOH) was evaporated and the residue was redissolved in tetrahydrofuran (THF).
  • 1.0M NaCNB3 ⁇ 4 in THF 1.1 equivalents
  • 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.
  • 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.
  • prevention refers to all actions that inhibit or delay the occurrence, spread, and recurrence of the disease by administration of a compound or pharmaceutical composition according to the present invention
  • ''Treatment'' refers to all activities in which the symptoms of the disease are improved or beneficially changed by administration of the compound or pharmaceutical composition according to the present invention.
  • 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.
  • 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.
  • 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 cancer, and includes various cancer types known in the art. Other cancers include 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.
  • 2022/249113 1 ⁇ (:1 ⁇ 2022/054935 may include, but is not limited to, other types of cancer cells include glioma (schwannoma, glioblastoma, astrocytoma), neuroblastoma, brown Cytocytoma, paraganglioma, meningioma, adrenocortical cancer, medulloblastoma, rhabdomyosarcoma, kidney cancer, various types of vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine myoma, salivary gland cancer, choroidal cancer, Breast cancer, pancreatic cancer, colon cancer, colorectal cancer and megakaryocytic leukemia; and malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, Skin cancer including keloid,
  • squamous cell cancer squamous cell carcinoma ( epithelial squamous cell cancer, lung cancer, small-cell lungcancer, non-small cell lungcancer, adenocarcinoma of the lung, 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, prostate cancer, vulvalcancer, thyroid cancer ), hepatic carcinoma, 2022/249113 ?01/162022/054935 anal carcinoma, penile carcinoma,
  • the pharmaceutical composition of the present invention can inhibit the activity or expression of KRAS.
  • 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.
  • the pharmaceutically acceptable carrier is one commonly used when formulating, 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.
  • 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 dependent on the condition and weight of the patient, and the severity of the disease. , depending on the drug type, route of administration and time, but 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.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at 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 can be determined according to sensitivity to drugs, administration time, route of administration and excretion rate, treatment period, factors including drugs used simultaneously, and other factors well known in the medical field. or in combination with other treatments 2022/249113 ?01/162022/054935 can be administered, sequentially or concurrently with conventional therapeutic agents, and single or multiple administrations. Considering all of the above factors, it is important to administer the 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.
  • 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, inactivity rate and excretion rate of the active ingredient in the body, disease type, and concomitant drugs, and in general, body weight 0.001 to 150, preferably 0.01 to 100 per 113 ⁇ 4 can 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, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the present invention provides a method for preventing, controlling or treating cancer comprising administering the pharmaceutical composition to a subject.
  • ''subject'' means a subject in need of treatment of a disease, and more specifically, mammals such as humans or non-human primates, mice (11101136), dogs, cats, horses, and cattle. it means.
  • mammals such as humans or non-human primates, mice (11101136), dogs, cats, horses, and cattle. it means.
  • 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.
  • Step 1 Synthesis of 5-(4-methoxy-3-methylphenyl)thiophene-2-carboxaldehyde (1(( ⁇ ?0(:1 2 .(:3 ⁇ 4(:1 2 (0.05 equivalent)) Degassed 5-bromothiophene-2-carboxaldehyde (5-1) 1'011101;11101) 11016-2 in ,4-dioxane(1,4-(110X3116) :3 ⁇ 40(4:1): 31'1) 0 table 31 (1613 ⁇ 4 wire 6) (1 equivalent) , 4 -methoxy-3-methylphenylboronic acid (4 - 11161;110 table 3161;11> ⁇ 11) 11611> ⁇ 11) 01'011 3 ((1) (1.2 equiv.), and (2 equiv.) were added to the solution.
  • Step 2 Synthesis of 2-Fluoro- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)aniline 2022/249113 ?01/162022/054935
  • Acetic acid ( ⁇ 3 (1) (2 equivalents): 5- (4 -methoxy- 3 -methylphenyl) thiophene- 2-carboxaldehyde (1 equivalent) and 2
  • -fluoroaniline 11101'0311111116
  • Step 2 Synthesis of (5-(3 -methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methanamine 5-(3-methyl-4-(trifluoroethylene) in ethanol (2 11 ) fluoromethoxy) phenyl) thiophene- 2- Hydroxylammonium chloride (40.8 1 , 0.59 1 1 0 1) was added to a solution of 2022/249113 ?01/162022/054935 carbaldehyde (140.0 1 , 0.49 ⁇ 0 1 ) and the reaction mixture was stirred at room temperature for 1 hour.
  • hydrochloric acid (12 3 ⁇ 41, 163.3 I ⁇ ) and zinc dust (80 1 , 1.23 1 1 0 1) were slowly added to the solution and the mixture was stirred at room temperature for 15 minutes.
  • Step 3 Synthesis of ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 112) Under Argon Atmosphere
  • 5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methanamine (10.5 11 ⁇ , 0.04 1 1 0 1) in pyridine (3 phase) at room temperature
  • 2-quinoxaloyl chloride (12.7 14, 0.07 ⁇ 01) was added.
  • the reaction mixture was stirred for 15 minutes while slowly ramping to 801:.
  • Step 1 General Procedure for Synthesis of 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde (Suzuki coupling: 31 11 nin 111) 111 pyeong) 2022/249113 ?01/162022/054935
  • Step 3 ⁇ (2-fluorophenyl)- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide ( Synthesis of Compound 129) General Procedure 0( Acylation, ⁇ 8071811011)
  • Step 1 Synthesis of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate (12) In a round bottom flask was added ethyl 5-bromo-1 ,3,4-thiadiazole-2-carboxylate (ethyl 5- bromo-l,3,4-thiadiazole-2-carboxylate), (4- (trifluoromethoxy) phenyl) boronic acid ((4 - (trifluoromethoxy)pheny1)boronic acid), Pd(0Ac)2 and xantphos.
  • ethyl 5-bromo-1 ,3,4-thiadiazole-2-carboxylate ethyl 5- bromo-l,3,4-thiadiazole-2-carboxylate
  • (4- (trifluoromethoxy) phenyl) boronic acid ((4 - (trifluoromethoxy)pheny1)boronic acid)
  • 1,4-dioxane (1,4-0 Table 3116): 3 ⁇ 40, 95 ° C, 12 hours; (b) i) 2-fluoroaniline (2_ fluoroani l ine), catalyst acetic acid (cat. acet ic acid), MeOH, ii) 1.0 M NaB3 ⁇ 4CN in tetrahydrofuran (THF), tetrahydrofuran ( THF), room temperature, 12 hours; (c) 2-quinoxaloyl chloride, triethylamine, CH2CI2, 0 ° C to room temperature, 12 hours; (d) propargyl amine, HATU, DIPEA, DMF, room temperature, 24 hours; (e) (PhSe) 2 , selectfluor, 3 ⁇ 40, CH 3 CN, room temperature, 12 hours; (f) ethyl 5-bromo- 1,3,4-thiadiazole- 2-carboxylate (ethyl 5-bromo-
  • RBF is ethyl 5 -bromo- 1,3, 4 -thiadiazole- 2 -carboxylate (ethyl 5_br omo_ 1,3,4- thiadiazole-2-carboxylate) , (4- (trifluoromethoxylate) )phenyl)boronic acid ((4-
  • Nano-Glo live cell assay system kit (Nanc ⁇ Glo Live Cel 1 Assay System Kit , Pro omega)
  • LgBiT-PRKAR2A PRKAR2A capable of co-expressing LgBiT
  • SmBiT-PRKACA (Biocon): Experimental example of PRKACA capable of co-expressing SmBiT 1. Protocol First, 200 6 pieces of 010-1 (100x15 cells were seeded on a cell culture dish and cultured for 24 hours). 2022/249113 ?01/162022/054935 Cells were transfected. Transfection
  • a 1.5 mL Eppendorf tube was prepared and each 4 yg of LgBiT-AIMP2-DX2 and SmBiT-KRAS was added thereto.
  • 600 y L of preheated serum-free RPMI medium was added to the tube containing the plasmid.
  • 16 y L of Turbofect was then added to the tube, mixed by vortexing for 5 seconds and left for 15 minutes.
  • 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 a cell culture dish, mixed gently, and incubated in a C0 2 incubator for 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 lOmL of RPMI growth medium. After adding 0.4% of 10 y L of trypan blue dye to 10 y L 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 y L of serum-free RPMI medium supplemented with the compound (3 yM) 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.
  • Nano-Glo Live Cell Assay Preparation Nano-Glo ® LCS dilution buffer was thawed and allowed to equilibrate to room temperature before use. 4 yg each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. 1.25 volume of Nano-Glo ® Live Cell substrate and 23.75 volume of Nano-Glo ® LCS dilution buffer were combined and mixed well by vortexing to obtain a predetermined amount of reconstituted Nano-Glo ® Live Cell reagent. 2022/249113 -01/162022/054935 was prepared.
  • Nano-Glo ® Live Cell l Reagents were mixed well by vortexing. After adding 25 y L of the prepared Nano-Glo ® Live Cell l reagent to all wells, the cells were incubated for 10 minutes in a humidified incubator at 37 ° C and 5% C0 2 conditions. Experimental Example 2. Confirmation of selectivity
  • a 1.5 mL Eppendorf tube was prepared and 4 yg each of LgBiT_PRKAR2A and SmBiT-PRKACA were added thereto.
  • the mixture was mixed by vortexing for 5 seconds.
  • 16 y L 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 a cell culture dish, mixed gently, and incubated in a C0 2 incubator for 4 hours. After 4 hours, the medium was exchanged with fresh cell culture medium.
  • the cells were removed from the culture dish and suspended in lOmL of RPMI growth medium. After adding 10 yL of trypan blue dye 0.4% to 10 yL of the cell suspension, the number of cells was immediately counted using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a flat bottom white 96-well plate. After 24 hours, the cell culture medium was removed, and 100 y L of serum-free RPMI medium supplemented with the compound (3 yM) was added to the cell plate for 4 hours. 2022/249113 -01/162022/054935 cultured. After 4 hours, Nanoluci ferase activity was measured at a measurement time of 0.4 seconds/well using the Glomax Discover Microplate Reader as follows.
  • Nano-Glo Ni 0611 Assay Preparation Nano-Glo® LCS Dilution Buffer was thawed and allowed to equilibrate to room temperature before use. 4 each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo® Live Cell 1 reagent was prepared by combining 1.25 volumes of Nano-Glo® Live Cell 1 substrate and 23.75 volumes of Nano-Glo® LCS dilution buffer and mixing well by vortexing.
  • Nano-Glo® Live Cell l Reagents were prepared for each experiment, and the reagent preparation procedure was performed under dark conditions.
  • Nano-Glo® Live Cell l Reagents were mixed well by vortexing. After adding 25 y L of the prepared Nano-Glo® Live Cell l reagent to all wells, it was incubated for 10 minutes in a humidified incubator at 37 ° C and 5% C0 2 conditions.
  • Experimental Example 3 Confirmation of dose dependence
  • the reaction mixture was added to the cell culture dish, mixed gently, and incubated in a C0 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 lOmL of RPMI growth medium. After adding 0.4% of 10 of trypan blue dye to 10 of the cell suspension, the cell number was immediately counted using a Countess II FL Automated Cell Counter. Based on the pre-determined cell number, 25,000 transfected cells were seeded in white flat-bottom 96-well plates.
  • Nano-Glo Live Cell Assay Preparation Nano-Glo ® LCS Dilution Buffer was thawed and allowed to equilibrate to room temperature before use. 4 each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo ® Live Cell 1 reagent was prepared by combining 1.25 volumes of Nano-Glo ® Live Cell 1 substrate and 23.75 volumes of Nano-Glo ® LCS dilution buffer and mixing well by vortexing.
  • Nano-Glo ® Live Cell l Reagents were mixed well by vortexing. After adding 25 y L of the prepared Nano-Glo ® Live Cell l reagent to all wells, the cells were incubated for 10 minutes in a humidified incubator at 37 ° C and 5% C0 2 conditions. 2022/249113 1 ⁇ (:1 ⁇ 2022/054935 The experimental results are shown in Table 4 below.

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Abstract

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

Description

2022/249113 ?01/162022/054935 2022/249113 ?01/162022/054935

【발명의 설명】 【Description of Invention】

【발명의 명칭】 【Name of Invention】

AIMP2-DX2와 KRAS의 결합을 억제하는 신규 화합물 및 이의 용도 {Novel compounds inhibi t ing the binding between AIMP2-DX2 and KRAS, and use thereof} Novel compounds inhibiting the binding between AIMP2-DX2 and KRAS, and use thereof {Novel compounds inhibit the binding between AIMP2-DX2 and KRAS, and use thereof}

【기술분야】 본 발명은 AIMP2-DX2와 KRAS의 결합을 억제하는 활성을 갖는 신규 화합물 , 및 KRAS 돌연변이나 과발현으로 인한 질환, 예컨대 암을 예방 또는 치료하기 위한 이의 용도에 관한 것이다. [Technical Field] 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 a disease caused by KRAS mutation or overexpression, such as cancer.

【발명의 배경이 되는 기술】 【Technology behind the invention】

AIMP2(aminoacyl-tRNA synthetase-interact ing mult i funct ional protein 2)는 아미노아실- tRNA 합성효소 (aminoacyl-tRNA synthetase, ARS) 복합체 (Mult i_tRNA synthetase complex: MSC)의 형성에 관여하는 단백질 중의 하나이다. AIMP2는 MSC 형성을 위한 기능 외에도, 다양한 기전을 통해 강력한 암 억제자 (tumor suppressor)로서의 기능을 수행한다. 한국특허공개공보 제 2006-0058014호 (공개일 : 2006.05.29)에서는 AIMP2의 엑손 2가 결손된 형태의 변이체인 A I MP2-DX2 ( ARS- interact ing mult i funct ional protein 2- Exon 2 deleted)가 폐암, 간암, 유방암, 피부암, 신장암, 골육종 등의 암 조직에서 특이적으로 발현되며 , AIMP2-DX2가 AIMP2의 타겟 단백질에 경쟁적으로 결합하여 AIMP2가 암 억제 작용을 발휘하지 못하게 하므로, 암을 유발하는 원인이 되고, 따라서 AIMP2-DX2의 생성을 억제하면 암을 예방 또는 치료할 수 있다고 보고한 바 있다. AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is one of the proteins involved in the formation of the aminoacyl-tRNA synthetase (ARS) complex (Mult i_tRNA synthetase complex: MSC). In addition to its function for MSC formation, AIMP2 functions as a potent tumor suppressor through various mechanisms. In Korean Patent Publication No. 2006-0058014 (published date: 2006.05.29), A I MP2-DX2 (ARS- interacting mult i functional protein 2- Exon 2 deleted), a variant in which AIMP2 has exon 2 deletion, is It is specifically expressed in cancer tissues such as lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, and osteosarcoma, and AIMP2-DX2 competitively binds to AIMP2's target protein to prevent AIMP2 from exerting its anticancer action, causing cancer. It has been reported that suppressing the production of AIMP2-DX2 can prevent or treat cancer.

KRAS는 암 세포에서 가장 빈번하게 변형되는 종양 형성 유전자로 잘 알려져 있다. 뿐만 아니라 암 환자의 생존률 감소에 영향을 미치며 , 초기 진단을 통한 처방에도 어려움을 주는 요소이다. KRAS가 암 치료에 중요한 타겟임에도, 암세포 내의 KRAS 단백질의 세포내 수준 조절에 관한 연구가 잘 밝혀져 있지 않다. 2022/249113 ?01/162022/054935 ¬에 돌연변이가 발생하면, 정상세포는 악성으로 진행할

Figure imgf000004_0001
돌연변이는췌장암, 대장암, 폐암등의 환자에서 높게 발견할 수 있다. 이전 연구에 따르면
Figure imgf000004_0002
종양 발생 변이체인 사 씽- 으가 돌연변이된
Figure imgf000004_0003
결합하여 1（1 를 안정화시키며 따라서 돌연변이된
Figure imgf000004_0004
인한 종양세포의 분화와 성장을 촉진한다（한국특허공개공보 제 2018-0015847호（공개일: 2018.02.14））. 그러므로,
Figure imgf000004_0005
억제가 암의 치료에 중요한 전략이 될 수 있다. 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 2022/249113 ?01/162022/054935 ¬, normal cells can progress to malignancy.
Figure imgf000004_0001
Mutations can be found in high levels in patients with pancreatic cancer, colon cancer, and lung cancer. According to previous studies
Figure imgf000004_0002
The oncogenic variant, Sa Thing-u, was mutated
Figure imgf000004_0003
binds to stabilize 1（1 and thus mutated
Figure imgf000004_0004
Promote the differentiation and growth of tumor cells due to (Korean Patent Publication No. 2018-0015847 (published date: 2018.02.14)). therefore,
Figure imgf000004_0005
Inhibition may be an important strategy in the treatment of cancer.

【발명의 내용】 【Contents of the invention】

【해결하고자하는과제】 본 발명의 하나의 목적은 사 씽- 요와 四^ 간의 결합 억제제로서 유용한 신규 화합물, 이의 이성질체 또는 이의 약학적으로허용가능한염을 제공하는 것이다. 본 발명의 다른 목적은

Figure imgf000004_0006
결합 억제제로서 유용한 신규 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 포함하는, 1¾ 3 돌연변이나 과발현으로 인한 질환, 예컨대 암을 예방 또는 치료하기 위한 약학 조성물을 제공하는것이다. [PROBLEMS TO BE SOLVED] One object of the present invention is to provide a novel compound, an isomer thereof, or a pharmaceutically acceptable salt thereof useful as an inhibitor of the binding between ssing-yo and ss^. Another object of the present invention is
Figure imgf000004_0006
To provide a pharmaceutical composition for preventing or treating a disease caused by 1¾ 3 mutation or overexpression, such as cancer, including a novel compound useful as a binding inhibitor, an isomer thereof, or a pharmaceutically acceptable salt thereof.

【과제의 해결 수단】 상기 목적을 달성하기 위하여 , 본 발명은 하기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로허용가능한 염을 제공한다: [Means for solving the problems] In order to achieve the above object, the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:

【화학식 1]

Figure imgf000004_0007
상기 식에서, [Formula 1]
Figure imgf000004_0007
In the above formula,

X 및 는각각독립적으로 0또는 이고; 2022/249113 ?01/162022/054935 X and are each independently 0 or ; 2022/249113 ?01/162022/054935

¾은 수소, 할로겐 , 하이드

Figure imgf000005_0001
■2, -0-（：1-6알킬- 0-（：1-6알킬, -0-（：0-5-6원 헤테로아릴, -0-쌨2-（：6-10아릴, 또는 -0 - （¾-（：6-1（）아릴이고, 이때 상기 -6알킬, -6알콕시 , -0-（：0-5-6원 헤테로아릴, -0- 502-06-10 아릴, 및 0-0½-（：6-1（） 아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로 치환될 수 있고, ¾ is hydrogen, halogen, hydride
Figure imgf000005_0001
2, -0-(: 1-6 alkyl-0-(: 1-6 alkyl, -0-(:0-5-6 membered heteroaryl, -0-Xia 2 -(: 6-10 aryl, or -0 - (¾- (: 6-1 () aryl, wherein - 6 alkyl, - 6 alkoxy , -0- (: 0-5-6 membered heteroaryl, -0- 50 2 -0 6-10 aryl, and 0-0½-(: 6-1 () aryl each independently may be unsubstituted or substituted with 1 to 3 halogens or 01-6 alkyl;

¾는 수소, 01-6알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6알킬이거나; 또는 ¾및 ¾는, 이들이 부착된 벤젠 고리와 함께 , 5- 10원 헤테로사이클릴 또는 5 - 10원 헤테로아릴을 형성할 수 있고; ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or ¾ and ¾, together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;

¾는 01-6 알킬 , 03-8 사이클로알킬 ,

Figure imgf000005_0002
알킬- ¾-8 사이클로알킬 , 06-10 아릴 , -01-6 알킬-（：6-10 아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴
Figure imgf000005_0003
헤테로사이클릴이고 , 이때 상기 01-6 알킬 , 03-8 사이클로알킬 , -01-6 알킬- ¾-8 사이클로알킬, 06-10 아릴, -01-6 알킬-（:6-10 아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴 및 - -6 알킬- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 , ^ -¥（¾, 01-6알킬 , -⑴- 내알킬 또는 -000- 01-6알킬로 치환될 수 있고; 묘4는 -6알킬, -⑴- -6알킬,
Figure imgf000005_0004
헤테로아릴 , 5- 10원 헤테로사이클릴, 또는 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 01- 6 알킬, -⑴- -6 알킬, 06-10 아릴, -00-06-10 아릴, 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴 및 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐,
Figure imgf000005_0005
_炯2, _¥（¾, 01-6 알킬, 01-6 알콕시 , 또는 - ■-（：0-（：1-6알킬로 치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 지방족 헤테로고리이다. 또한, 본 발명은 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 담채를 포함하는, ^ 돌연변이나 과발현으로 인한 질환, 예컨대 암을 예방 또는 치료하기 위한 약학 조성물을 2022/249113 ?01/162022/054935 제공한다. ¾ is 01-6 alkyl, 0 3-8 cycloalkyl,
Figure imgf000005_0002
Alkyl- ¾- 8 cycloalkyl, 06-10 aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl
Figure imgf000005_0003
heterocyclyl, wherein the above 0 1-6 alkyl, 0 3-8 cycloalkyl, -0 1-6 alkyl-¾- 8 cycloalkyl, 0 6-10 aryl, -01-6 alkyl-(: 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and - - 6 alkyl- 5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, ^ -¥ (¾, may be substituted with 0 1-6 alkyl, -⑴-inalkyl or -000-01-6alkyl; Myo 4 is -6 alkyl, -⑴- -6 alkyl,
Figure imgf000005_0004
Heteroaryl , 5-10 membered heterocyclyl, or -5-6 membered heteroaryl- 5-6 membered heterocyclyl, wherein the above 0 1 -6 alkyl, -⑴- -6 alkyl, 0 6 -10 aryl, -00-06-10 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 dog halogen,
Figure imgf000005_0005
_炯2, _¥（¾, 01-6 alkyl, 01-6 alkoxy , or - ■-(:0-(: 1-6 alkyl; The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. In addition, the present invention provides a pharmaceutical preparation for preventing or treating diseases caused by 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 2022/249113 ?01/162022/054935 provides.

【발명의 효과】 본 발명의 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한

Figure imgf000006_0001
세포내 수준을 감소시키는 효과가 있으므로,
Figure imgf000006_0002
돌연변이나과발현이 원인이 되는질환, 예컨대 암의 예방 또는 치료에 유용하게 사용될 수 있다. [Effect of the invention] The compound of formula 1, an isomer thereof or a pharmaceutically acceptable compound of the present invention
Figure imgf000006_0001
Because it has the effect of reducing intracellular levels,
Figure imgf000006_0002
It can be usefully used for the prevention or treatment of diseases caused by mutation or overexpression, such as cancer.

【도면의 간단한설명】 도 1은 본 발명에 따른 (3) 화합물 44 및 0)) 화합물 48에

Figure imgf000006_0003
결합의 억제효능을루시퍼라제 활성 측정으로평가한결과를나타낸그래프이다. [Brief description of the drawings] Figure 1 is (3) compound 44 and 0)) compound 48 according to the present invention
Figure imgf000006_0003
It is a graph showing the results of evaluating the inhibitory effect of binding by measuring luciferase activity.

【발명을실시하기 위한구체적인 내용】 이하 본 발명을보다구체적으로설명한다. 본 발명에서 용어 "할로겐”은다른 언급이 없으면 01, 또는 I를의미한다. 용어 ’’ -6알킬”은 1 내지 6개의 탄소 원자를 갖는 선형 또는 분지형의 포화된 탄화수소 잔기를 의미한다. 구체적으로 01-6 알킬은 메틸, 에틸, 11-프로필, 이소프로필, 11-부틸, 이소부틸,

Figure imgf000006_0004
-펜틸, 이소펜틸, 네오펜틸, 펜틸, 1 -메틸부틸, 11-핵실, 1 -메틸펜틸, 2 -메틸펜틸, 4 -메틸- 2 -펜틸, 3,3- 디메틸부틸, 2 -에틸부틸 등을 포함하나 이들로 한정되지 않는다. 일 구현에에서 알킬기는 하나 이상의 치환기로 치환될 수 있으며, 예컨대 1 내지 3개의 할로겐 또는 01-6알킬로치환될 수 있다. 용어 ’’ -6알콕시”는 화학식 -^(:내알킬을 의미하며 , 예를 들어 메톡시 , 에톡시 , 11-프로폭시, 이소프로폭시, 11-부톡시, 이소부톡시, ᄃ 부톡시, 11-펜톡시, 이소펜톡시 ,
Figure imgf000006_0005
네오펜톡시 , 핵실옥시 등을포함하나 이들로 한정되지 않는다. 일 구현예에서 알콕시기는 하나 이상의 치환기로 치환될 수 있으며 , 예컨대 1내지 3개의 할로겐 또는 01-6알킬로치환될 수 있다. 2022/249113 ?01/162022/054935 용어 "사이클로알킬”은 하나 이상의 포화 고리를 갖거나 하나 이상의 비-방향족 고리를 갖는 탄화수소 3 내지 8원 일환형 또는 7 내지 14원 이환형 고리 시스템을 지칭하고, 이때 비-방향족 고리는 어느 정도의 불포화도를 가질 수 있다. 사이클로알킬 기는 하나 이상의 치환기로 임의적으로 치환될 수 있다. 본 발명의 일 구현예에서 03-8사이클로알킬은 탄소수 3 내지 8의 일환형 고리를 지칭한다. 일 구현예에서 사이클로알킬 기의 각각의 고리의 0 1 2 3 또는 4개의 원자는 치환기로 치환될 수 있다. 사이클로알킬 기의 대표적인 예는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로핵실, 사이클로헵틸, 사이클로펜텐일, 사이클로펜타다이엔일, 사이클로핵센일, 사이클로핵사다이엔일, 사이클로옥틸 등을 포함하나, 이에 한정되지 않는다. 용어
Figure imgf000007_0001
탄화수소 일환형 또는 이환형 방향족 고리를지칭한다. 즉, 본 명세서에서 아릴은 달리 정의하지 않는 한 페닐, 나프틸 등과 바이아릴을 포함할 수 있다. 본 발명의 일 구현예에서
Figure imgf000007_0002
아릴은 탄소수 6 내지 10의 방향족 고리를 지칭한다. 일 구현예에서 아릴 기의 각각의 고리의 0, 1, 2, 3, 4, 5 또는 6개의 원자는치환기로치환될 수 있다. 용어 “헤테로아릴 01 라03 1)” 은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 5원 내지 10원 일환 또는 이환 헤테로고리를 지칭한다. 즉, 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 5원 또는 6원의 방향족 헤테로고리이거나, 또는 상기 헤테로아릴 고리가 벤젠 고리 또는 다른 헤테로아릴 고리에 융합된 2환식 고리를 지칭한다. 일 구현예에서, 헤테로아릴 기의 각각의 고리의 0, 1, 2, 3, 또는 4개의 원자는 치환기로 치환될 수 있다. 모노사이클릭 헤테로아릴의 예로는 티아졸릴, 옥사졸릴, 티오페닐, 퓨라닐, 피롤릴, 이미다졸릴, 이소옥사졸릴, 이소티아졸릴, 피라졸릴, 트리아졸릴 , 트리아지닐 , 티아디아졸릴 , 테트라졸릴 , 옥사디아졸릴 , 피리디닐, 피리다지닐, 피리미디닐, 피라지닐 및 이와 유사한 그룹을 들 수 있으나, 이들로 한정되는 것은 아니다. 비사이클릭 헤테로아릴의 예로는 인돌릴, 아자인돌릴, 인돌리닐 , 벤조티오페닐 , 벤조퓨라닐 , 벤즈이미다졸릴 , 벤조옥사졸릴 , 2022/249113 ?01/162022/054935 벤즈이속사졸릴 , 벤즈티아졸릴 , 벤즈티아디아졸릴 , 벤즈트리아졸릴 , 퀴놀리닐 , 이소퀴놀리닐 , 퀴녹살리닐 , 퓨리닐 , 퓨로피리디닐 및 이와 유사한 그룹을 들 수 있으나 이들로 한정되는 것은 아니다. 용어
Figure imgf000008_0001
탄소 원자 이외에 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 고리원자수 5 내지 10의 포화되거나 부분적으로 불포화된 카보사이클릭 고리를 나타낸다. 일 구현예에서 상기 헤테로사이클릴은 5원 또는 6원 지방족 헤테로고리이거나, 또는 상기 헤테로사이클릴 고리가 벤젠 고리 또는 다른 헤테로사이클릴 고리에 융합된 2환식 고리일 수 있다. 일 구현예에서 , 헤테로사이클릴 기의 각각의 고리의 0, 1, 2, 3, 또는 4개의 원자는 치환기로 치환될 수 있다. 예를 들어 , 헤테로사이클릴은 아제티디닐 , 피롤리디닐 , 테트라하이드로푸라닐 , 테트라하이드로-티에닐 , 피라졸리디닐 , 이미다졸리디닐 , 옥사졸리디닐 , 아이소옥사졸리디닐 , 티아졸리디닐 , 디옥솔릴 , 피페리디닐 , 테트라하이드로피라닐 , 테트라하이드로티오피라닐 , 피페라지닐 , 모르폴리닐 , 티오모르폴리닐 , 1, 1 -다이옥소-티오모르폴린- 4 -일 , 아제파닐 , 다이아제파닐 , 호모피페라지닐 , 옥사제파닐 , 인돌릴 , 이소인돌릴 , 디하이드로인돌릴 , 디옥소이소인돌리닐 , 디하이드로푸릴 , 디하이드로이미다졸리닐 , 디하이드로옥사졸릴 , 디하이드로벤조디옥시닐 , 테트라하이드로피리디닐 , 디하이드로피라닐, 디하이드로벤조퓨라닐, 벤조디옥솔릴, 또는 벤조디옥사닐이다. 용어 "치환"은, 지정된 원자 상의 원자가（＞316¾：6）를 초과하지 않으면서 이러한 치환으로부터 화학적으로 안정한 화합물이 되도록, 분자 구조체 내의 수소 원자를 치환기로 대체하는 것을 지칭한다. 예를 들어 "그룹 쇼가 치환기 8로 치환”된다는 것은, 그룹 쇼의 골격을 구성하는 탄소 등의 원자에 결합된 수소 원자가 치환기 묘로 대체되어 , 그룹 쇼와 치환기 8가 공유 결합을 형성함을 의미할 수 있다. 본 발명은 하기 화학식 1의 화합물 , 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다: [Specific content for carrying out the invention] Hereinafter, the present invention will be described in more detail. In the present invention, the term "halogen" means 01, or I unless otherwise specified. The term '' - 6 alkyl" means a linear or branched, saturated hydrocarbon residue having 1 to 6 carbon atoms. Specific 01-6 alkyl is methyl, ethyl, 11-propyl, isopropyl, 11-butyl, isobutyl,
Figure imgf000006_0004
-Pentyl, isopentyl, neopentyl, pentyl, 1-methylbutyl, 11-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. Including but not limited to these. In one embodiment, an alkyl group may be substituted with one or more substituents, such as 1 to 3 halogen or 01-6 alkyl. The term '' -6 alkoxy” means an alkyl in the formula -^(:, for example, methoxy, ethoxy, 11-propoxy, isopropoxy, 11-butoxy, isobutoxy, ᄃ butoxy, 11 -Pentoxy, isopentoxy,
Figure imgf000006_0005
including, but not limited to, 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 0 1-6 alkyl. 2022/249113 -01/162022/054935 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, In this case, the non-aromatic ring may have some degree of unsaturation. The cycloalkyl group may be optionally substituted with one or more substituents. In one embodiment of the present invention, 0 3-8 cycloalkyl is a monocyclic group having 3 to 8 carbon atoms. In one embodiment, 0 1 2 3 or 4 atoms of each ring of a cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclo but is not limited to hexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctyl, and the like.
Figure imgf000007_0001
Hydrocarbon refers to a 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
Figure imgf000007_0002
Aryl refers to an aromatic ring containing 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 01 ra03 1)” refers to an aromatic 5- to 10-membered monocyclic or bicyclic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. That is, heteroaryl is a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, or a bicyclic ring in which the heteroaryl ring is fused to a benzene ring or another heteroaryl ring. refers to 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 is not limited thereto. Examples of bicyclic heteroaryls include indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzooxazolyl, 2022/249113 ?01/162022/054935 benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, purinyl, puropyridinyl and similar groups may be mentioned, but is not limited thereto. Terms
Figure imgf000008_0001
represents 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 0 and £. In one embodiment, the heterocyclyl may be a 5-membered 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, Tetrahydrothiopyranyl, Piperazinil, Morpholinil, Thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, Azefanil, Diazepa Nil, Homopiperazinyl, Oxazepanil, Indolyl, Isoindolyl, Dihydroindolyl, Dioxoisoindolinyl, Dihydrofuryl, Dihydroimidazolinyl, Dihydrooxazolyl, Dihydrobenzodioxy nyl, 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 valency (>316¾:6) on the designated atom is not exceeded and the compound is chemically stable from such substitution. For example, "group show is substituted with substituent 8" means that a hydrogen atom bonded to an atom such as carbon constituting the backbone of group show is replaced with a substituent moiety, and group show and substituent 8 form a covalent bond. The present invention provides a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

【화학식 1] 2022/249113 ?01/162022/054935

Figure imgf000009_0001
상기 식에서, [Formula 1] 2022/249113 ?01/162022/054935
Figure imgf000009_0001
In the above formula,

X 및 는 각각 독립적으로 0 또는 이고; X and are each independently 0 or ;

¾은 수소, 할로겐 , 하이드

Figure imgf000009_0002
■2, -0-^-6알킬- 0- -6알킬, -0-(：0-5-6원 헤테로아릴, 어- ，아릴, 또는 -0 - (¾-(：6-1()아릴이고, 이때 상기 -6알킬, -6알콕시 , -0-(：0-5-6원 헤테로아릴, -0- 502-06-10 아릴, 및 0-0½-(：6-1() 아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로 치환될 수 있고, ¾ is hydrogen, halogen, hydride
Figure imgf000009_0002
■ 2 , -0-^- 6 alkyl- 0- - 6 alkyl, -0-(: 0-5-6 membered heteroaryl, uh-, aryl, or -0 - (¾-(: 6-1() aryl, wherein the above -6 alkyl, -6 alkoxy, -0-(: 0-5-6 membered heteroaryl, -0- 50 2 -0 6-10 aryl, and 0-0½-(: 6-1( ) each aryl can be independently unsubstituted or substituted with 1 to 3 halogen or 01-6 alkyl,

¾는 수소, 01-6알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6알킬이거나; 또는 ¾및 ¾는, 이들이 부착된 벤젠 고리와 함께 , 5- 10원 헤테로사이클릴 또는 5 - 10원 헤테로아릴을 형성할 수 있고; ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or ¾ and ¾, together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl;

¾는 01-6 알킬 , 03-8 사이클로알킬 , - -6 알킬- ¾-8 사이클로알킬 , 06-10 아릴 , -01-6 알킬- (：6-10 아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴 또는

Figure imgf000009_0003
헤테로사이클릴이고 , 이때 상기 01-6 알킬 , 03-8 사이클로알킬 , -01-6 알킬- ¾-8 사이클로알킬, 06-10 아릴, -01-6 알킬- (:6-10 아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴 및 - -6 알킬- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 , ^ -¥(¾, 01-6알킬 , -⑴- 내알킬 또는 -000- 01-6알킬로 치환될 수 있고; 묘4는 -6알킬, -⑴- -6알킬,
Figure imgf000009_0004
헤테로아릴 , 5- 10원 헤테로사이클릴, 또는 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 01- 6 알킬, -⑴- -6 알킬, 06-10 아릴, -00-06-10 아릴, 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴 및 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐,
Figure imgf000009_0005
ᅰ02, _¥(¾, 01-6 알킬, 01-6 알콕시 , 또는 - ■-(：0-(：1-6알킬로 치환될 수 있고; 2022/249113 ?01/162022/054935 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 지방족 헤테로고리이다. 일 구현예로서 , 상기 화학식 1의 화합물에서 ¾은 수소 , 할로겐 , 하이드록시 , 01-6 알킬, 01-6알콕시 , 01-6알킬 _ ¾， -。0-1^¾， -302_ ¾， -0-。¾-0-。¾ , -0-00 -퓨라닐， - 0-302 -페닐 , 또는 -0-(¾-페닐이고 , 이때 상기 -6알킬 , -6알콕시 , -6알킬-· 2,
Figure imgf000010_0001
-퓨라닐, _0-302_페닐 및 _0-0¾ -페닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로 치환될 수 있다. 예컨대 , 메톡시키 (-0대3)는 1 내지 3개의 할로겐으로 치환되어 - 的 또는 - 형태일 수 있고; 상기 -0- ⑴-퓨라닐, -0-쌨2 -페닐 및 -0-대2-페닐은 예컨대 ¾ is 01-6 alkyl, 0 3-8 cycloalkyl, -6 alkyl- ¾- 8 cycloalkyl, 0 6-10 aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl , 5-6 membered heterocyclyl or
Figure imgf000009_0003
Heterocyclyl, wherein the above 0 1-6 Alkyl, 0 3-8 Cycloalkyl, -0 1-6 Alkyl- ¾- 8 Cycloalkyl, 0 6-10 Aryl, -01-6 Alkyl- (: 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and - - 6 alkyl-5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, ^ -¥ (¾, may be substituted with 0 1-6 alkyl, -⑴-inalkyl or -000-01-6alkyl; seed 4 is -6 alkyl, -⑴- -6 alkyl,
Figure imgf000009_0004
Heteroaryl , 5-10 membered heterocyclyl, or -5-6 membered heteroaryl- 5-6 membered heterocyclyl, wherein the above 0 1 -6 alkyl, -⑴- -6 alkyl, 0 6 -10 aryl, -00-06-10 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 dog halogen,
Figure imgf000009_0005
ᅰ0 2 , _¥(¾, 01-6 alkyl, 01-6 alkoxy , or - ■-(:0-(: 1-6 alkyl; 2022/249113 ?01/162022/054935 The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, and the heterocyclyl contains 1 to 4 heteroatoms selected from 0 and £ It is an aliphatic heterocycle that As an embodiment, in the compound of Formula 1, ¾ is hydrogen, halogen, hydroxy, 01-6 alkyl, 01-6 alkoxy, 01-6 alkyl _ ¾, -。0-1^¾, -302 _ ¾, -0-。¾-0-。¾ , -0-00 -furanyl, -0-30 2 -phenyl, or -0-(¾-phenyl, wherein -6alkyl, -6alkoxy, -6alkyl -· 2,
Figure imgf000010_0001
-Furanyl, _0-302_phenyl and _0-0¾ -phenyl may each independently be unsubstituted or substituted with 1 to 3 halogen or 0 1-6 alkyl. For example, a methoxy group (-0 to 3 ) may be substituted with 1 to 3 halogens to be in the -的 or - form; The above -0- (1)-furanyl, -0-x 2 -phenyl and -0-to 2 -phenyl are for example

〒

Figure imgf000010_0006
있다. 일 구현예로서, 상기 화학식 1의 화합물에서 ¾는 수소, 01-6 알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6 알킬일 수 있다 . 구체적으로 , 상기 ¾는
Figure imgf000010_0002
-
Figure imgf000010_0003
있으며, 이에 한정되는 것은 아니다. 또한, 일 구현예로서 , 상기 화학식 1의 화합물에서 ¾및 ¾는, 이들이 부착된 벤젠 고리와 함께 , 벤조디옥솔 , 벤즈옥사졸 , 벤조퓨란 , 디하이드로벤조퓨란 , 디옥소이소인돌린 고리를 형성할 수 있다. 예컨대, 상기 화학식 2의 화합물에서 ¾ 및 ¾는, 이들이 부착된 벤젠 고리와 함께,
Figure imgf000010_0004
Figure imgf000010_0005
형태의 고리를 형성할 수 있다. 일 구현예로서 , 상기 화학식 1의 화합물에서 ¾는 -6 알킬 , ¾-8사이클로알킬 , - 0½ 3-8 사이클로알킬, 페닐, 벤질, 피리디닐, 피리미디닐, 피라졸릴, 2022/249113 1^(:1^ 2022/054935 테트라하이드로피라닐 , 피페리디닐 또는 모르폴리노에틸이고 , 이때 상기 01-6알킬 , 03-8 사이클로알킬, _0½_（：3-8 사이클로알킬, 페닐, 벤질. 피리디닐, 피리미디닐, 피라졸릴, 테트라하이드로피라닐, 피페리디닐 및 모르폴리노에틸은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, ^ _（：0（¾, -6알킬, - ¬대
Figure imgf000011_0001
Figure imgf000011_0004
,
Figure imgf000011_0002
형성할 수 있다. 일 구현예로서 , 상기 화학식 1의 화합물에서 묘4는 01-6 알킬 , -00-01-6 알킬 , 페닐 , 나프틸, -⑴-페닐, 퓨라닐, 옥사졸릴, 이소옥사졸릴, 티아졸릴, 피리디닐, 피라지닐, 벤조퓨라닐 , 퀴녹살리닐 , 디하이드로벤조디옥시닐 ,
Figure imgf000011_0003
2022/249113 1^(:1^ 2022/054935
Figure imgf000012_0001
이고, 이때 상기 _6 알킬, -⑴- _6 알킬, 페닐, 나프틸, -（：0 -페닐, 퓨라닐, 옥사졸릴, 티아졸릴, 피리디닐, 피라지닐, 벤조퓨라닐, 퀴녹살리닐 및 디하이드로벤조디옥시닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐,
Figure imgf000012_0002
치환될 수 있다. 구체적으로,
Figure imgf000012_0003
〒
Figure imgf000010_0006
have. As an embodiment, ¾ in the compound of Formula 1 may be hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens. Specifically, the ¾ is
Figure imgf000010_0002
-
Figure imgf000010_0003
Yes, but is not limited thereto. In addition, as an embodiment, ¾ and ¾ in the compound of Formula 1, together with the benzene ring to which they are attached, form a benzodioxol, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring can For example, ¾ and ¾ in the compound of Formula 2, together with the benzene ring to which they are attached,
Figure imgf000010_0004
Figure imgf000010_0005
It can form a ring shape. As an embodiment, in the compound of Formula 1, ¾ is -6 alkyl, ¾- 8 cycloalkyl, -0½ 3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, 2022/249113 1^(:1^ 2022/054935 tetrahydropyranyl, piperidinyl or morpholinoethyl, wherein the above 01-6alkyl, 0 3-8 cycloalkyl, _0½_(: 3-8 cycloalkyl, Phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, tetrahydropyranyl, piperidinyl and morpholinoethyl are each independently unsubstituted or 1 to 4 halogen, ^_(:0（¾, - 6 alkyl, - ¬ units
Figure imgf000011_0001
Figure imgf000011_0004
,
Figure imgf000011_0002
can form As an embodiment, in the compound of Formula 1, the parent 4 is 01-6 alkyl, -00-01-6 alkyl, phenyl, naphthyl, -⑴-phenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, benzofuranil, quinoxalinyl, dihydrobenzodioxinyl,
Figure imgf000011_0003
2022/249113 1^(:1^ 2022/054935
Figure imgf000012_0001
_ 6 alkyl, -⑴- _ 6 alkyl, phenyl, naphthyl, -(: 0 -phenyl, furanyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, benzofuranyl, quinoxalinyl and each dihydrobenzodioxinyl is independently unsubstituted or contains 1 to 4 halogen;
Figure imgf000012_0002
can be substituted. Specifically,
Figure imgf000012_0003

0 0 0 0

' , 또는 、 '' 일 수 있고, 이에 한정되는 것은 아니다. 본 발명의 다른 구현예에서, 상기 화학식 1의 화합물은 하기 화학식 2의 화합물일 수 있다: 2022/249113 ?01/162022/054935 ' , or 、 '' , 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: 2022/249113 ?01/162022/054935

【화학식 2]

Figure imgf000013_0001
상기 식에서, [Formula 2]
Figure imgf000013_0001
In the above formula,

¾ 은 수소, 할로겐 , 하이드록시 , -6알킬 , -6알콕시 , _0~ ⑴ -5-6원 헤테로아릴 , - 0-502_06-10아릴, 또는 -0세½-06-10아릴이고, 이때 상기 01-6알킬, 01-6알콕시 , _0 - 0）-5-6원 헤테로아릴, -0-502-06-10 아릴, 및 0-^2-06-10 아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로 치환될 수 있고,¾ is hydrogen, halogen, hydroxy, -6 alkyl, -6 alkoxy, _0 to ⑴ -5-6 membered heteroaryl, -0-502_06-10 aryl, or -0 ½-06-10 aryl, In this case, the 01-6 alkyl, 01-6 alkoxy, _ 0 - 0) -5-6 membered heteroaryl, -0-502-06-10 aryl, and 0-^2-06-10 aryl are each independently substituted or may be substituted with 1 to 3 halogens or 01-6 alkyl,

¾ 는 수소, 01-6알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6알킬이거나; 또는 ¾및 는, 이들이 부착된 벤젠 고리와 함께 , 5- 10원 헤테로사이클릴 또는 5 - 10원 헤테로아릴을 형성할 수 있고; 묘3는 03-8사이클로알킬 , -01-6알킬- ¾-8사이클로알킬 , 06-10아릴 , -01-6알킬-（：6-10아릴 , 5-6원 헤테로아릴, 또는 5-6원 헤테로사이클릴이고, 이때 상기 ¾-8사이클로알킬, 아릴, 5-6원 헤테로아릴 및 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, 01-6 알킬, 또는 -000-01-6 알킬로 치환될 수 있고; 묘4는 -6알킬 , -⑴- 내알킬 , ，아릴 , -⑴ - ，아릴 , 5- 10원 헤테로아릴 , 5- 10원 헤테로사이클릴, 또는 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 -6알킬 , -⑴- 내알킬 , 아릴 , -⑴ _（〕6，아릴 , 5- 10원 헤테로아릴 , 5- 10원 헤테로사이클릴 및 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐,

Figure imgf000013_0002
ᅰ02, _¥（¾, 01-6 알킬, 01-6 알콕시 , 또는 - ■-（：0-（：1-6알킬로 치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 지방족 헤테로고리이다. 일 구현예로서 , 상기 화학식 2의 화합물에서 ¾은 수소 , 할로겐 , 하이드록시 , 01-6 알킬 , -6알콕시 , -0 -⑴ -퓨라닐 , -0-302 -페닐 , 또는 -0-（：¾-페닐이고, 이때 상기 01- 2022/249113 1^(:1^ 2022/054935 ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or ¾ and , together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl; Cat 3 is 0 3 -8 cycloalkyl, -01-6 alkyl- ¾- 8 cycloalkyl, 06-10 aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl, or 5- 6-membered heterocyclyl, wherein the ¾- 8 cycloalkyl, aryl, 5-6-membered heteroaryl and 5-6-membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, 01-6 alkyl , or -000-01-6 alkyl; Key 4 is -6 alkyl, -⑴-internal alkyl, aryl, -⑴-, aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or -5-6 membered heteroaryl-5-6 membered Heterocyclyl, wherein the above -6 alkyl, -⑴-internal alkyl, aryl, -⑴ _(] 6 , aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and -5-6 membered heteroaryl - each 5-6 membered heterocyclyl is independently unsubstituted or contains 1 to 4 halogen;
Figure imgf000013_0002
ᅰ0 2 , _¥ (¾, 01-6 alkyl, 01-6 alkoxy , or - ■-(:0-(: 1-6 alkyl; The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. As an embodiment, in the compound of Formula 2, ¾ is hydrogen, halogen, hydroxy, 0 1-6 alkyl, -6 alkoxy, -0 -⑴ -furanyl, -0-30 2 -phenyl, or -0- (:¾-phenyl, wherein the above 0 1 - 2022/249113 1^(:1^ 2022/054935

6 알킬 , 01-6알콕시 , -0- ⑴-퓨라닐 , _0-엤2 -페닐 및 -0-（¾-페닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6 알킬로 치환될 수 있다. 예컨대 , 메톡시키（-0（：¾）는 1 내지 3개의 할로겐으로 치환되어 - 的 또는 -0CF2H 형태일 수 있고; 상기 -0-（：0 -퓨라닐， -0-쌨2 -페닐 및 -0-（¾-페닐은 예컨대

Figure imgf000014_0001
Figure imgf000014_0002
있다. 일 구현예로서, 상기 화학식 2의 화합물에서 ¾는 수소, 01-6 알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6 알킬일 수 있다. 구체적으로, 상기 ¾는
Figure imgf000014_0003
-
Figure imgf000014_0004
있으며, 이에 한정되는 것은 아니다. 또한, 일 구현예로서 , 상기 화학식 2의 화합물에서 ¾및 ¾는, 이들이 부착된 벤젠 고리와 함께 , 벤조디옥솔 , 벤즈옥사졸 , 벤조퓨란 , 디하이드로벤조퓨란 , 디옥소이소인돌린 고리를 형성할 수 있다. 예컨대, 상기 화학식 2의 화합물에서 ¾ 및 묘2는, 이들이 부착된 벤젠 고리와 함께
Figure imgf000014_0005
Figure imgf000014_0006
형태의 고리를 형성할 수 있다. 일 구현예로서, 상기 화학식 2의 화합물에서 묘3는 03-8 사이클로알킬, _（〕¾-03-8 사이클로알킬, 페닐, 벤질, 피리디닐, 피라졸릴, 테트라하이드로피라닐 또는 피페리디닐이고, 이때 상기 ¾-8사이클로알킬 , _0½_（：3-8사이클로알킬 , 페닐 , 벤질 . 피리디닐 , 피라졸릴 , 테트라하이드로피라닐 및 피페리디닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, 01-6 알킬, 또는 -000-01-6 알킬로 2022/249113 ?01/162022/054935
Figure imgf000015_0001
있고, 이에 한정되는 것은 아니다. 일 구현예로서 , 상기 화학식 2의 화합물에서 묘4는 01-6 알킬 -00-01-6 알킬, 페닐, 나프틸 , -⑴-페닐 , 퓨라닐 , 옥사졸릴 , 이소옥사졸릴 , 티아졸릴, 피라지닐, 벤조퓨라닐 , 퀴녹살리닐 , 디하이드로벤조디옥시닐 ,
Figure imgf000015_0002
Figure imgf000015_0003
이고, 이때 상기 01-6 알킬, -⑴- -6 알킬 , 페닐 , 나프틸 , -⑴-페닐 , 퓨라닐, 옥사졸릴, 티아졸릴, 피라지닐 , 벤조퓨라닐 , 퀴녹살리닐 , 디하이드로벤조디옥시닐 ,
Figure imgf000015_0004
각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, - 2, _炯2, -0^, 01-6 알킬 또는 01-6 알콕시로 치환될 수 있다. 구체적으로, 상기 묘4는 예컨대 2022/249113 ?01/162022/054935
Figure imgf000016_0001
있고, 이에 한정되는 것은 아니다. 본 발명에 따른 상기 화학식 2의 화합물의 구체적인 예는 아래와 같으며 , 이에 한정되는 것은 아니다: 6 alkyl , 01-6 alkoxy , -0- ⑴-furanyl , _0-x 2 -phenyl and -0- (¾-phenyl are each independently unsubstituted, or with 1 to 3 halogen or 01-6 alkyl can be substituted. For example, methoxyoxy (-0(:¾) may be substituted with 1 to 3 halogens to form -的 or -0CF 2 H; The -0- (: 0 -furanyl, -0-x 2 -phenyl and -0- (¾-phenyl are, for example
Figure imgf000014_0001
Figure imgf000014_0002
have. As an embodiment, ¾ in the compound of Formula 2 may be hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens. Specifically, the ¾ is
Figure imgf000014_0003
-
Figure imgf000014_0004
Yes, but is not limited thereto. In addition, as an embodiment, ¾ and ¾ in the compound of Formula 2, together with the benzene ring to which they are attached, form a benzodioxol, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring can For example, in the compound of Formula 2, ¾ and 2 are together with the benzene ring to which they are attached.
Figure imgf000014_0005
Figure imgf000014_0006
It can form a ring shape. As an embodiment, in the compound of Formula 2, parent 3 is 03-8 cycloalkyl, _ (]¾-03-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrazolyl, tetrahydropyranyl or piperidinyl, , wherein the above ¾- 8 cycloalkyl, _0½_ (: 3-8 cycloalkyl, phenyl, benzyl. Pyridinyl , pyrazolyl , tetrahydropyranyl and piperidinyl are each independently unsubstituted or represented by 1 to 4 halogen, 01-6 alkyl, or -000-01-6 alkyl. 2022/249113 ?01/162022/054935
Figure imgf000015_0001
Yes, but not limited thereto. As an embodiment, in the compound of Formula 2, Cat 4 is 01-6 alkyl-00-01-6 alkyl, phenyl, naphthyl, -⑴-phenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyra Zinyl, Benzofuranil, Quinoxalinil, Dihydrobenzodioxinyl,
Figure imgf000015_0002
Figure imgf000015_0003
, wherein the 0 1-6 alkyl, -⑴- -6 alkyl, phenyl, naphthyl, -⑴-phenyl, furanyl, oxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxalinyl, dihydrobenzo deoxinyl,
Figure imgf000015_0004
Each may be independently unsubstituted or substituted with 1 to 4 halogens, - 2 , _炯2 , -0^, 0 1-6 alkyl or 0 1-6 alkoxy. Specifically, the grave 4 is, for example 2022/249113 ?01/162022/054935
Figure imgf000016_0001
Yes, but 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） 於（2 -플루오로페닐）- 聲（（5 -페닐티오펜- 2 -일）메틸）퀴녹살린- 2 -카르복사미드;(1) 於（2-fluorophenyl）-聲（(5-phenylthiophen-2-yl)methyl）quinoxaline-2-carboxamide;

（2） 於（2 -플루오로페닐）-於（（5 -페닐티오펜- 2 -일）메틸）퓨란 -2 -카르복사미드 : (2) 於（2-fluorophenyl）-於（(5-phenylthiophen-2-yl)methyl）furan-2-carboxamide:

（3） （2 -플루오로페닐）- 7 :（5-細_톨릴）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드; (3) (2-fluorophenyl)-7:(5-細_tolyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（4） （2 -플루오로페닐）- 7 :（5- 톨릴）티오펜- 2 -일）메틸）퓨란 -2 -카르복사미드 ;(4) (2-fluorophenyl)-7:(5-tolyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（5） 於사이클로펜틸-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (5) 於cyclopentyl-於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）furan-2-carboxamide;

（6） 於사이클로핵실-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; 2022/249113 ?01/162022/054935 (6) 於cyclohexyl-於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）furan-2-carboxamide; 2022/249113 ?01/162022/054935

（7） 於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）-於페닐퓨란- 2 -카르복사미드 ;(7) 於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）-於phenylfuran-2-carboxamide;

（8） （2 -클루오로페닐）-7\^-（（5-（4 -클루오로페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드 ; (8) (2-chlorophenyl)-7\^-((5-(4-chlorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（9） 於（2 -플루오로페닐）-7^（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）옥사졸- 4- 카르복사미드 ; (9) 於(2-fluorophenyl)-7^((5-(4-fluorophenyl)thiophen-2-yl)methyl)oxazole-4-carboxamide;

（ 10）於（2 -플루오로페닐）-7^（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）티아졸- 4- 카르복사미드 ; (10)於(2-fluorophenyl)-7^((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-4-carboxamide;

（ 11）於（2 -플루오로페닐）-7^（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）티아졸- 2- 카르복사미드 ; (11)於(2-fluorophenyl)-7^((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-2-carboxamide;

（ 12） （2 -플루오로페닐）-7^（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）피라진- 2- 카르복사미드 ; (12) (2-fluorophenyl)-7^((5-(4-fluorophenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（13）於（（5-（4 -플루오로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (13) 於（(5-(4-fluoro-3-methylphenyl)thiophen-2-yl）methyl）-於(2-fluorophenyl)quinoxaline-2-carboxamide;

（14） 71^（（5-（4 -플루오로- 3 -메틸페닐）티오펜- 2 -일）메틸）- （3- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (14) 71^((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)quinoxaline-2-carboxamide;

（ 15）於벤질-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2 -카르복사미드 ;( 15) benzyl-於 ((5-(4-fluorophenyl) thiophen-2-yl) methyl) furan-2-carboxamide;

（16） 7^（（5-（4 -클로로페닐）티오펜- 2 -일）메틸）- （2 -플루오로페닐）퓨란- 2- 카르복사미드 ; (16) 7^((5-(4-chlorophenyl)thiophene-2-yl)methyl)-(2-fluorophenyl)furan-2-carboxamide;

（17） （（5-（4 -클로로페닐）티오펜- 2 -일）메틸）- （3 -플루오로페닐）퓨란- 2- 카르복사미드 ; (17) ((5-(4-chlorophenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)furan-2-carboxamide;

（18） 7^（（5-（4 -클로로페닐）티오펜- 2 -일）메틸）- （2 -플루오로페닐）퀴녹살린- 2- 카르복사미드 ; (18) 7^((5-(4-chlorophenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（19） 7^（（5-（4 -클로로- 3 -메틸페닐）티오펜- 2 -일）메틸）- （2 -플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (19) 7^((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（20）於（（5-（4 -클로로페닐）티오펜- 2 -일）메틸）-於（3 -플루오로페닐）퀴녹살린- 2- 카르복사미드 ; 2022/249113 ?01/162022/054935 (20) 於（(5-(4-chlorophenyl)thiophen-2-yl）methyl）-於(3-fluorophenyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935

（21） 71^（（5-（4 -클로로- 3 -메틸페닐）티오펜- 2 -일）메틸）- （3 -플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (21) 71^((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)quinoxaline-2-carboxamide;

（22） （3 -플루오로페닐）-7^（（5-（4 -메틸- 3-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (22) (3-fluorophenyl)-7^((5-(4-methyl-3-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（23） （2 -플루오로페닐）- （（5-（4-（트리플루오로메틸）페닐）티오펜- 2 -일）메틸）퓨란- 2 -카르복사미드 ; (23) (2-fluorophenyl)-((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（24） （3 -플루오로페닐）-7^（（5-（4-（트리플루오로메틸）페닐）티오펜- 2 -일）메틸）퓨란_ 2 -카르복사미드 ; (24) (3-fluorophenyl)-7^((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan_2-carboxamide;

（25） （2 -플루오로페닐）-7^（（5-（4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (25) (2-fluorophenyl)-7^((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（26） （3 -플루오로페닐）-7^（（5-（4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (26) (3-fluorophenyl)-7^((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（27） （3 -플루오로페닐）-7^（（5-（3 -메틸- 4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (27) (3-fluorophenyl)-7^((5-(3-methyl-4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（28）於벤질-於（（5-（4-（트리플루오로메틸）페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (28) benzyl-於（(5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl）furan-2-carboxamide;

（29） （ 2 -플루오로페닐）- （（5-（4 -하이드록시페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (29) (2-fluorophenyl)-((5-(4-hydroxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（30） （2 -플루오로페닐）-7^（（5-（4 -하이드록시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (30) (2-fluorophenyl)-7^((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（31） （（5-（3 -에틸- 4 -하이드록시페닐）티오펜- 2 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (31) ((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（32） （3 -플루오로페닐）-7^（（5-（4 -하이드록시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (32) (3-fluorophenyl)-7^((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（33） （（5-（3 -에틸- 4 -하이드록시페닐）티오펜- 2 -일）메틸）- （3- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (33) ((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)quinoxaline-2-carboxamide;

（34）於（（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）-於페닐퓨란- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (34) 於（(5-(4-methoxyphenyl)thiophen-2-yl)methyl）-於phenylfuran-2-carboxamide; 2022/249113 ?01/162022/054935

（35） （2 -플루오로페닐）- 7 :（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드; (35) (2-fluorophenyl)-7:(5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（36） （2 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (36) (2-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（37） （3 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）벤즈아미드; (37) (3-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;

（38） 4 -아미노- （3 -플루오로페닐）- ^（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）벤즈아미드; (38) 4-amino-(3-fluorophenyl)-^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;

（39） 4-（（3 -플루오로페닐）（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）카바모일）벤조산; (39) 4-((3-fluorophenyl)((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)carbamoyl)benzoic acid;

（40） （2 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）피라진- 2- 카르복사미드; (40) (2-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（41） （2 -플루오로페닐）- 5 -메톡시- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (41) (2-fluorophenyl)-5-methoxy- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（42） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 2- 나프타미드; (42) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-2-naphthamide;

（43） （2 -플루오로페닐）-7^（（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드; (43) (2-fluorophenyl)-7^((5-(4-methoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（44） （2 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 ; (44) (2-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（45） 1^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）- 페닐퀴녹살린- 2- 카르복사미드; (45) 1^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-phenylquinoxaline-2-carboxamide;

（46）於（2 -플루오로페닐）-於（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）퀴놀린- 2- 카르복사미드; (46) 於(2-fluorophenyl)-於（(5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl）quinoline-2-carboxamide;

（47） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）벤조퓨란- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (47) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide; 2022/249113 ?01/162022/054935

（48） （3 -플루오로페닐）- 7 :（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드 ; (48) (3-fluorophenyl)-7:(5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（49） （3 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드 ; (49) (3-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（50） （3 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）피라진- 2- 카르복사미드 ; (50) (3-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（51） 6 -클로로-於（2 -플루오로페닐）-於（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (51) 6-chloro-於(2-fluorophenyl)-於((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（52） 5 -클로로-於（2 -플루오로페닐）-於（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (52) 5-chloro-於(2-fluorophenyl)-於((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（53）於（3 -플루오로페닐）-於（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 ; (53)於(3-fluorophenyl)-於（(5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl）quinoxaline-2-carboxamide;

（54） （4 -플루오로페닐）-7^（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 ; (54) (4-fluorophenyl)-7^((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（55） （（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）- （피리딘- 2 -일）퓨란 -2 -카르복사미드 ;(55) ((5-(4-methoxyphenyl)thiophen-2-yl)methyl)-(pyridin-2-yl)furan-2-carboxamide;

（56） 벤질- ^（（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퓨란 -2 -카르복사미드 ; (56) benzyl-^((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（57） （2 , 4 -디플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (57) (2,4-difluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（58） （3 , 4 -디플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (58) (3,4-difluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（59） （（5-（4 -에톡시페닐）티오펜- 2 -일）메틸）- （2 -플루오로페닐）퓨란 -2- 카르복사미드 ; (59) ((5-(4-ethoxyphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)furan-2-carboxamide;

（60） （（5-（4 -에톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- （2 -플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (60) ((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（61） （（5-（4 -에톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- （3 -플루오로페닐）퀴녹살린_ 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (61) ((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)quinoxaline_2-carboxamide; 2022/249113 ?01/162022/054935

（62） （2 -플루오로페닐）-7^（（5-（4 -프로폭시페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드 ; (62) (2-fluorophenyl)-7^((5-(4-propoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（63） （2 -플루오로페닐）-7^（（5-（3 -메틸- 4 -프로폭시페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (63) (2-fluorophenyl)-7^((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（64） （3 -플루오로페닐）-7^（（5-（3 -메틸- 4 -프로폭시페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (64) (3-fluorophenyl)-7^((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（況） （2 -플루오로페닐）-7^（（5-（4 -이소프로폭시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (況) (2-fluorophenyl)-7^((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（66） （3 -플루오로페닐）-7^（（5-（4 -이소프로폭시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (66) (3-fluorophenyl)-7^((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（67） （（5-（4-（디플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (67) ((5-(4-(difluoromethoxy)phenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（68） （（5-（4-（디플루오로메톡시）- 3 -메틸페닐）티오펜- 2 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (68) ((5-(4-(difluoromethoxy)-3-methylphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（69） （2 -클루오로페닐）- _（（5-（4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (69) (2-chlorophenyl)-_((5-(4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（70） （3 -클루오로페닐）- _（（5-（4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (70) (3-chlorophenyl)-_((5-(4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（71） （2 -플루오로페닐）-7^（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）옥사졸- 5 -카르복사미드 ; (71) (2-fluorophenyl)-7^((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)oxazole-5-carboxamide;

（72） （2 -플루오로페닐）-7^（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）이소옥사졸- 5 -카르복사미드 ; (72) (2-fluorophenyl)-7^((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)isoxazole-5-carboxamide ;

（73） （2 -플루오로페닐）-5 -니트로- （（5-（4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (73) (2-fluorophenyl)-5-nitro- ((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（74） （2 -플루오로페닐）-7^（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (74) (2-fluorophenyl)-7^((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; 2022/249113 ?01/162022/054935

（75） 6 -클로로-於（2 -플루오로페닐）-於（（5-（3 -메틸- 4-(75) 6-chloro-於（2-fluorophenyl）-於（（5-（3-methyl- 4-

（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）피라진- 2 -카르복사미드 ; (trifluoromethoxy)phenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide;

（76） （2 -플루오로페닐）-7^（（5-（4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (76) (2-fluorophenyl)-7^((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（77） （3 -플루오로페닐）-7^（（5-（4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (77) (3-fluorophenyl)-7^((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（78） （2 -클루오로페닐）- _（（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (78) (2-chlorophenyl)-_((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（79） （3 -클루오로페닐）- _（（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (79) (3-chlorophenyl)-_((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（80） （4 -클루오로페닐）- _（（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (80) (4-chlorophenyl)-_((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（81） 4-（5-（（於（3 -클로로페닐）펜탄아미도）메틸）티오펜- 2 -일）페닐 퓨란 -2- 카르복실례이트; (81) 4-(5-((於(3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl furan-2-carboxylate;

（82） 4-（5-（（於（3 -클로로페닐）펜탄아미도）메틸）티오펜- 2 -일）페닐 벤젠설포네이트;(82) 4-(5-((於(3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl benzenesulfonate;

（83）於（（5-（4-（벤질옥시）페닐）티오펜- 2 -일）메틸）-於（3 -클로로페닐）펜탄아미드;(83) 於 ((5-(4-(benzyloxy)phenyl)thiophen-2-yl)methyl)-於(3-chlorophenyl)pentanamide;

（84）於（3 -클로로페닐）-聲（（5-（4-（（4 -메틸벤질）옥시）페닐）티오펜- 2- 일）메틸）펜탄아미드; （84）於（3-chlorophenyl）-聲（（5-（4-（（4-methylbenzyl）oxy）phenyl）thiophen-2-yl）methyl）pentanamide;

（85）於（（5-（벤조［비［1,到디옥솔- 5 -일）티오펜- 2 -일）메틸）-於（2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (85)於((5-(benzo[bi[1,到dioxol-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide;

（86）於（（5-（벤조［ 옥사졸- 5 -일）티오펜- 2 -일）메틸）-於（2 -플루오로페닐）퀴녹살린- 2- 카르복사미드; (86) 於 ((5-(benzo[oxazol-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide;

（87）於（（5-（벤조퓨란- 5 -일）티오펜- 2 -일）메틸）-於（2 -플루오로페닐）퀴녹살린- 2- 카르복사미드; (87) 於（(5-(benzofuran-5-yl)thiophen-2-yl）methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide;

（88）於（（5-（벤조퓨란- 5 -일）티오펜- 2 -일）메틸）-於（4 -플루오로페닐）퀴녹살린- 2- 카르복사미드; 2022/249113 ?01/162022/054935 (88) 於（(5-(benzofuran-5-yl)thiophen-2-yl）methyl)-於(4-fluorophenyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935

（89） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 5- 모르폴리노피라진- 2 -카르복사미드 ; (89) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-morpholinopyrazine-2-carboxamide;

（90） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 5-（4- 메틸피페라진 - 1 -일）피라진 -2 -카르복사미드 ; (90) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperazine-1-yl)pyrazine- 2-carboxamide;

（91） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 5-（4- 메틸피페리딘- 1 -일）피라진- 2 -카르복사미드 ; (91) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperidin-1-yl)pyrazine -2-carboxamide;

（92）於（2 -플루오로페닐）-於（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）퀴녹살린- 6 -카르복사미드; (92)於(2-fluorophenyl)-於（(5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl）quinoxaline-6-carboxamide;

（93） （2 -클루오로페닐）- _（（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (93) (2-chlorophenyl)-_((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（94） （2 -클루오로페닐）- _（（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）벤조퓨란- 2 -카르복사미드 ; (94) (2-chlorophenyl)-_((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide;

（95） 於（（5-（2, 3 -디히드로벤조퓨란- 5 -일）티오펜- 2 -일）메틸）-於（2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (95) 於((5-(2,3-dihydrobenzofuran-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide;

（96） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）아세타마이드; (96) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)acetamide;

（97） 4 -아세타미도- （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）벤즈아마이드; (97) 4-acetamido-(2-fluorophenyl)-(5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide;

（98） 於（2 -플루오로페닐）-於（（5-（2 -메틸- 1 , 3 -디옥소이소이돌린- 5 -일）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (98) 於（2-fluorophenyl）-於（(5-(2-methyl-1,3-dioxoisoidoline-5-yl)thiophen-2-yl)methyl）quinoxaline-2-carb duplicating mid;

（99） （2 -클루오로페닐）- （（5-（ 3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）- 2 , 3 -디히드로벤조 [비 [ 1 , 4]디옥신- 2 -카르복사미드 ; (99) (2-chlorophenyl)- ((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)-2,3-dihydrobenzo [B [1,4]dioxin-2-carboxamide;

（100） 中（3 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드; (100) 中(3-fluorophenyl)-((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（101） 中（4 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드; 2022/249113 ?01/162022/054935 (101) in (4-fluorophenyl)-((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide; 2022/249113 ?01/162022/054935

（102） 於（2 -브로모페닐）-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (102) 於(2-bromophenyl)-於（(5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide;

（103） 於（（ 5-（4 -플루오로페닐）티오펜- 2 -일）메틸）-於（ 0 -톨릴）퓨란- 2 -카르복사미드 ;(103) 於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）-於(0-tolyl)furan-2-carboxamide;

（104） （2 -플루오로페닐）- 5 -메톡시- （（5-（3 -메틸- 4-(104) (2-fluorophenyl)-5-methoxy- (5-(3-methyl-4-

（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）벤조퓨란- 2 -카르복사미드 ; (trifluoromethoxy)phenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide;

（ 105） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）- 5 -니트로퓨란 -2 -카르복사미드 ; (105) (2-fluorophenyl)- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-5-nitrofuran-2-carboxamide ;

（ 106） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）- 5- 니트로벤조퓨란- 2 -카르복사미드 ; (106) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-nitrobenzofuran-2-carboxamide;

（107） （2 -플루오로페닐）- 5 -메톡시- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）벤조퓨란- 2 -카르복사미드 ; (107) (2-fluorophenyl)-5-methoxy- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide;

（ 108） 사이클로부틸- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; ( 108) cyclobutyl- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（ 109） 사이클로펜틸- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; ( 109) cyclopentyl- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（110） 於사이클로핵실-於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (110) 於cyclohexyl-於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl）quinoxaline-2-carboxamide;

（111） 於（사이클로핵실메틸）-於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (111) 於(cyclohexylmethyl)-於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide;

（112） 於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드; (112) 於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl）quinoxaline-2-carboxamide;

（113） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （테트라히드로- 211-피란- 4 -일）퀴녹살린- 2 -카르복사미드 ; (113) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-(tetrahydro-211-pyran-4-yl)quinoxaline-2-carb duplicating mid;

（114） 打-부틸 4-（於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미도）피퍼리딘- 1 -카르복시레이트 ; (114) 打-butyl 4-（於（（5-（3 -methyl- 4-（trifluoromethoxy）phenyl）thiophen- 2-yl）methyl）quinoxaline- 2-carboxamido）piperidine- 1-carboxylate;

（115） 於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）-於（피퍼리딘- 4 -일）퀴녹살린- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (115) 於（(5-(3-methyl-4-(trifluoromethoxy)phenyl）thiophen-2-yl)methyl）-於(piperidin-4-yl)quinoxaline-2-carboxamide ; 2022/249113 ?01/162022/054935

（116） 於（（5-（4 -플루오로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（2- 플루오로페닐 1）퀴녹살린- 2 -카르복사미드 ; (116) 於((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl)-於(2-fluorophenyl 1)quinoxaline-2-carboxamide;

（117） （（ 5-（3 -에틸- 4 -플루오로페닐）티오펜- 2 -일）메틸）- （ 2- 플루오로페닐 1）퀴녹살린- 2 -카르복사미드 ; (117) ((5-(3-ethyl-4-fluorophenyl)thiophen-2-yl)methyl)-(2-fluorophenyl 1)quinoxaline-2-carboxamide;

（118） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （피라진- 2- 일）퀴녹살린- 2 -카르복사미드 ; (118) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-(pyrazin-2-yl)quinoxaline-2-carboxamide;

（119） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （피리미딘- 5 -일）퀴녹살린- 2 -카르복사미드; 및 (119) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-(pyrimidin-5-yl)quinoxaline-2-carboxamide; and

（120） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （내- 피라졸- 4 -일）퀴녹살린- 2 -카르복사미드 . 본 발명의 일 구현예에서 , 상기 화학식 1의 화합물은 하기 화학식 3의 화합물일 수 있다: (120) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophene-2-yl)methyl)-(in-pyrazol-4-yl)quinoxaline-2-carboxamide . In one embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 3 below:

【화학식 3】

Figure imgf000025_0001
상기 식에서 , [Formula 3]
Figure imgf000025_0001
In the above formula,

¾ 은 수소, 할로겐 , 하이드록시 , -6 알킬 , -6 알콕시 ,（:1-6 알킬-· 2 , _（:0 - 502 ■2, 또는 -에내 알킬 - 내 알킬이고, 이때 상기 01-6 알킬 및 01-6 알콕시는 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐으로 치환될 수 있고; 묘2는 수소, 01-6 알킬 , 또는 1 내지 3개의 할로겐으로 치환된 01-6 알킬이며 ; 묘3는 01-6 알킬 , 03-8 사이클로알킬 , 06-10 아릴 , 5-6원 헤테로아릴 , 5-6원 헤테로사이클릴 , 또는 - -6 알킬- 5-6원 헤테로사이클릴이고, 이때 상기 01-6 알킬 , ¾-8 사이클로

Figure imgf000025_0002
5-6원 헤테로아릴 , 5-6원 헤테로사이클릴 및 -01-6 2022/249113 ?01/162022/054935 알킬- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 , ^ -⑴에, 01-6알킬 , 또는 -⑴- -6알킬로치환될 수 있고; 묘4는 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴, 또는 5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴 및 5 6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6알킬로치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를포함하는지방족헤테로고리이다. 일 구현예로서 , 상기 화학식 3의 화합물에서 ¾은 수소 , 할로겐 , 하이드록시 , 01-6 알킬, 01-6알콕시 , 01-6알킬 ¾, -（1）-에2, -302_1^¾, 또는 -0-0¾-0-0¾이고, 이때 상기 01-6알킬 및 01-6알콕시는 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐으로 치환될 수 있다. 예컨대 , 메톡시키（-0（：¾）는 1 내지 3개의 할로겐으로치환되어 -00的또는 -«王出형태일 수 있다. 일 구현예로서 , 상기 화학식 3의 화합물에서 ¾는 수소, -6알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6알킬일 수 있다. 구체적으로, 상기 ¾는
Figure imgf000026_0001
-
Figure imgf000026_0002
있으며 , 이에 한정되는 것은 아니다. 일 구현예로서 , 상기 화학식 3의 화합물에서 ¾는 -6알킬 , 사이클로프로필 , 페닐 , 피리디닐, 피리미디닐, 또는 모르폴리노에틸이고, 이때 상기 01-6 알킬, 사이클로프로필, 페닐, 피리디닐, 피리미디닐 및 모르폴리노에틸은 각각 독립적으로치환되지 않거나, 또는 1내지 4개의 할로겐, ^ _（：0（¾, -6알킬 또는 -00-01-6 알킬로 치환될 수 있다. 구체적으로, 상기 ¾는 예컨대 에틸,
Figure imgf000026_0003
2022/249113 1^(:1^2022/054935
Figure imgf000027_0005
일 구현예로서, 상기 화학식 3의 화합물에서 ¾는 피리디닐, 피라지닐, 퀴녹살리닐, 디하이드로벤조디옥시닐，
Figure imgf000027_0001
이고, 이때 상기 피리디닐¾ is hydrogen, halogen , hydroxy , -6 alkyl , -6 alkoxy ,（:1-6 alkyl- 2 , _（:0-50 2 2 , or alkyl within -alkyl, wherein the above 01- 6 alkyl and 01-6 alkoxy each independently may be unsubstituted or substituted with 1 to 3 halogen; parent 2 is hydrogen, 01-6 alkyl, or 01-6 alkyl substituted with 1 to 3 halogens; Symptom 3 is 01-6 alkyl, 0 3-8 cycloalkyl, 06-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, or - - 6 alkyl-5-6 membered heterocyclyl; wherein the 0 1-6 alkyl, ¾- 8 cyclo
Figure imgf000025_0002
5-6 membered heteroaryl , 5-6 membered heterocyclyl and -0 1-6 2022/249113 ?01/162022/054935 alkyl-5-6 membered heterocyclyl each independently unsubstituted, or 1 to 4 halogen, ^-⑴, 01-6alkyl, or -⑴- -6 alkyl may be substituted with; Catalyst 4 is a 5-10 membered heteroaryl, a 5-10 membered heterocyclyl, or a 5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the above 5-10 membered heteroaryl, 5-10 membered heterocycle aryl and 5 6-membered heteroaryl-5-6 membered heterocyclyl may each independently be unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl; The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. As an embodiment, in the compound of Formula 3, ¾ is hydrogen, halogen, hydroxy, 01-6 alkyl, 01-6 alkoxy, 01-6 alkyl ¾, -(1)-e2, -302 _ 1^¾ , or -0-0¾-0-0¾, wherein the 01-6alkyl and 01-6alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens. For example, methoxyoxy (-0(:¾) may be substituted with 1 to 3 halogens to be in the form of -00 or -«. As an embodiment, in the compound of Formula 3, ¾ may be hydrogen, -6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens. Specifically, the ¾ is
Figure imgf000026_0001
-
Figure imgf000026_0002
, and is not limited thereto. As an embodiment, in the compound of Formula 3, ¾ is -6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl, or morpholinoethyl, wherein the 01-6 alkyl, cyclopropyl, phenyl, pyridinyl , pyrimidinyl and morpholinoethyl may each independently be unsubstituted or substituted with 1 to 4 halogens, ^_(:0(¾, -6 alkyl or -00-01-6 alkyl. Specifically, the ¾ is, for example, ethyl,
Figure imgf000026_0003
2022/249113 1^(:1^2022/054935
Figure imgf000027_0005
As an embodiment, in the compound of Formula 3, ¾ is pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl,
Figure imgf000027_0001
Wherein the pyridinyl

，公、 ，公、

、 피라지닐, 퀴녹살리닐, 디하이드로벤조디옥시닐, —、， 및

Figure imgf000027_0002
각각 독립적으로치환되지 않거나, 또는 1내지 4개의 할로겐 또는 01-6알킬로치환될 수 있는 것일 수 있다. 구체적으로, 상기 묘4는 예컨대
Figure imgf000027_0003
Figure imgf000027_0004
이고, 이에 한정되는것은 아니다. 본 발명에 따른 상기 화학식 3의 화합물의 구체적인 예는 아래와 같으며, 이에 한정되는 것은아니다: 、 pyrazinil, quinoxalinyl, dihydrobenzodioxinyl, —、， and
Figure imgf000027_0002
Each independently may be unsubstituted or may be substituted with 1 to 4 halogen or 0 1-6 alkyl. Specifically, the grave 4 is, for example
Figure imgf000027_0003
Figure imgf000027_0004
and is not limited thereto. Specific examples of the compound represented by Formula 3 according to the present invention are as follows, but are not limited thereto:

（121） 7^（（2 -（4 -플루오로- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (121) 7^((2-(4-fluoro-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（122） 7^（（2-（4 -클로로- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (122) 7^((2-(4-chloro-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935

（ 123） （2 -플루오로페닐）- （（2-（4 -메톡시 -3 -메틸페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (123) (2-fluorophenyl)-((2-(4-methoxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（124） （（ 2-（4-（디플루오로메톡시）페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (124) ((2-(4-(difluoromethoxy)phenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（125） （（ 2-（4-（디플루오로메톡시）- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (125) ((2-(4-(difluoromethoxy)-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（ 126） 6 -클로로-於（ 2 -플루오로페닐）-於（（ 2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）피라진- 2 -카르복사미드 ; ( 126) 6-chloro-於 ( 2-fluorophenyl) -於 ( ( 2- (4- (trifluoromethoxy) phenyl) thiazol-5-yl) methyl) pyrazine- 2-carboxamide;

（ 127） 於（2 -플루오로페닐）- 6 -모르폴리 - （（2 -（4 -（ 127 ） 於（2-fluorophenyl）- 6-morphopoly-（（2-（4-

（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）피라진- 2 -카르복사미드 ; (trifluoromethoxy)phenyl)thiazol-5-yl)methyl)pyrazine-2-carboxamide;

（ 128） （2 -플루오로페닐）- （（2-（3 -메틸- 4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (128) (2-fluorophenyl)-((2-(3-methyl-4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（ 129） （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (129) (2-fluorophenyl)-(2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（130） N（4 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (130) N(4-fluorophenyl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（131） （3 -플루오로페닐）- （（ 2-（ 4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (131) (3-fluorophenyl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（ 132） （4 -플루오로페닐）- （（2-（3 -메틸- 4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (132) (4-fluorophenyl)-((2-(3-methyl-4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（133） （피리딘- 2 -일）- （（ 2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (133) (pyridin-2-yl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（134） （피리딘- 3 -일）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (134) (pyridin-3-yl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（135） 에틸- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드 ; (135) ethyl- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（ 136） （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）피페리딘- 1-일）티아졸- 5 - 2022/249113 ?01/162022/054935 일）메틸）퀴녹살린- 2 -카르복사미드 ; ( 136) (2-Fluorophenyl)- ((2-(4-(trifluoromethoxy)piperidin-1-yl)thiazole-5- 2022/249113 ?01/162022/054935 day）methyl）quinoxaline-2-carboxamide;

（137） （피리딘- 3 -일）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (137) (pyridin-3-yl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（138） 3-（於（（2-（4-（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미도）피리딘- 1 -이움 클로라이드; (138) 3-(於((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamido)pyridin-1-ium chloride;

（139） （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）_ 2 , 3 -디하이드로벤조比] [ 1 , 4]디옥신- 2 -카르복사미드 ; (139) (2-fluorophenyl)- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)_ 2,3-dihydrobenzo] [1,4] dioxin-2-carboxamide;

（140） （4 -플루오로페닐）- （（2-（4-（메톡시메톡시）- 3 -메틸페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (140) (4-fluorophenyl)-((2-(4-(methoxymethoxy)-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（141） （4 -플루오로페닐）- （（2-（4 -히드록시 -3 -메틸페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (141) (4-fluorophenyl)-((2-(4-hydroxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（142） （（2-（4 -메톡시페닐）티아졸- 5 -일）메틸）- （3 -메틸피리딘- 2 -일）퀴녹살린- 2- 카르복사미드; (142) ((2-(4-methoxyphenyl)thiazol-5-yl)methyl)-(3-methylpyridin-2-yl)quinoxaline-2-carboxamide;

（143） 於（（ 2-（4 -메톡시페닐）티아졸- 5 -일）메틸）-聲（피리미딘- 2 -일）퀴녹살린- 2- 카르복사미드; (143) 於（（2-(4-methoxyphenyl)thiazol-5-yl）methyl）-聲(pyrimidin-2-yl)quinoxaline-2-carboxamide;

（144） （2 -플루오로페닐）- （（2-（4 -메톡시페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드; (144) (2-fluorophenyl)-((2-(4-methoxyphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide;

（145） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸） -聲사이클로프로필퀴녹살린- 2- 카르복사미드; (145) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲cyclopropylquinoxaline-2-carboxamide;

（146） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸）-聲（ 2 -플루오로페닐）피콜린아미드 ;(146) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲(2-fluorophenyl)picolinamide;

（147） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸）-聲（4 -시아노페닐）퀴녹살린- 2- 카르복사미드; (147) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲(4-cyanophenyl)quinoxaline-2-carboxamide;

（148） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸）-聲（ 2 -모르폴리노에틸）퀴녹살린- 2- 카르복사미드; (148) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲(2-morpholinoethyl)quinoxaline-2-carboxamide;

（ 149） （2-（4 -클로로페닐）티아졸- 5 -일）메틸）퀴녹살린- 2 -카르복사미드）벤조산 ;(149) (2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide)benzoic acid;

（150） （（ 2-（4-（아미노메틸）페닐）티아졸- 5 -일）메틸）-於（ 2 -플루오로페닐）퀴녹살린_ 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (150) (( 2-(4-(aminomethyl)phenyl)thiazol-5-yl)methyl)-於(2-fluorophenyl)quinoxaline_ 2-carboxamide; 2022/249113 ?01/162022/054935

（151） 7^（（2 -（4 -카바모일페닐）티아졸- 5 -일）메틸）-於（ 2 -플루오로페닐）퀴녹살린- 2- 카르복사미드; (151) 7^((2-(4-carbamoylphenyl)thiazol-5-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide;

（152） 7^（（2 -（4 -카바모일- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (152) 7^((2-(4-carbamoyl-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide;

（ 153） （2 -플루오로페닐）- （（2-（4 -설퍼모일페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드; 및 (153) (2-fluorophenyl)-((2-(4-sulfurmoylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; and

（154） （3 -아세틸페닐）- （（2-（4 -클로로페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드. 본 발명의 일 구현예에서 , 상기 화학식 1 의 화합물은 하기 화학식 4의 화합물일 수 있다: (154) (3-acetylphenyl)- ((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:

【화학식 4]

Figure imgf000030_0001
상기 식에서 , [Formula 4]
Figure imgf000030_0001
In the above formula,

¾ 은 수소, 할로겐 , 하이드록시 , 01-6 알킬 , 또는 01-6 알콕시이고, 이때 상기 01-6 알킬 및 01-6 알콕시는 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐으로 치환될 수 있고; ¾ is hydrogen, halogen , hydroxy , 0 1-6 alkyl , or 0 1-6 alkoxy, wherein the 0 1-6 alkyl and 0 1-6 alkoxy are each independently unsubstituted, or with 1 to 3 halogen can be substituted;

¾ 는 수소, 01-6 알킬 , 또는 1 내지 3개의 할로겐으로 치환된 01-6 알킬이며 ; 묘3는 06-10 아릴 또는 5-6원 헤테로아릴이고, 이때 상기 06-10 아릴 및 5-6원 헤테로아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6 알킬로 치환될 수 있고; 묘4는 5-10원 헤테로아릴이고, 이때 상기 5-10원 헤테로아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6 알킬로 치환될 수 있고; 2022/249113 ?01/162022/054935 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이다. 일 구현예에서 , 상기 화학식 4의 화합물에서 ¾는 페닐 또는 피리디닐이고, 이때 상기 페닐 및 피리디닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6 알킬로 치환될 수 있다. 구체적으로, 상기 ¾는 예컨대

Figure imgf000031_0001
이고, 이에 한정되는 것은 아니다. 일 구현예에서 , 상기 화학식 4의 화합물에서 ¾는 피라지닐 또는 퀴녹살리닐이고, 이때 상기 피라지닐 및 퀴녹살리닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6 알킬로 치환될 수 있다. 구체적으로, 상기 묘4는 예컨대
Figure imgf000031_0002
이고, 이에 한정되는 것은 아니다. 본 발명에 따른 상기 화학식 4의 화합물의 구체적인 예는 아래와 같으며 , 이에 한정되는 것은 아니다: ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; Cat 3 is 0 6-10 aryl or 5-6 membered heteroaryl, wherein the 0 6-10 aryl and 5-6 membered heteroaryl are each independently unsubstituted, or 1 to 4 halogen or 01-6 alkyl may be substituted with; parent 4 is a 5-10 membered heteroaryl, wherein each of the 5-10 membered heteroaryls may be independently unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl; 2022/249113 ?01/162022/054935 The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. In one embodiment, ¾ in the compound of Formula 4 is phenyl or pyridinyl, wherein the phenyl and pyridinyl may each independently be unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl. Specifically, the ¾ is for example
Figure imgf000031_0001
and is not limited thereto. In one embodiment, in the compound of Formula 4, ¾ is pyrazinyl or quinoxalinyl, wherein the pyrazinyl and quinoxalinyl are each independently unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl It can be. Specifically, the grave 4 is, for example
Figure imgf000031_0002
and is not limited thereto. Specific examples of the compound represented by Formula 4 according to the present invention are as follows, but are not limited thereto:

（ 155） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）- 1 , 3 , 4 -티아디아졸- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (155) (2-Fluorophenyl)- (5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2-carboxamide ;

（ 156） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）- 1 , 3 , 4- 티아디아졸- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 ; 및 (156) (2-Fluorophenyl)- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline- 2-carboxamide; and

（157） （2 -플루오로페닐）- （（5-（4-（트리플루오로메톡시）페닐）- 1,3, 4 -티아디아졸- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 . 본 발명은 상기 화학식 1의 화합물의 약학적으로 허용가능한 염을 포함한다. 상기 약학적으로 허용가능한 염은 인간에 대한 독성이 낮아야 하며 , 모 화합물의 생물학적 활성 및 물리화학적 특성에 임의의 부정적인 영향을 주지 않아야 한다. 예를 들어 , 상기 약학적으로 허용가능한 염은 약학적으로 허용가능한 유리 산（紅66 % ）에 의해 형성된 산부가염일 수 있다. 상기 유리 산으로는 무기 산 또는 유기 산을 사용할 수 있으며 , 이때 무기 산은 2022/249113 ?01/162022/054935 염산, 황산, 질산, 인산, 과염소산, 브롬산 등일 수 있고, 유기 산은 아세트산, 메탄설폰산, 에탄설폰산, I） -톨루엔설폰산, 푸마르산, 말레산, 말론산, 프탈산, 석신산, 락트산, 시트르산, 글루콘산, 타르타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파트산, 글루탐산 등일 수 있다. 상기 산부가염은 통상의 방법 , 예를 들어 상기 화학식 1의 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매 , 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조될 수 있다. 또한, 상기 약학적으로 허용가능한 염은 알칼리금속염（나트륨염 등） 또는 알칼리토금속염（칼륨염 등）일 수 있다. 상기 알칼리금속염 또는 알칼리토금속염은, 예를 들어 상기 화학식 1의 화합물을 과량의 알칼리금속 수산화물 또는 알칼리토금속 수산화물 용액 중에 용해시키고, 미용해된 화합물 염을 여과한 후 여액을 증발 및 건조시켜 얻을 수 있다. 또한, 본 발명의 화합물은 키랄 탄소 중심을 가질 수 있으며 , 이에 따라 묘 또는 £ 이성질체 , 라세미 화합물, 개개의 거울상 이성질체 또는 혼합물, 개개의 부분입체 이성질체 또는 혼합물 형태로 존재할 수 있으며 , 이러한 모든 입체 이성질체 및 이들의 혼합물이 본 발명의 범주에 속할 수 있다. 또한, 본 발명의 화합물은 상기 화학식 1의 화합물의 수화물 및 용매화물을 포함할 수 있다. 상기 수화물 및 용매화물은 공지된 방법을 사용하여 제조될 수 있으며 , 무독성 및 수용성인 것이 바람직하다. 특히 , 바람직하게는 상기 수화물 및 용매화물은 각각 물 및 알코올성 용매（특히 , 에탄올 등）의 1 내지 5개의 분자가 결합된 것일 수 있다. 또한, 본 발명은 상기 화학식 1의 화합물에 대한 제조 방법을 제공한다. 구체적으로, 상기 화학식 1의 화합물은 하기 반응식들에 도시된 방법에 의하여 제조할 수 있지만, 이러한 방법에 의해 제조되는 것으로 한정되지 않는다. 특히 , 통상의 기술자라면 당해 분야에서 잘 알려진 공지의 기술을 사용하여 다양한 방법에 의하여 , 본 발명의 상기 화학식 1의 화합물을 제조할 수 있음을 충분히 2022/249113 ?01/162022/054935 이해할 수 있을 것이다. 하기 반응식들은 본 발명에 따른 대표적인 화합물들의 제조방법을 제조 단계별로 나타내는 것으로서 , 본 발명의 여러 화합물들은 이하 제조 단계에서 사용되는 시약과 용매를 변경하거나 반응 순서를 바꿔 제조될 수도 있다. 일반 절차 본 발명의 화합물은 아릴 브로마이드 (aryl bromide) , 아릴 보론산 (aryl boronic acid) , 또는 아릴 보론산 피나콜 에스테르 (aryl boronic acid pinacol ester)와 헤테로아릴 카르복스알데히드 (heteroaryl carboxaldehyde)를 스즈키 커플링 반응시킨 다음 (단계 b) 환원적 아미노화 시키고 (단계 c) 이어서 아실화하는 (단계 c) 것에 의해 합성하였다.

Figure imgf000033_0001
2022/249113 ?01/162022/054935
Figure imgf000034_0001
(157) (2-fluorophenyl)- ((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2-carboxyl mid . 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 by a pharmaceutically acceptable free acid (紅66%). An inorganic acid or an organic acid may be used as the free acid, wherein the inorganic acid is 2022/249113 ?01/162022/054935 Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc., organic acids may be acetic acid, methanesulfonic acid, ethanesulfonic acid, I） -toluenesulfonic acid, fumaric acid, maleic acid, malic acid ronic 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 excess acid aqueous solution 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 a chiral carbon center and thus may exist in the form of myo or £ 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, each of the hydrate and the solvate may be a combination of 1 to 5 molecules of water and an alcoholic solvent (eg, ethanol). In addition, the present invention provides a preparation method for 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, it is fully known that the compound represented by Formula 1 of the present invention can be prepared by a person skilled in the art by various methods using known techniques well known in the art. 2022/249113 ?01/162022/054935 You will understand. 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 sequence. General Procedure Compounds of the present invention are prepared by combining an aryl bromide, an aryl boronic acid, or an aryl boronic acid pinacol ester with a heteroaryl carboxaldehyde by a Suzuki couple. It was synthesized by ring reaction (step b) followed by reductive amination (step c) followed by acylation (step c).
Figure imgf000033_0001
2022/249113 ?01/162022/054935
Figure imgf000034_0001

0°(：에서 실온, 12시간 단계 a: MOM 보호 (MOM protection) 단계 b의 스즈키 커플링 반응을 수행하기에 앞서 페놀성 수산기를 갖는 출발 물질은 MOM-CKChloromethyl methyl ether : 클로로메틸 메틸 에테르) , DIPEA (ᄊ於 디이소프로필에틸아민) 및 DCM(CH2C12)를 첨가하고 0°C에서 실온으로 온도를 서서히 올리면서 12시간동안 교반하는 것에 의해 메톡시메틸 (M0M) 에테르를 형성하여 페놀성 수산기를 보호하였다. 단계 b: 스즈키 커플링 (Suzuki Coupling) 0 ° (: at room temperature, 12 hours Step a: MOM protection Prior to carrying out the Suzuki coupling reaction of step b, the starting material with phenolic hydroxyl groups is MOM-CKChloromethyl methyl ether: Chloromethyl methyl ether) , DIPEA (ᄊ於 diisopropylethylamine) and DCM (CH 2 C1 2 ) were added and methoxymethyl (M0M) ether was formed by stirring for 12 hours while slowly raising the temperature from 0 ° C to room temperature to form phenol The acidic hydroxyl group was protected. Step b: Suzuki Coupling

1,4 -디옥산 (l,4-dioxane) :H20(9: l) 혼합물 중의 탈기된 아릴 브로마이드 (aryl bromide) (1.0 당량) 및 보론산 (boronic acid)/에스테르 (1. 1 당량) 용액에 Pd(dppf)Cl2.CH2Cl2 (0.05 당량)를 첨가하였다. 반응 혼합물에 Na2C03 (2.5 당량)를 첨가하고 95°C에서 가열하였다. 반응 완료 후, 반응 혼합물을 실온으로 냉각하고 에틸 아세테이트 (EtOAc)로 셀라이트 (cel ite) 세척을 통해 여과하였다. 유기층을 염수로 세척하고, MgS04로 건조하여 진공에서 농축시켰다. 잔류물은 플래시 칼럼 크로마토그래피로 정제하였다 . 단계 0 환원적 아미노화 (모6(!11(:1: 1 6 ½1패1八011) 2022/249113 ?01/162022/054935 아릴 아민 (Aryl amine) (2.0 당량)과 촉매량의 아세트산을 C¾C12의 알데히드 (1.0 당량) 용액에 첨가하였다. 반응 혼합물은 TLC를 통해 관찰하면서 이민 ( imine)이 완전히 형성될 때까지 실온에서 교반하였다. 여분의 메탄올 (MeOH)을 증발시키고 잔류물을 테트라하이드로퓨란 (THF)에 재용해시켰다. THF 중 1.0M NaCNB¾(l. l 당량)를 반응 혼합물에 첨가하고 12시간동안 교반하였다. 반응 완료 후, 진공에서 용매를 제거하였다. 잔류물은 에틸 아세테이트 (EtOAc)에 재용해하고 염수로 세척한 다음 MgS04로 건조한 후 진공에서 농축하였다. 잔류물은 플래시 칼럼 크로마토그래피로 정제하였다 . 단계 d: /V·아실화 (N-acylation) Degassed aryl bromide (1.0 equiv.) and boronic acid/ester (1.1 equiv.) in a mixture of 1,4-dioxane:H 2 0 (9: l) ) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (0.05 eq) to the solution. 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 0 Reductive Amination (Mo6(!11(:1: 1 6 ½ 1 18011) 2022/249113 ?01/162022/054935 Aryl amine (2.0 equiv) and a catalytic amount of acetic acid were added to a solution of the aldehyde of C¾C1 2 (1.0 equiv). The reaction mixture was stirred at room temperature while observing through TLC until imine was completely formed. Excess methanol (MeOH) was evaporated and the residue was redissolved in tetrahydrofuran (THF). 1.0M NaCNB¾ in THF (1.1 equivalents) 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: /V · Acylation (N-acylation)

C¾C12중의 2차 아민 (amine) (1.0 당량)과 트리에틸아민 (tr iethylamine) (3.0 당량) 용액에 염화 아실 (Acyl chloride)/염화 술포닐 (sulfonyl chloride) (2.0 당량)을 0°C에서 천천히 첨가하였다. 반응 혼합물을 12시간동안 교반하면서 서서히 실온으로 온도를 높였다. 반응 완료 후, 반응 혼합물을 C¾C12로 희석하고, 염수로 세척하고, MgS04로 건조한 후 진공에서 증발시켜 미정제된 조질 생성물을 수득하였다. 잔류물은 플래시 칼럼 크로마토그래피로 정제하였다. 상기 반응식에서 생성된 목적 화합물들은 통상적인 방법 , 예를 들면 관크로마토그래피 , 재결정화 등의 방법을 이용하여 분리 정제할 수 있다. 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염은 KRAS 활성 또는 발현을 억제하는 효과가 우수하므로, 상기 화합물 또는 이를 포함하는 약학 조성물은 KRAS 돌연변이나 과발현으로 인한 질환, 예컨대 암의 예방 또는 치료에 유용하게 사용될 수 있다. 구체적으로, 본 발명에 따른 화합물 또는 이를 포함하는 약학 조성물은 각종 암에 대한 표적 항암제로서 유용하게 사용될 수 있고, 기존 항암제나 면역치료제와 병용요법으로 약물 내성이나 방사선 내성을 극복할 수 있는 항암제로서 사용될 수 있다. 2022/249113 ?01/162022/054935 본 발명에 사용된 용어 "예방"이란 본 발명에 따른 화합물 또는 약학 조성물의 투여로 상기 질환의 발생 , 확산 및 재발을 저해시키거나 지연시키는 모든 행위를 의미하고, ’’치료’’는 본 발명에 따른 화합물 또는 약학 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다. 본 발명은 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 KRAS 돌연변이나 과발현으로 인한 질환, 예컨대 암을 예방 또는 치료하기 위한 용도를 제공한다. 본 발명은 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 KRAS 활성 또는 발현을 억제하기 위한 용도를 제공한다. 본 발명은 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 KRAS 돌연변이나 과발현으로 인한 질환, 예컨대 암의 예방 또는 치료용 약제의 제조를 위한 용도를 제공한다. 본 발명은 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 KRAS 활성 또는 발현 억제용 약제의 제조를 위한 용도를 제공한다. 또한 본 발명은 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 필요로 하는 대상에 투여하는 것을 포함하는, KRAS 돌연변이나 과발현으로 인한 질환, 예컨대 암을 예방 또는 치료하는 방법을 제공한다. 또한 본 발명은 KRAS의 활성 또는 발현 억제를 필요로 하는 개체에게 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 투여하는 것을 포함하는, KRAS의 활성 또는 발현을 억제하는 방법을 제공한다. 상기 KRAS 돌연변이나 과발현으로 인한 질환은 암일 수 있다. 본 발명의 조성물에 의한 예방, 치료 대상 질병인 "암"은 정상인 조직세포가 어떤 원인으로 무제한 증식하여 그 생체의 생활현상이나 주위의 조직상태 등에 관계없이 급속한 발육을 계속하는 질환으로 구분되며 , "암"은 이형성 , 과다형성 , 고형 종양 및 조혈모세포 암을 포함하며 , 이로 한정되지는 않으며 , 당해 분야에 공지되어 있는 다양한 암 유형을 포함한다. 또 다른 암으로는 다음의 장기 또는 기관: 뇌 , 심장, 폐 , 위장, 대장, 비뇨생식관, 간, 뼈 , 신경계 , 부인과, 혈액 , 피부, 유방 및 부신의 암을 2022/249113 1^(:1^ 2022/054935 포함할 수 있으나， 이로 한정되지는 않는다.또 다른 유형의 암세포로는 신경교종 (신경초종(Schwannoma)， 교모소포종， 성상세포종)， 신경모세포종， 갈색세포종， 부신경절종， 뇌수막종， 부신피질암， 수모세포종， 횡문근육종， 신장암， 다양한 유형의 혈관암， 골모세포성 골암(osteoblastic osteocarcinoma)， 전립선암， 난소암， 자궁근종， 침샘암， 맥락총암， 유방암， 췌장암， 결장암， 대장암 및 거대핵세포성 백혈병; 및 악성 흑색종， 기저세포암， 편평세포암， 카포시 육종 (Karposi’s sarcoma),이형성 모반 (moles dysplastic nevi),지방종， 혈관종， 피부섬유종， 켈로이드， 섬유육종 또는 혈관육종과 같은 육종， 및 흑색종을 포함한 피부암이 포함된다. 일 구현예로서， 본 발명에 따른 화합물 또는 약학 조성물로 예방 또는 치료가능한 암은 암종(carcinoma)， 림프종 (lymphoma),모세포종 (blastoma),육종 (sarcoma), 지방육종 (liposarcoma), 신경내분비종 (neuroendocrine tumor)，중피종Acyl chloride/sulfonyl chloride (2.0 equiv.) was added to a solution of secondary amine (1.0 equiv.) and triethylamine (3.0 equiv.) in C¾C1 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 C¾C1 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, column 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 2022/249113 ?01/162022/054935 The term "prevention" as used herein refers to all actions that inhibit or delay the occurrence, spread, and recurrence of the disease by administration of a compound or pharmaceutical composition according to the present invention, ''Treatment'' refers to all activities in which the symptoms of the disease are improved or beneficially changed by administration of the compound or pharmaceutical composition according to the present invention. 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 cancer, and includes various cancer types known in the art. Other cancers include 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. 2022/249113 1^(:1^ 2022/054935 may include, but is not limited to, other types of cancer cells include glioma (schwannoma, glioblastoma, astrocytoma), neuroblastoma, brown Cytocytoma, paraganglioma, meningioma, adrenocortical cancer, medulloblastoma, rhabdomyosarcoma, kidney cancer, various types of vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine myoma, salivary gland cancer, choroidal cancer, Breast cancer, pancreatic cancer, colon cancer, colorectal cancer and megakaryocytic leukemia; and malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, Skin cancer including keloid, sarcoma such as fibrosarcoma or hemangiosarcoma, and melanoma.In one embodiment, cancers that can be prevented or treated by the compound or pharmaceutical composition according to the present invention include carcinoma, lymphoma , blastoma, sarcoma, liposarcoma, neuroendocrine tumor, mesothelioma

(mesothelioma), 신경초종 (schwanoma), 수막종 (meningioma), 샘암종(adenocarcinoma),목색종 (melanoma),백혈병 (leukemia),악성 림프종 (lymphoidmalignancy),편평세포암종 (squamous cell cancer),편평상피세포암 (epithelial squamous cell cancer),폐암 (lung cancer),소세포폐암 (small-cell lungcancer), 비소세포폐암 (non-small cell lungcancer), 폐샘암종 (adenocarcinoma of the lung), 폐편평암종 (squamous carcinoma of the lung),복막종 (cancer of the peritoneum),간세포성종 (hepatocellular cancer), 위암종 (gastric or stomach cancer),위장관종 (gastrointestinal cancer), 췌장암(pancreatic cancer),뇌암 (brain cancer),아교모세포종 (glioblastoma), 자궁경부암 (cervical cancer),난소암 (ovarian cancer),간암 (liver cancer), 방광암 (bladder cancer),간암 (hepatoma),유방암 (breast cancer),결장암 (colon cancer),직장암 (rectal cancer),결장직장암 (colorectal cancer), 자궁내막 또는 자궁암 (endometrial or uterine carcinoma),침샘암 (salivary gland carcinoma),신장암 (kidney andrenalcancer),전립선암 (prostatecancer), 외음암 (vulvalcancer),갑상선암 (thyroid cancer),간암종 (hepatic carcinoma), 2022/249113 ?01/162022/054935 항문암종 (anal carcinoma) , 음경암종 (peni le carcinoma) , 고환암 (testicular cancer) , 식도정맥류암 (esophageal cancer) , 담도암 (bi liary tract) , 대장암 (colorectal cancer) 및 두경부암 (head and neck cancer)으로 구성되는 군으로부터 선택되는 어느 하나일 수 있다. 본 발명의 약학 조성물은 KRAS의 활성 또는 발현을 억제할 수 있다. 본 발명에서 사용되는 용어 , "억제"는 유전자의 전사, mRNA 프로세싱 , 번역 , 전좌 및 성숙 중 임의의 단계를 억제하거나, 단백질과 단백질간의 결합, 단백질의 활성화 또는 이를 통한 신호전달의 억제를 의미한다. 본 발명의 약학 조성물은 유효성분 이외에 약학적으로 허용되는 담체를 포함할 수 있다. 이때 , 약학적으로 허용되는 담체는 제제화할때 통상적으로 이용되는 것으로서 , 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴 , 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽 , 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석 , 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제 , 습윤제 , 감미제 , 향미제 , 유화제 , 현탁제 , 보존제 등을 추가로 포함할 수 있다. 본 발명의 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여 (예를 들어 , 정맥 내 , 피하, 복강 내 또는 국소에 적용)할 수 있으며 , 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태 , 투여경로 및 시간에 따라 다르지만, 통상의 기술자에 의해 적절하게 선택될 수 있다. 본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양”은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며 , 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성 , 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 따른 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 2022/249113 ?01/162022/054935 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며 , 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며 , 이는 당업자에 의해 용이하게 결정될 수 있다. 구체적으로 본 발명의 약학 조성물의 유효량은 환자의 연령 , 성별 , 상태 , 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며 , 일반적으로는 체중 11¾ 당 0.001 내지 150 , 바람직하게는 0.01 내지 100 을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별 , 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다 . 또한, 본 발명은 상기 약학 조성물을 개체에 투여하는 단계를 포함하는 암의 예방, 조절 또는 치료방법을 제공한다. 본 발명에서 ’’개체 ’’란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐（11101136）, 개 , 고양이 , 말 및 소 등의 포유류를 의미한다. 이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로서 , 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아니다. (mesothelioma), schwanoma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoidmalignancy, squamous cell cancer, squamous cell carcinoma ( epithelial squamous cell cancer, lung cancer, small-cell lungcancer, non-small cell lungcancer, adenocarcinoma of the lung, 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, prostate cancer, vulvalcancer, thyroid cancer ), hepatic carcinoma, 2022/249113 ?01/162022/054935 anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, biliary tract, colorectal cancer 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 when formulating, 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 dependent on the condition and weight of the patient, and the severity of the disease. , depending on the drug type, route of administration and time, but 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 at 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 can be determined according to sensitivity to drugs, administration time, route of administration and excretion rate, treatment period, factors including drugs used simultaneously, and other factors well known in the medical field. or in combination with other treatments 2022/249113 ?01/162022/054935 can be administered, sequentially or concurrently with conventional therapeutic agents, and single or multiple administrations. Considering all of the above factors, it is important to administer the 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, inactivity rate and excretion rate of the active ingredient in the body, disease type, and concomitant drugs, and in general, body weight 0.001 to 150, preferably 0.01 to 100 per 11¾ can 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, sex, weight, age, etc., the dosage is not intended to limit 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, ''subject'' means a subject in need of treatment of a disease, and more specifically, mammals such as humans or non-human primates, mice (11101136), dogs, cats, horses, and cattle. it means. 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.

［실시예］ 실시예 1. ·（2 -플루오로페닐）- ·（（5-（4 -메특시- 3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 （화합물 44） [Example] Example 1. (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide ( compound 44)

［반응식 到 2022/249113 ?01/162022/054935

Figure imgf000040_0001
단계 1： 5-（4 -메특시- 3 -메틸페닐）티오펜- 2 -카르복스알데히드의 합성 （1（（切?0（:12.（:¾（:12（0.05당량）을 1 ,4 -디옥산（1 ,4-（110X3116） :¾0 （4: 1）에 있는 탈기된 5 -브로모티오펜- 2 -카르복스알데히드（5-1）1'011101;11101）11016-2 ：31'1）0표31（161¾선6）（1 당량） , 4 -메특시- 3 -메틸페닐보론산（4 - 11161;110표 3161;11>^11）11611>^11）01'011 3（ （1）（1.2당량） , 및 （2 당량）의 용액에 첨가하였다. 반응 혼합물을 8시간동안 환류시켰다. 반응 혼합물을 실온으로 냉각시키고 , 에틸 아세테이트（ 로 희석하여 셀라이트（ 11比）를 통해 여과하였다. 여과액을 염수로 세척하고, ¾¾쌨4로 건조하여 진공에서 농축하였다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-5% 로 정제하여 표제 화합물을 황색 고체（수율 70%）로 수득하였다. [reaction formula] 2022/249113 ?01/162022/054935
Figure imgf000040_0001
Step 1: Synthesis of 5-(4-methoxy-3-methylphenyl)thiophene-2-carboxaldehyde （1（（切?0（:1 2 .（:¾（:1 2 (0.05 equivalent）） Degassed 5-bromothiophene-2-carboxaldehyde (5-1) 1'011101;11101) 11016-2 in ,4-dioxane（1,4-（110X3116） :¾0（4:1）： 31'1) 0 table 31 (161¾ wire 6) (1 equivalent) , 4 -methoxy-3-methylphenylboronic acid (4 - 11161;110 table 3161;11>^11) 11611>^11) 01'011 3 ((1) (1.2 equiv.), and (2 equiv.) were added to the solution. The reaction mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate ( ) and filtered through Celite ( 11%). The filtrate was washed with brine, dried over ¾¾ 4 and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-5% in nucleic acid) gave the title compound as a yellow solid (70% yield).

¾ ■!?（400 ¾1¾， 00013） 5 9.85 ， 내）， 7.70 （（1, / = 4.0 ¾， 내）， 7.49 （（1, / = 8.4 ¾， 내）， 7.45 ， 내）， 7.29 （（1, / = 4.0 ¾， 내）， 6.86 （（1, / = 8.8 ¾， 내）， 3.87 , 해）， 2.26 , 해）. 단계 2： 2 -플루오로- ·（（5-（4 -메특시- 3 -메틸페닐）티오펜- 2 -일）메틸）아닐린의 합성 2022/249113 ?01/162022/054935 아세트산（ 比 3 （1）（2당량）을 :이에 있는 5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 카르복스알데히드（1 당량） 및 2 -플루오로아닐린（2 11101'0311111116）（0.83 당량）의 용액에 첨가한 후 이민（^ ）이 완전히 형성될 때까지 孔（：로 관찰하면서 실온에서 교반하였다. 그 다음 ：이과 아세트산（ 比 3 （1）을 증발시켜 제거하였다. 반응 혼합물을 메탄올（¾¾0的에 재용해시켰다.

Figure imgf000041_0001
（3당량）을 0° （：에서 반응혼합물에 첨가하고 8시간동안 실온에서 교반하였다. 용매는 진공에서 제거하였다. 잔류물은 에틸 아세테이트（ 0此）에 재용해하고 염수로 세척하여 ¾¾쌨4로 건조시켜 감압상태에서 증발시켰다 . 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산（116X31163） 중 0-5% 0此）로 정제하여 표제 화합물을 백색 고체（수율 65%）로 수득하였다.¾ ■!?（400 ¾1¾， 0001 3 ） 5 9.85，within），7.70 （（1, / = 4.0 ¾，within），7.49 （（1, / = 8.4 ¾，within），7.45 ，within），7.29 （ （1, / = 4.0 ¾, within)， 6.86 （（1, / = 8.8 ¾, within）， 3.87 , , 2.26 , ). Step 2: Synthesis of 2-Fluoro- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)aniline 2022/249113 ?01/162022/054935 Acetic acid ( 比 3 (1) (2 equivalents): 5- (4 -methoxy- 3 -methylphenyl) thiophene- 2-carboxaldehyde (1 equivalent) and 2 After adding to a solution of -fluoroaniline (2 11101'0311111116) (0.83 eq.), the mixture was stirred at room temperature while observing with a conduit (:) until imine (^ ) was completely formed. Then: Diperacetic acid ( 比 3 (1) was removed by evaporation. The reaction mixture was redissolved in methanol (¾¾0).
Figure imgf000041_0001
(3 equivalents) was added to the reaction mixture at 0 ° (:) and stirred at room temperature for 8 hours. Solvent was removed in vacuo. The residue was redissolved in ethyl acetate (0此), washed with brine, dried to ¾¾ 4, and evaporated under reduced pressure. Purification by flash column chromatography (silica gel, 0-5% 0% in nucleic acid (116X31163)) gave the title compound as a white solid (yield: 65%).

¾ ■!? 00013） 5 7.35 （（1, / = 8.8 ¾， 내）， 7.34 ， 내）， 7.03-6.96 （뺘 해）， 6.94 （（1, / = 3.6 ¾， 내）， 6.80 （（1, / = 8.0 ¾， 에）， 6.66 （ / = 6.8 ¾， 내）， 4.53 （（1, / = 5.6 ¾， 211）， 4.34 0， 내）， 3.84 , 3 ， 2.23 , 해） . 단계 3: （2 -플루오로페닐）- （（5-（4 -메특시- 3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드（화합물 44）의 합성 ¾ ■!? 0001 3 ) 5 7.35 （(1, / = 8.8 ¾, within)， 7.34 ， within)， 7.03-6.96 （subtracted year）， 6.94 （（1, / = 3.6 ¾， within）， 6.80 （（1, / = . Step 3: Synthesis of (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 44)

0½（：12에 있는 2 -플루오로- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）아닐린（1 당량） 및 트리에

Figure imgf000041_0002
용액에 염화 2 -퀴녹살로일（2- 요1^110표310 1 （止10!'1（16） （1.5 당량）을 아르곤환경의 0° 0에서 천천히 첨가하였다. 반응 혼합물을 8시간동안 교반하면서 천천히 실온으로 높였다. 반응 혼합물을 （¾（：12로 희석하고 , ¾0 및 염수로 세척하여 무수 ¾¾¾로 건조시켜 진공에서 농축하였다. FCC（실리카 겔 , 핵산 0½표31163）에 있는 0-25% 에틸 아세테이트（ 0此））로 정제하여 표제 화합물을 황색 고체（수율 80%）로 수득하였다.
Figure imgf000041_0003
5 9.23 ， 내）， 8.01 （（1, / = 8.0 ¾， 내）， 7.72-7.60 （뺘 2 -Fluoro-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)aniline (1 equiv.) and trie in 0½(:1 2
Figure imgf000041_0002
To the solution, 2-quinoxaloyl chloride (2-yo 1^110 Table 310 1 （止10!'1（16） （1.5 eq.） was slowly added at 0 ° 0 in an argon environment. The reaction mixture was slowly warmed to room temperature while stirring for 8 hours. The reaction mixture was diluted with (¾(:1 2 ) , washed with ¾0 and brine, dried to anhydrous ¾¾¾ and concentrated in vacuo. Purification with 0-25% ethyl acetate (0 step) in FCC (silica gel, nucleic acid 0½ table 31163) gave the title compound as a yellow solid (80% yield).
Figure imgf000041_0003
5 9.23 ， within)， 8.01 （(1, / = 8.0 ¾， within)， 7.72-7.60 （subtracted

310， 7.36 （（1, / = 7.2 ¾， 내）， 7.35 ， 내）， 7.14-7.08 （뺘 내）， 7.07 ， / = 7.6 ¾， 내）， 6.97 （（1, / = 3.6 ¾， 내）， 6.95-6.90 （뺘 에）， 6.84 （（1, / = 3.6 ¾， 내）， 6.78 （（1, / = 8.8 ¾， 내）， 5.57 （（1, / = 14.8 ¾， 내）， 4.95 （（1, / = 14.8 ¾， 2022/249113 ?01/162022/054935 내）, 3.81 , 3 , 2.22 , 해）. 실시예 2. · (2 -플루오로페닐)- · ((5-(3 -메틸- 4-(트리플루오로메특시)페닐)티오펜- 2 -일)메틸)퀴녹살린- 2 -카르복사미드 (화합물 78) 310， 7.36 （(1, / = 7.2 ¾, within)， 7.35 ， within)， 7.14-7.08 （ subtracted within）， 7.07 ， / = 7.6 ¾， within）， 6.97 （（1, / = 3.6 ¾， within） , 6.95-6.90 (subtracted from)， 6.84 （(1, / = 3.6 ¾, within)， 6.78 （(1, / = 8.8 ¾, within)， 5.57 （（1, / = 14.8 ¾, within)， 4.95 （ （1, / = 14.8 ¾， 2022/249113 ?01/162022/054935), 3.81 , 3 , 2.22 , year). Example 2. (2-fluorophenyl)- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxyl Mead (Compound 78)

[반응식 3]

Figure imgf000042_0001
시약 및 조건 : a) 5 -포밀- 2 -티오펜보론산 (5-formyl-2-thiopheneboronic acid) , K3PO4 , PcKdppOCb.CIfeCh, 1,4 -디옥산 (1,4-dioxane) :¾0 (4: 1) 혼합물 , 8시간동안 환류; b)[Scheme 3]
Figure imgf000042_0001
Reagents and conditions: a) 5-formyl-2-thiopheneboronic acid, K 3 PO 4 , PcKdppOCb.CIfeCh, 1,4-dioxane: ¾0 (4:1) mixture, refluxing for 8 hours; b)

2 -플루오로아닐린 (2-f luoroani l ine) , NaCNBHs, 아세트산, DCM, 메탄올 (MeOH) , 실온에서 8시간; c) 염화 2 -퀴녹살로일 (2-quinoxaloyl chloride) , TEA, DCM,2-fluoroaniline (2-f luoroani l ine), NaCNBHs, acetic acid, DCM, methanol (MeOH), 8 h at room temperature; c) 2-quinoxaloyl chloride, TEA, DCM,

8시간동안 0°C에서 실온. 단계 1： 5-(3 -메틸- 4-(트리플루오로메특시)페닐)티오펜- 2 -카르복스알데히드의 합성 room temperature at 0 ° C for 8 hours. Step 1: Synthesis of 5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophene-2-carboxaldehyde

Pd(dppf)Cl2.CH2Cl2 (0.05당량)을 1.4 -디옥산 (1,4-dioxane) :¾0 (4: 1)에 있는 탈기된 5 -브로모- 2 -트리플루오로메특시톨루엔 (5-brom (广 2-t r i f 1 uo r ome t hoxy 101 uene ) ( 1 당량) , 5 -포밀- 2 -티오펜보론산 (5-formyl-2-thiopheneboronic acid)(1.2 당량) 및 K3P04 (2 당량)의 용액에 첨가하였다. 반응 혼합물을 8시간동안 환류시켰다. 반응 혼합물을 실온으로 냉각시키고, 에틸 아세테이트 (EtOAc)로 희석하여 셀라이트 (cel ite)를 통해 여과하였다. 여과액을 염수로 세척하고, MgS04로 건조하여 진공에서 농축하였다. 플래시 칼럼 크로마토그래피로 정제하여 표제 화합물 (70%)을 수득하였다. 2022/249113 ?01/162022/054935 단계 2: 2 -플루오로- ·（（5-（3 -메틸- 4-（트리플루오로메특시）페닐）티오펜- 2- 일）메틸）아닐린의 합성 상기한 시약 및 반응조건에서 반응시킨 후 실리카겔 칼럼 크로마토그래피（핵산: 0此 = 60: 1）로 정제하여 황색 액체（80% 수율）의 표제 화합물을 수득하였다. Pd(dppf)Cl 2 .CH 2 Cl 2 (0.05 eq.) was dissolved in degassed 5-bromo-2-trifluoromethoxy in 1.4-dioxane:¾0 (4:1). Toluene (5-brom (广 2-trif 1 uo r ome t hoxy 10 1 uene ) (1 eq.), 5-formyl-2-thiopheneboronic acid (1.2 eq.) and K 3 PO 4 (2 eq.) was added to the solution.Reaction mixture was refluxed for 8 hours.Reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc) and filtered through celite.Filtration The liquor was washed with brine, dried over MgS0 4 and concentrated in vacuo Purification by flash column chromatography gave the title compound (70%). 2022/249113 ?01/162022/054935 Step 2: Synthesis of 2-Fluoro-((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 by silica gel column chromatography (nucleic acid: 0% = 60: 1).

¾ ■!? （400

Figure imgf000043_0001
00013） 57.43 ， 내）， 7.39 （（1, / = 8.3 ¾， 내）， 7.19 （（1, / =¾ ■!? （400
Figure imgf000043_0001
0001 3 ) 57.43 , within)， 7.39 （（1, / = 8.3 ¾， within）， 7.19 （（1, / =

8.3 ¾， 내）， 7.13 （（1, / = 2.9 ¾， 내）， 7.01 （（1（1， / = 12.9， 5.7 ¾， 해）， 6.79 （ / = 8.2 ¾， 내）， 6.71 - 6.65 （뺘 내）， 4.55 ， 에）， 4.40 ， 내）， 2.34 ， 해）. 단계 3： ·（2 -플루오로페닐）- ·（（5-（3 -메틸- 4-（트리플루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 （화합물 78）의 합성 상기한 시약 및 반응조건에서 반응시킨 후 실리카겔 칼럼 크로마토그래피（핵산: 0此 = 4: 1）로 정제하여 황색 고체（90% 수율）의 표제 화합물을 수득하였다. 8.3 ¾, within)， 7.13 （(1, / = 2.9 ¾, within)， 7.01 （（1（1， / = 12.9， 5.7 ¾， year））， 6.79 （ / = 8.2 ¾， within）， 6.71 - 6.65 （ Subtract my), 4.55 , in), 4.40 , in), 2.34 , in). Step 3: (2-fluorophenyl)- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide Synthesis of (Compound 78) After reaction with the above reagents and reaction conditions, the title compound was obtained as a yellow solid (90% yield) by purification by silica gel column chromatography (nucleic acid: 0% = 4: 1).

¾ ■!? （400 »¾， 00013） 59.23 ， 내）， 8.03 （（1, / = 6.7 ¾， 내）， 7.78 - 7.70 （ 내）， 7.67 ， 에）， 7.45 ， 내）， 7.40 （（1, / = 7.0 ¾， 내）， 7.18 （（1, / = 6.5 ¾ ， 에）， 7.08 （（1, / = 2.0 ¾， 에）， 6.96 （（1, / = 7.1 ¾， 에）， 6.89 （（1, / = 1.8 내）， 5.55 （（1, / = 14.5 ¾， 내）， 4.99 （（1, / = 14.9 ¾， 내）， 2.33 （ 해） . 실시예 3. ·（（5-（3 -메틸- 4-（트리플루오로메특시）페닐）티오펜- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 （화합물 112） ¾ ■!? （400 »¾， 0001 3 ） 59.23 , within)， 8.03 （(1, / = 6.7 ¾， within)， 7.78 - 7.70 （ within)， 7.67 ， in)， 7.45 ， within)， 7.40 （（1, / = 7.0 ¾, within)， 7.18 （（1, / = 6.5 ¾， to）， 7.08 （（1, / = 2.0 ¾， to）， 6.96 （（1, / = 7.1 ¾， to）， 6.89 （（1, / = within 1.8）， 5.55 （（1, / = 14.5 ¾， within）， 4.99 （（1, / = 14.9 ¾， within）， 2.33 （ year） . Example 3. ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 112)

[반응식 4] 2022/249113 ?01/162022/054935

Figure imgf000044_0001
시약 및 조건: （3） 5 -브로모- 2 -트리플루오로메톡시톨루엔, 5 -포르밀- 2 -티오펜보론산, （02作1¾3）2, 2¥3， 1，2 -디메톡시에탄: （¾:¾0 （2:1:1）, , 18 （I）） »¾내（：1,
Figure imgf000044_0002
（0） 2 -퀴녹살린카르복실산, （：14, 피리딘, 80 C, 6노 단계 1: 5-（3 -메틸- 4-（트리플루오로메특시）페닐）티오펜- 2 -카르발데히드의 합성 [Scheme 4] 2022/249113 ?01/162022/054935
Figure imgf000044_0001
Reagents and Conditions: (3) 5-bromo-2-trifluoromethoxytoluene, 5-formyl-2-thiophenboronic acid, (0 2 1¾ 3 ) 2 , 2 ¥3, 1,2 -dimethoxy Toxyethane: (¾:¾0 (2:1:1), , 18 (I)) within »¾ (:1,
Figure imgf000044_0002
(0) 2-quinoxalinecarboxylic acid, (:1 4 , pyridine, 80 C, 6-no step 1: 5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophene-2-carb synthesis of aldehydes

DME：Et0H：H20 (4:2:2.5) (30 mL) 중의 5 -브로모- 2 -트리플루오로메톡시톨루엔 (2.0 g, 7.84 mmol), 5 -포르밀- 2 -티오펜보론산 (1.59 g, 10.20 mmol), 및 무수 Na2C03 (2.49 g, 23.53 mmol)의 탈기 용액 (degassed solution)에 Pd(dppf )Cl2_C¾Cl2 (0.27 g, 0.39 mmol)를 첨가하였다. 반응 혼합물을 실온에서 24h동안 교반하였다. 반응물 (react ion mass)를 ¾0로 희석하고 EtOAc로 추출하였다. 유기층을 합하여 ¾0 및 염수 (brine)로 세척하였다. MgS04 상에서 건조하고, 여과하고, 진공 하에서 농축하였다. Purification by 플래쉬 칼럼 크로마토그라피로 정제하여 (실리카겔, 핵산 중의 0-5% EtOAc) 황색고체의 표제 화합물을 수득하였다 (1.99 g, 89%). 5-bromo-2-trifluoromethoxytoluene (2.0 g, 7.84 mmol), 5-formyl-2-thiophenboronic acid (1.59 g, 10.20 mmol), and anhydrous Na2CO3 (2.49 g, 23.53 mmol) was added Pd(dppf )Cl 2 _C¾Cl 2 (0.27 g, 0.39 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction ion mass was diluted ¾0 and extracted with EtOAc. The combined organic layers were washed with ¾0 and brine. Dried over MgS0 4 , filtered and concentrated under vacuum. Purification by flash column chromatography (silica gel, 0-5% EtOAc in nucleic acid) gave the title compound as a yellow solid (1.99 g, 89%).

¾ NMR (400 MHz, CDCb) 6 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)； 13C NMR (100 MHz, CDCb) 6 182.92, 152.75, 148.59, 142.95, 137.51, 132.13, 131.75, 129.70, 125.32, 124.63, 121.64, 121.63, 16.40. 단계 2： （5-（3 -메틸- 4-（트리플루오로메특시）페닐）티오펜- 2 -일）메탄아민의 합성 에탄올（2 11 ） 중 5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 2022/249113 ?01/162022/054935 카르발데히드（140.0 1 , 0.49 ■01）의 용액에 히드록실암모늄 클로라이드（40.8 1 , 0.59 1 101）를 첨가하고 반응 혼합물을 실온에서 1시간 동안 교반하였다. 이어서 , 염산（12 ¾1, 163.3 I止） 및 아연 더스트（80 1 , 1.23 1 101）를 용액에 서서히 첨가하고 혼합물을 실온에서 15분 동안 교반하였다. 암모니아（30%, 140 I止） 및 수산화나트륨（6 I 300 I止）의 용액을 생성된 슬러리에 적가하고 , 혼합물을 실온에서 15분 동안 교반하였다. 생성된 용액을 디클로로메탄으로 추출하고 무수 황산나트륨으로 건조한 후 여과하였다. 용매를 진공 하에 제거하여 갈색 액체로서 표제 화합물을 수득하였다（27.8 11塔, 20%）.

Figure imgf000045_0001
6 7.43 ， 내）， 7.39 （（1（1， / = 8.4， 1.8 ¾， 내）， 7.19¾ NMR (400 MHz, CDCb) 6 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); 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 5-(3-methyl-4-(trifluoroethylene) in ethanol (2 11 ) fluoromethoxy) phenyl) thiophene- 2- Hydroxylammonium chloride (40.8 1 , 0.59 1 1 0 1) was added to a solution of 2022/249113 ?01/162022/054935 carbaldehyde (140.0 1 , 0.49 ■ 0 1 ) and the reaction mixture was stirred at room temperature for 1 hour. did Subsequently, hydrochloric acid (12 ¾1, 163.3 I止) and zinc dust (80 1 , 1.23 1 1 0 1) were slowly added to the solution and the mixture was stirred at room temperature for 15 minutes. A solution of ammonia (30%, 140 I°) and sodium hydroxide (6 I 300 I°) 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 11 塔, 20%).
Figure imgf000045_0001
6 7.43, within), 7.39 （（1（1， / = 8.4， 1.8 ¾， within）， 7.19

（（1, / = 8.2 ¾， 내）， 7.11 （（1, / = 3.5 ¾， 내）， 6.88 （（1, / = 3.3 ¾， 내）， 4.06 , 210 , 2.34 , 3 , 1.75 , 2 . 단계 3： ·（（5-（3 -메틸- 4-（트리플루오로메특시）페닐）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드 （화합물 112）의 합성 아르곤 분위기 하에 실온에서 피리 딘（3 此） 중 （5-（3 -메틸- 4- （트리플루오로메톡시）페닐）티오펜- 2 -일）메탄아민（10.5 11塔, 0.04 1 101）의 용액에 2 - 퀴녹살로일 클로라이드（12.7 1四, 0.07 ■01）를 첨가하였다. 반응 혼합물을 801：로 천천히 상승시키면서 15 분 동안 교반하였다. 이어서 , 1X11（14%, 110 I止） 중의 티타늄（IV） 클로라이드 용액을 반응 혼합물에 적가하고 , 801：에서 6 시간 동안 교반하였다. 반응 혼합물을 0½（：12 로 희석하고 ¾0 및 염수로 세척하였다. ¾¾쌨4 상에서 건조하고 , 진공 하에서 농축하였다. 플래쉬 칼럼 크로마토그라피로 정제하여（실리카겔 , 핵산 중의 0-30% 0此） 황색고체의 표제 화합물을 수득하였다（15.0轉, 91%）. （(1, / = 8.2 ¾， within)， 7.11 （（1, / = 3.5 ¾， within）， 6.88 （（1, / = 3.3 ¾， within）， 4.06 , 210 , 2.34 , 3 , 1.75 , 2 . Step 3: Synthesis of ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide (Compound 112) Under Argon Atmosphere In a solution of (5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methanamine (10.5 11 塔, 0.04 1 1 0 1) in pyridine (3 phase) at room temperature 2-quinoxaloyl chloride (12.7 14, 0.07 ■01) was added. The reaction mixture was stirred for 15 minutes while slowly ramping to 801:. Then, a solution of titanium (IV) chloride in 1X11 (14%, 110 I) was added dropwise to the reaction mixture, and stirred at 801: for 6 hours. The reaction mixture was diluted with 0½(:1 2 ) and washed with ¾0 and brine. Dried over ¾¾ sia4 and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-30% 0% in nucleic acid) gave the title compound as a yellow solid (15.0%, 91%).

¾ ■!? （400

Figure imgf000045_0002
이比-쑈） 6 9.59 ， 내）， 9.25 （加， 내）， 8.19 （（1, / = 7.9 ¾ ， 내）， 8. 13 （（1（1， / = 8.1， 1.1 ¾， 내）， 8.02 - 7.90 （뺘 에）， 7.62 （（1, / = 1.3 ¾ ， 내）， 7.55 （（1（1， / = 8.5， 1.9 ¾， 내）， 7.33 （（1, / = 3.6 ¾， 내）， 7.29 （（1, / 2022/249113 ?01/162022/054935 ¾ ■!? （400
Figure imgf000045_0002
This 比-show） 6 9.59 ， My)， 9.25 （加， My）， 8.19 （(1, / = 7.9 ¾， My）， 8. 13 （（1（1， / = 8.1， 1.1 ¾， My）， 8.02 - 7.90 （subtracted from）， 7.62 （(1, / = 1.3 ¾， within)， 7.55 （（1（1， / = 8.5， 1.9 ¾， within）， 7.33 （（1, / = 3.6 ¾， within） ，7.29 （（1, / 2022/249113 ?01/162022/054935

= 8.6 Hz, 1H）, 7.13 （d, J 3.6 Hz, 1H） , 4.90 （s, 2H） , 2.34 （s, 3H） ; 130 ■!? （100 MHz, acetone- d；） 6 163.96, 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, 128.17, 125.14 , 124.49, 122.63, 122.39, 120.59, 38.60, 16.04. 상기 실시예 1 내지 3과 동일한 방법을 사용하여 하기 표 1에 나타낸 화합물 1 내지 120을 제조하였다. = 8.6 Hz, 1H）, 7.13 (d, J 3.6 Hz, 1H) , 4.90 (s, 2H) , 2.34 (s, 3H) ; 13 0 ■!? (100 MHz, acetone-d;) 6 163.96, 147.60, 144.85, 144.63, 143.29, 142.66, 141.07, 134.39, 132.57 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.

【표 1】

Figure imgf000046_0001
2022/249113 1^（:1^2022/054935
Figure imgf000047_0001
2022/249113 1^（:1^2022/054935
Figure imgf000048_0001
2022/249113 1^（:1^2022/054935
Figure imgf000049_0001
2022/249113 1^（:1^2022/054935
Figure imgf000050_0001
2022/249113 1^（:1^2022/054935
Figure imgf000051_0001
2022/249113 1^（:1^2022/054935
Figure imgf000052_0001
2022/249113 1^（:1^2022/054935
Figure imgf000053_0001
2022/249113 1^（:1^2022/054935
Figure imgf000054_0001
2022/249113 1^（:1^2022/054935
Figure imgf000055_0001
2022/249113 1^（:1^2022/054935
Figure imgf000056_0001
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Figure imgf000057_0001
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Figure imgf000058_0001
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Figure imgf000059_0001
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Figure imgf000060_0001
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Figure imgf000061_0001
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Figure imgf000062_0001
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Figure imgf000063_0001
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Figure imgf000064_0001
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Figure imgf000065_0001
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Figure imgf000066_0001
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Figure imgf000067_0001
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Figure imgf000068_0001
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Figure imgf000069_0001
2022/249113 1^（:1^2022/054935
Figure imgf000070_0001
2022/249113 ?01/162022/054935
Figure imgf000071_0002
실시예 4. ·（2 -플루오로페닐）- ·（（2-（4-（트리플루오로메특시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 （화합물 129） 【Table 1】
Figure imgf000046_0001
2022/249113 1^（:1^2022/054935
Figure imgf000047_0001
2022/249113 1^（:1^2022/054935
Figure imgf000048_0001
2022/249113 1^（:1^2022/054935
Figure imgf000049_0001
2022/249113 1^（:1^2022/054935
Figure imgf000050_0001
2022/249113 1^（:1^2022/054935
Figure imgf000051_0001
2022/249113 1^（:1^2022/054935
Figure imgf000052_0001
2022/249113 1^（:1^2022/054935
Figure imgf000053_0001
2022/249113 1^（:1^2022/054935
Figure imgf000054_0001
2022/249113 1^（:1^2022/054935
Figure imgf000055_0001
2022/249113 1^（:1^2022/054935
Figure imgf000056_0001
2022/249113 1^（:1^2022/054935
Figure imgf000057_0001
2022/249113 1^（:1^2022/054935
Figure imgf000058_0001
2022/249113 1^（:1^2022/054935
Figure imgf000059_0001
2022/249113 1^（:1^2022/054935
Figure imgf000060_0001
2022/249113 1^（:1^2022/054935
Figure imgf000061_0001
2022/249113 1^（:1^2022/054935
Figure imgf000062_0001
2022/249113 1^（:1^2022/054935
Figure imgf000063_0001
2022/249113 1^（:1^2022/054935
Figure imgf000064_0001
2022/249113 1^（:1^2022/054935
Figure imgf000065_0001
2022/249113 1^（:1^2022/054935
Figure imgf000066_0001
2022/249113 1^（:1^2022/054935
Figure imgf000067_0001
2022/249113 1^（:1^2022/054935
Figure imgf000068_0001
2022/249113 1^（:1^2022/054935
Figure imgf000069_0001
2022/249113 1^（:1^2022/054935
Figure imgf000070_0001
2022/249113 ?01/162022/054935
Figure imgf000071_0002
Example 4. (2-fluorophenyl)- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide (Compound 129 )

[반응식 5]

Figure imgf000071_0001
단계 1： 2-（4-（트리플루오로메특시）페닐）티아졸- 5 -카르복스알데히드의 합성 일반적 과정 요 （스즈키 커플링 : 31 11닌 111）111평） 2022/249113 ?01/162022/054935 [Scheme 5]
Figure imgf000071_0001
Step 1: General Procedure for Synthesis of 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde (Suzuki coupling: 31 11 nin 111) 111 pyeong) 2022/249113 ?01/162022/054935

1,4 -디옥산 (l,4-dioxane) :H20(9: l) 혼합물 중의 탈기된 아릴 브로마이드 (aryl bromide) (1.0 당량) 및 보론산 (boronic acid)/에스테르 (1. 1 당량) 용액에 Pd(dppf)Cl2.CH2Cl2 (0.05 당량)를 첨가하였다. 반응 혼합물에 Na2C03 (2.5 당량)를 첨가하고 95°C에서 가열하였다. 반응 완료 후, 반응 혼합물을 실온으로 냉각하고 에틸 아세테이트 (EtOAc)로 셀라이트 (cel ite) 세척을 통해 여과하였다. 유기층을 염수로 세척하고, MgS04로 건조하여 진공에서 농축시켰다. 잔류물은 플래시 칼럼 크로마토그래피로 정제하였다 . 일반적 과정 A에 따라 2 -브로모- 5 -카르복스알데히드 ^-bromothiazole-S- carboxaldehyde)와

Figure imgf000072_0001
(트리플루오로메특시 )페닐 ]보론산 ( [4-Degassed aryl bromide (1.0 equiv.) and boronic acid/ester (1.1 equiv.) in a mixture of 1,4-dioxane:H 2 0 (9: l) ) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (0.05 eq) to the solution. Na 2 C0 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 ^-bromothiazole-S-carboxaldehyde) and
Figure imgf000072_0001
(trifluoromethoxy)phenyl]boronic acid ([4-

(Tr i f luoromethoxy)phenyl ]boronic acid)을 반응시켜 표제 화합물을 제조하였다. 플래시 칼럼 크로마토그래피 (실리카 겔 , 핵산 중 0-5% EtOAc)로 정제하여 표제 화합물 35i를 황색 고체 (수율 70%)로 수득하였다. (Tr i f luoromethoxy)phenyl ]boronic acid) to prepare the title compound. Purification by flash column chromatography (silica gel, 0-5% EtOAc in nucleic acid) gave the title compound 35i as a yellow solid (70% yield).

¾ NMR (CDCb, 400 MHz) 510.06 (s, 1H) , 8.44 (s, 1H) , 8.08 (d, J = 8.4 Hz, 2H) , 7.34 (d, J = 8.4 Hz, 2H) 단계 2： 2 -플루오로-서· ((2-(4-(트리플루오로메특시)페닐)티아졸- 5 -일)메틸)아닐린 의 합성 일반적 과정 B (환원적 아미노화: Reductive Amination) 아릴 아민 (Aryl amine) (2.0 당량)과 촉매량의 아세트산을 C¾C12의 알데히드 (1.0 당량) 용액에 첨가하였다. 반응 혼합물은 TLC를 통해 관찰하면서 이민 ( imine)이 완전히 형성될 때까지 실온에서 교반하였다. 여분의 메탄올 (MeOH)을 증발시키고 잔류물을 테트라하이드로퓨란 (THF)에 재용해시켰다. THF 중 1.0M NaCNB¾(l. l 당량)를 반응 혼합물에 첨가하고 12시간동안 교반하였다. 반응 완료 후, 진공에서 용매를 제거하였다. 잔류물은 에틸 아세테이트 (EtOAc)에 재용해하고 염수로 세척한 다음 MgS04로 건조한 후 진공에서 농축하였다. 잔류물은 플래시 칼럼 2022/249113 ?01/162022/054935 크로마토그래피로 정제하였다 . 단계 1에서 제조한 2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 카르복스알데히드로부터 일반적 과정 8에 따라 표제 화합물을 제조하였다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-5% 0此）로 정제하여 표제 화합물 36]3를 옅은 황색 고체（0.15 §, 수율 80%）로 수득하였다. ¾ NMR (CDCb, 400 MHz) 510.06 (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 - Synthesis of fluoro-ser ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)aniline General Procedure B (Reductive Amination) Aryl amine ) (2.0 equiv.) and a catalytic amount of acetic acid were added to a solution of the aldehyde of C¾C1 2 (1.0 equiv.). The reaction mixture was stirred at room temperature while observing through TLC until imine was completely formed. Excess methanol (MeOH) was evaporated and the residue was redissolved in tetrahydrofuran (THF). 1.0M NaCNB¾ in THF (1.1 equivalents) 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. Residue flash column 2022/249113 - 01/162022/054935 Purified by chromatography. The title compound was prepared according to General Procedure 8 from 2-(4-(trifluoromethoxy)phenyl)thiazole-5-carboxaldehyde prepared in Step 1. Purification by flash column chromatography (silica gel, 0-5% 0% in nucleic acid) gave the title compound 36]3 as a pale yellow solid (0.15 § , yield 80%).

¾ ■!? （00013, 400

Figure imgf000073_0001
5 7.93 （山 / = 8.4 ¾， 에）， 7.74 ， 내）， 7.27 （（1, / =¾ ■!? (0001 3 , 400
Figure imgf000073_0001
5 7.93 （山 / = 8.4 ¾， 에）， 7.74 ， mine）， 7.27 （（1, / =

8.4 ¾， 에）， 7.00 ， / = 8.6 ¾， 에）， 6.78 ， / = 8.2 ¾， 내）， 6.70 （ / = 6.8 ¾， 내）， 4.62 （（1, / = 6.0 ¾， 에）， 4.37 ， 내） 단계 3： ·（2 -플루오로페닐）- ·（（2-（4-（트리플루오로메특시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 （화합물 129）의 합성 일반적 과정 0（ 아실화, ^8071811011） 8.4 ¾， in）， 7.00 ， / = 8.6 ¾， in）， 6.78 ， / = 8.2 ¾， in）， 6.70 （ / = 6.8 ¾， in)， 4.62 （（1, / = 6.0 ¾， in）， 4.37 , within) Step 3: ・(2-fluorophenyl)- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide ( Synthesis of Compound 129) General Procedure 0（ Acylation, ^8071811011）

（¾（：12중의 2차 아민（31 !16） （1.0 당량）과 트리에틸아민（비 11＞ 11111116） （3.0 당량） 용액에 염화 아실（ （±101 （16）/염화 술포닐

Figure imgf000073_0002
（2.0 당량）을 0°（：에서 천천히 첨가하였다. 반응 혼합물을 12시간동안 교반하면서 서서히 실온으로 온도를 높였다. 반응 완료 후, 반응 혼합물을 0½（：12로 희석하고, 염수로 세척하고, ¾¾엤4로 건조한 후 진공에서 증발시켜 미정제된 조질 생성물을 수득하였다. 잔류물은 플래시 칼럼 크로마토그래피로 정제하였다. 단계 2에서 제조한 2 -플루오로-於（（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）아닐린로부터 일반적 과정 （：에 따라 표제 화합물을 제조하였다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-30% 0此）로 정제하여 표제 화합물 37크6를 밝은 갈색 고체（40.0 , 수율 28%）로 수득하였다. Acyl chloride ( (±101 (16))/sulfonyl chloride
Figure imgf000073_0002
(2.0 eq.) was slowly added at 0 ° (:). 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 0½ (:1 2 ) , washed with brine, dried with ¾¾ 4 and evaporated in vacuo to obtain crude crude product. The residue was purified by flash column chromatography. The title compound was prepared according to the general procedure (: from 2-fluoro-於((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)aniline prepared in Step 2. Purification by flash column chromatography (silica gel, 0-30% 0% in nucleic acid) gave the title compound 37C6 as a light brown solid (40.0%, yield 28%).

¾ ■!? 0103, 400

Figure imgf000073_0003
5 9.24 ， 내）， 8.04 （（1, / = 8.8 ¾， 내）， 7.98 （（1, / =¾ ■!? 010 3 , 400
Figure imgf000073_0003
5 9.24 ， within)， 8.04 （（1, / = 8.8 ¾， within）， 7.98 （（1, / =

8.4 ¾， 에）， 7.77 -7.73 （뺘 내）， 7.66 （（1, / = 3.2 ¾， 에）， 7.59 （ 내）， 7.28 2022/249113 ?01/162022/054935 8.4 ¾, in), 7.77 -7.73 (within), 7.66 ((1, / = 3.2 ¾, in), 7.59 (within), 7.28 2022/249113 ?01/162022/054935

（（1, /= 8.8 ¾， 에）， 7.19 （ / = 6.7 ¾， 내）， 7.07 ， /= 7.8 ¾， 내）， 6.98 （ /= 8.4 ¾， 에）， 5.48 （（1, /= 14.4 ¾， 내）， 5.13 （（1, /= 15.3 ¾， 내） 상기 실시예 4의 방법에 따라 다양한 브로모티아졸 유도체와 보론산 유도체를 사용하여 , 하기 표 2에 나타낸 화합물 121 내지 154를 제조하였다. （（(1, /= 8.8 ¾， 에）， 7.19 （ / = 6.7 ¾， within）， 7.07 ， /= 7.8 ¾， within）， 6.98 （ /= 8.4 ¾， 에）， 5.48 （（1, /= 14.4 ¾, within), 5.13 ((1, /= 15.3 ¾, within) Compounds 121 to 154 shown in Table 2 below were prepared using various bromotiazole derivatives and boronic acid derivatives according to the method of Example 4 above. .

【표 2】

Figure imgf000074_0001
2022/249113 1^（:1^2022/054935
Figure imgf000075_0001
2022/249113 1^（:1^2022/054935
Figure imgf000076_0001
2022/249113 1^（:1^2022/054935
Figure imgf000077_0001
2022/249113 1^（:1^2022/054935
Figure imgf000078_0001
2022/249113 1^（:1^2022/054935
Figure imgf000079_0001
2022/249113 1^（:1^2022/054935
Figure imgf000080_0001
2022/249113 1^（:1^2022/054935
Figure imgf000081_0001
실시예 5. （2 -플루오로페닐）- （（5-（4-（트리플루오로메특시）페닐）- 1，3,4- 티아디아졸- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 （화합물 157） 【Table 2】
Figure imgf000074_0001
2022/249113 1^（:1^2022/054935
Figure imgf000075_0001
2022/249113 1^（:1^2022/054935
Figure imgf000076_0001
2022/249113 1^（:1^2022/054935
Figure imgf000077_0001
2022/249113 1^（:1^2022/054935
Figure imgf000078_0001
2022/249113 1^（:1^2022/054935
Figure imgf000079_0001
2022/249113 1^（:1^2022/054935
Figure imgf000080_0001
2022/249113 1^（:1^2022/054935
Figure imgf000081_0001
Example 5. (2-fluorophenyl)-(5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2- Carboxamide (Compound 157)

[반응식 6] [Scheme 6]

2022/249113 1^(:1^ 2022/054935

Figure imgf000082_0001
시약 및 조건: (a) 상응하는 보론산(boronic acid)/에스테르， Pd(0Ac)2, 잔트포스(xantphos )， 메틸 몰포린0V~methylmorpholine)， 톨루엔:¾0 (2:1)， 실온， 7시간; (b) NaBH4, MeOH, 0°C, 1시간; (c)데스-마틴 페리오디난(Dess-Martin periodinane), CH2CI2,실온， 12시간; (d) i) 2-플루오로아닐린(2-fluoroani1ine)， 촉매 아세트산(cat. acetic acid), MeOH, ii) THF중 1.0M NaBHsCN, THF,실온， 12시간; (e)염화 2-퀴녹살로일(2-quinraaloyl chloride),트리에틸아민， C¾C12, 0°C에서 실온， 12시간. 단계 1: 에틸 5-(4-(트리플루오로메톡시 )페닐)- 1，3,4 -티아디아졸- 2 -카르복실례이트 (12)의 합성 둥근 바닥 플라스크를 에틸 5-브로모-1，3,4-티아디아졸-2-카르복실레이트(ethyl 5- bromo-l,3,4-thiadiazole-2-carboxylate),(4-(트리플루오로메특시)페닐)보론산((4- (trifluoromethoxy)pheny1)boronic acid), Pd(0Ac)2 및 잔트포스(xantphos)로 채웠다. 톨루엔 중 메틸 몰포린 CV~methyl morpholine)용액을 첨가한 후 2022/249113 ?01/162022/054935 물（¾0）를 첨가하였다. 반응 혼합물을 실온에서 7시간동안 강하게 교반하였다. 반응이 완료된 후, 잔류물을 에틸 아세테이트（ 0此）에 재용해시키고 유기층을 물（¾0）과 염수로 세척한 후 ¾¾쌨4로 건조시켜 감압상태에서 증발시켰다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-10% 0此）로 정제하여 표제 화합물을 흰색 고체（0.52 §, 수율 77%）로 수득하였다.
Figure imgf000083_0001
5 8.08（山 /= 8.4 ¾， 에）， 7.37（（1,/= 8.4 ¾， 에），2022/249113 1^(:1^ 2022/054935
Figure imgf000082_0001
Reagents and conditions: (a) corresponding boronic acid / ester, Pd (0Ac) 2, xantphos, methyl morpholine 0V ~ methylmorpholine), toluene: ¾0 (2: 1), room temperature, 7 hour; (b) NaBH 4 , MeOH, 0 ° C, 1 hour; (c) Dess-Martin periodinane, CH2Cl2, room temperature, 12 hours; (d) i) 2-fluoroaniline (2-fluoroaniline), catalyst acetic acid (cat. acetic acid), MeOH, ii) 1.0M NaBHsCN in THF, THF, room temperature, 12 hours; (e) 2-quinoxaloyl chloride (2-quinraaloyl chloride), triethylamine, C¾C1 2 , room temperature at 0 ° C, 12 hours. Step 1: Synthesis of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate (12) In a round bottom flask was added ethyl 5-bromo-1 ，3,4-thiadiazole-2-carboxylate (ethyl 5- bromo-l,3,4-thiadiazole-2-carboxylate), (4- (trifluoromethoxy) phenyl) boronic acid ((4 - (trifluoromethoxy)pheny1)boronic acid), Pd(0Ac)2 and xantphos. After adding a solution of methyl morpholine (CV ~ methyl morpholine) in toluene 2022/249113 ?01/162022/054935 Water (¾0) was added. The reaction mixture was vigorously stirred at room temperature for 7 hours. After the reaction was completed, the residue was redissolved in ethyl acetate (0此), and the organic layer was washed with water (¾0) and brine, dried at ¾¾ 4, and evaporated under reduced pressure. Purification by flash column chromatography (silica gel, 0-10% 0% in nucleic acid) gave the title compound as a white solid (0.52 § , yield 77%).
Figure imgf000083_0001
5 8.08（山 /= 8.4 ¾， 에）， 7.37（（1,/= 8.4 ¾， 에），

4.55（ / = 7.2 ¾， 에）， 1.49 ，/= 7.2 ¾， 해） 단계 2： 5-（4-（트리플루오로메특시）페닐）- 1,3, 4 -티아디아졸- 2 -카르복스알데히드4.55（ / = 7.2 ¾， 에）， 1.49 ，/= 7.2 ¾， year） Step 2： 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carb boxaldehyde

（½）의 합성 무수 MeOH 중의 에틸 5-（4-（트리플루오로메톡시）페닐）-1,3,4-티아디아졸-2- 카르복실례이트 용액에 NaB¾를 0°C에서 조심스럽게 첨가한 후 반응 혼합물을 0°C에서 1시간동안 교반하였다. 반응이 완결된 후에 과량의 MeOH를 증발시키고, 0°C에서 물을 천천히 첨가하여 반응물을 급냉시키고 EtOAc로 추출하였다. 유기층을 모아서 염수（brine）로 세척하고, MgS04로 건조시킨 다음 여과하고 감압하에 농축하였다. 무수 DCM중 알코올 용액에 Dess-Martin periodinane을 첨가하고, 반응 혼합물을 실온에서 12시간동안 교반하였다. 반응이 완결된 후에 반응물을 DCM으로 희석하고 포화 중탄산나트륨 용액 , 물 및 염수로 세척하였다. 유기층을 MgS04로 건조시킨 다음 여과하고 감압하에 농축하였다. 잔류을 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-15% EtOAc）로 정제하여 표제 화합물을 흰색 고체（0.26 g,수율 88%）로 수득하였다. Synthesis of (½) To a solution of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate in anhydrous MeOH was carefully added NaB¾ at 0°C. After that, the reaction mixture was stirred at 0 ° C for 1 hour. 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 MgS0 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 nucleic acid) to give the title compound as a white solid (0.26 g, yield 88%).

¾ NMR（CDCls,400 MHz） 510.25（s, 1H）,8.13（d,J = 8.0 Hz,2H）,7.39（d,J = 8.4 Hz,2H） 단계 3： 2 -플루오로-서·（（5-（4-（트리플루오로메특시）페닐）- 1,3, 4 -티아디아졸- 2- 일）메틸）아닐린 （15）의 합성 2022/249113 ?01/162022/054935 상기 실시예 4의 일반적 과정 8 에 따라 표제 화합물을 합성하였다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-15% 0此）로 정제하여 표제 화합물을 흰색 고체（0.12 § 1 수율 57%）로 수득하였다. ¾ NMR（CDCls,400 MHz） 510.25（s, 1H）,8.13（d,J = 8.0 Hz,2H）,7.39（d,J = 8.4 Hz,2H） Step 3： 2-Fluoro-ser（（ Synthesis of 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)aniline (15) 2022/249113 -01/162022/054935 The title compound was synthesized according to the general procedure 8 of Example 4 above. Purification by flash column chromatography (silica gel, 0-15% 0% in nucleic acid) gave the title compound as a white solid (0.12 § 1 yield 57%).

¾ ■!? （00013, 400

Figure imgf000084_0001
57.96 （山 / = 8.4 ¾， 에）， 7.30 （（1, / = 8.4 ¾， 에），¾ ■!? (0001 3 , 400
Figure imgf000084_0001
57.96 （山 / = 8.4 ¾， to）， 7.30 （（1, / = 8.4 ¾， to），

7.05-6.96 （ 210 , 6.78-6.70 （뺘 211） , 4.87 （（1, / = 6.4

Figure imgf000084_0002
211） , 4.78 , 내） 단계 4： ·（2 -플루오로페닐）- ·（（5-（4-（트리플루오로메특시）페닐）- 1,3,4- 티아디아졸- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 （16） （화합물 157）의 합성 상기 실시예 4의 일반적 과정 （：에 따라 표제 화합물을 합성하였다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-30% 0此）로 정제하여 표제 화합물을 흰색 고체（24.0 1四, 수율 19%）로 수득하였다. 7.05-6.96 （ 210 , 6.78-6.70 （ subtract 211） , 4.87 （ （1, / = 6.4
Figure imgf000084_0002
211) , 4.78 , within) Step 4: (2-fluorophenyl)- (5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl Synthesis of )methyl)quinoxaline-2-carboxamide (16) (Compound 157) The title compound was synthesized according to the general procedure of Example 4 above (:). Purification by flash column chromatography (silica gel, 0-30% 0% in nucleic acid) gave the title compound as a white solid (24.0 14, yield 19%).

¾ ■!? （00013, 400

Figure imgf000084_0003
59.28 （ 내）， 8.07 ， 1胎 6（1, 내）， 8.05 （（1, / = 8.4¾ ■!? (0001 3 , 400
Figure imgf000084_0003
59.28 (inside)， 8.07 ， 1st 6（1, inside）， 8.05 （（1, / = 8.4

¾ ， 2¾， 7.78 （ / = 7.6

Figure imgf000084_0004
내）， 7.70-7.64 （ 211）， 7.34 （（1, / = 8.4
Figure imgf000084_0005
211），¾ ， 2¾， 7.78 （ / = 7.6
Figure imgf000084_0004
My)， 7.70-7.64 （ 211）， 7.34 （（1, / = 8.4
Figure imgf000084_0005
211),

7.29-7.27 （［ 선， 내）， 7.20 （＜¾， / = 6.8 ¾， 내）， 7.05 0；， / = 7.6 ¾， 내），7.29-7.27 （【 Line, within）， 7.20 （＜¾， / = 6.8 ¾， within）， 7.05 0；， / = 7.6 ¾， within），

6.95 ， / = 9.4 ¾， 내）， 5.64 （（1, / = 14.0 ¾， 내）， 5.44 （（1, / = 15.2 ¾， 내） 상기 실시예 5의 방법으로 사용하되 , 실시예 5의 단계 1에서 에틸 5 -브로모- 1,3,4- 티아디아졸- 2 -카르복실례이트와 （4-（트리플루오로메톡시）페닐）보론산 대신에 다양한 브로모티아디아졸 유도체와 보론산 유도체를 출발물질로 하여 , 하기 표 3에 나타낸 화합물 155 내지 157을 제조하였다. 6.95, / = 9.4 ¾, within), 5.64 ((1, / = 14.0 ¾, within), 5.44 ((1, / = 15.2 ¾, within) used in the method of Example 5, but the steps of Example 5 Various bromotiadiazole derivatives and boronic acid derivatives instead of 1 to ethyl 5 -bromo- 1,3,4- thiadiazole- 2 -carboxylate and (4-(trifluoromethoxy)phenyl)boronic acid Using as a starting material, compounds 155 to 157 shown in Table 3 below were prepared.

【표 3】

Figure imgf000084_0006
2022/249113 ?01/162022/054935
Figure imgf000085_0001
중간체의 제조 일부 화합물을 합성함에 있어 스즈키 커플링 반응을 하기 위한 중간체는 하기 방법으로 제조하였다. 【Table 3】
Figure imgf000084_0006
2022/249113 ?01/162022/054935
Figure imgf000085_0001
Preparation of Intermediates Intermediates for the Suzuki coupling reaction in synthesizing some compounds were prepared by the following method.

[반응식 7] \¥02022/249113 1(17182022/054935

Figure imgf000086_0001
시약 및 조건 : (a) 상응하는 아릴 브로마이드 (aryl bromide) , Pd(dppf)Cl2.CH2Cl2,[Scheme 7] \¥02022/249113 1(17182022/054935
Figure imgf000086_0001
Reagents and conditions: (a) corresponding aryl bromide, Pd(dppf)Cl 2 .CH 2 Cl 2 ,

1.4-디옥산(1,4- 0표3116) :¾0, 95 °C , 12시간; (b) i ) 2 -플루오로아닐린(2_ f luoroani l ine) , 촉매 아세트산 (cat . acet ic acid) , MeOH, i i) 테트라하드로퓨란 (THF)에 있는 1.0 M NaB¾CN, 테트라하드로퓨란 (THF) , 실온, 12시간; (c) 염화 2 -퀴녹살로일 (2-quinoxaloyl chloride) , 트리에틸아민 (triethylamine) , CH2CI2, 0°C에서 실온, 12시간; (d) 프로파길 아민 (propargyl amine) , HATU, DIPEA, DMF, 실온, 24시간; (e) (PhSe)2, 셀렉트플루오 (selectf luor) , ¾0, CH3CN, 실온, 12시간; (f) 에틸 5 -브로모- 1,3, 4 -티아디아졸- 2 -카르복실례이트 (ethyl 5-bromo-1,4-dioxane (1,4-0 Table 3116): ¾0, 95 ° C, 12 hours; (b) i) 2-fluoroaniline (2_ fluoroani l ine), catalyst acetic acid (cat. acet ic acid), MeOH, ii) 1.0 M NaB¾CN in tetrahydrofuran (THF), tetrahydrofuran ( THF), room temperature, 12 hours; (c) 2-quinoxaloyl chloride, triethylamine, CH2CI2, 0 ° C to room temperature, 12 hours; (d) propargyl amine, HATU, DIPEA, DMF, room temperature, 24 hours; (e) (PhSe) 2 , selectfluor, ¾0, CH 3 CN, room temperature, 12 hours; (f) ethyl 5-bromo- 1,3,4-thiadiazole- 2-carboxylate (ethyl 5-bromo-

1.3.4-thi ad i azole- 2-carboxyl ate) , Pd(0Ac)2, 잔트포스 (xantphos) ,

Figure imgf000086_0002
몰포린 (yV_me比 lyl morphol ine) , 톨루엔 : ¾0 (2: 1) , 실온, 7시간; (g) NaB¾, MeOH, 0°C , 1시간; (h) 데스-마틴 페리오디난 (Dess-Mart in per iod inane) , CH2CI2, 실온, 12시간. 1.3.4-thi ad i azole- 2-carboxyl ate), Pd(0Ac)2, xantphos,
Figure imgf000086_0002
Morpholine (yV_me 比 lyl morphol ine), toluene: ¾0 (2: 1), room temperature, 7 hours; (g) NaB¾, MeOH, 0 ° C, 1 hour; (h) Dess-Mart in per iod inane, CH2CI2, room temperature, 12 hours.

［제조예］ 제조예 1. 에틸 5-(4 -메특시- 3 -메틸페닐)- 1,3, 4 -티아디아졸- 2 -카르복실례이트 (18) [Production Example] Production Example 1. Ethyl 5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazole-2-carboxylate (18)

RBF를 에틸 5 -브로모- 1,3, 4 -티아디아졸- 2 -카르복실례이트 (ethyl 5_br omo_ 1,3,4- thiadiazole-2-carboxylate) , (4-(트리플루오로메특시 )페닐)보론산 ((4-RBF is ethyl 5 -bromo- 1,3, 4 -thiadiazole- 2 -carboxylate (ethyl 5_br omo_ 1,3,4- thiadiazole-2-carboxylate) , (4- (trifluoromethoxylate) )phenyl)boronic acid ((4-

( t r i f 1 uo r ome t hoxy ) pheny 1 ) bo r on i c acid) , Pd(0Ac)2 및 잔트포스 (xantphos)로 2022/249113 ?01/162022/054935 채웠다. 톨루엔（1:01116116）에 있는 71^ 메틸 몰포린 （7\½161;11 1 111이*1）11011116） 용액을 첨가한 후 물（¾0）를 첨가하였다. 반응 혼합물을 실온에서 7시간동안 강하게 교반하였다. 반응이 완료된 후, 잔류물을 에틸 아세테이트（ 0此）에 재용해시키고 유기층을 물（¾0）과 염수로 세척한 후 ¾位304로 건조시켜 감압 상태에서 증발시켰다. 플래시 칼럼 크로마토그래피（실리카겔 , 핵산 중 0-10% 0此）로 정제하여 표제 화합물을 흰색 고체（0.65 §, 수율 84%）로 수득하였다.

Figure imgf000087_0002
제조예 2. 5-（4 -메특시- 3 -메틸페닐）- 1,3, 4 -티아디아졸- 2- ）메탄올（19） 무수 메탄올（¾¾（»） （5.011） 중 에스테르 라） （1.0당량）의 용액에 則4 （2.0당량）을 0°（：에서 아르곤 대기하에 조심스럽게 첨가하고 반응 혼합물을 0°（：에서 1시간동안 교반하였다. 반응이 완료된 후 , 여분의 메탄올（¾¾（¾）를 증발시키고 반응물을 0°（：에서 물을 천천히 첨가하여 급냉시키고 에틸 아세테이트（ 0此）로 추출하였다. 혼합된 유기층을 염수로 세척하고 ¾¾쌨4로 건조시켜 여과한 다음 진공에서 농축시켰다. 플래시 칼럼 크로마토그래피（실리카 겔 , 핵산 중 0-50% 로 정제하여 표제 화합물을 흰색 고체（0.58 §, 수율 100%）로 수득하였다.( trif 1 uo r ome t hoxy ) pheny 1 ) bo r on ic acid), Pd(0Ac) 2 and xantphos 2022/249113 ?01/162022/054935 filled. A solution of 71^ methylmorpholine (7\½161;11 1 111 * 1) 11011116) in toluene (1:01116116) was added followed by water (¾0). The reaction mixture was vigorously stirred at room temperature for 7 hours. After the reaction was completed, the residue was redissolved in ethyl acetate (0此), and the organic layer was washed with water (¾0) and brine, dried with ¾030 4 and evaporated under reduced pressure. Purification by flash column chromatography (silica gel, 0-10% 0% in nucleic acid) gave the title compound as a white solid (0.65 § , yield 84%).
Figure imgf000087_0002
Production Example 2. Esters of 5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazole-2-)methanol (19) anhydrous methanol (¾¾ (») (5.011) (5.011) Ester R) (1.0 equivalent) was carefully added to a solution of 則4 (2.0 equivalent) at 0 ° (: under an argon atmosphere, and the reaction mixture was stirred at 0 ° (:) for 1 hour. After the reaction was completed, excess methanol (¾¾ (¾) was evaporated, and the reactant was quenched by slowly adding water at 0 ° (:) and extracted with ethyl acetate (0此). The combined organic layers were washed with brine, dried over ¾ sie4, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-50% in nucleic acid) gave the title compound as a white solid (0.58 § , yield 100%).

¾ ■!? 0103 , 400

Figure imgf000087_0001
6 7.76 （（1, / = 6.8 ¾， 내）， 7.75 ， 내）， 6.89 （（1, / =¾ ■!? 0103 , 400
Figure imgf000087_0001
6 7.76 （(1, / = 6.8 ¾, within)， 7.75 ， within)， 6.89 （（1, / =

8.4 ¾， 내）， 5.09 （（1, / = 6.4 ¾， 에）， 3.89 ， 해）， 2.78 （ / = 6.4 ¾， 내）， 2.27 , 해） 8.4 ¾, within)， 5.09 （(1, / = 6.4 ¾， within)， 3.89 ， year）， 2.78 （ / = 6.4 ¾， within）， 2.27 ， year）

［실험예］ [Experimental example]

KRAS와 AIMP2-DX2의 발암성 상호작용에 대한 PPI（protein-protein interaction） 억제제를 발굴하기 위해 NanoBiT 기반 스크리닝 시스템을 사용한 화합물 2022/249113 ?01/162022/054935 라이브러리 스크리닝을 진행하였다. 본 실험예에서는 하기 재료와 기기를 사용하였다. Compounds using a NanoBiT-based screening system to discover protein-protein interaction (PPI) inhibitors for the oncogenic interaction of KRAS and AIMP2-DX2 2022/249113 ?01/162022/054935 library screening was performed. In this experimental example, the following materials and equipment were used.

• 화합물 라이브러리 (동국대 제공의 1 , 697개의 다양한 화합물 라이브러리 ) 및 1 , 102개의 상업용 화합물 라이브러리 (셀렉캠 : Sel leckchem) • Compound library (1,697 various compound libraries provided by Dongguk University) and 1,102 commercial compound libraries (Seleckchem: Sel leckchem)

• RPMI + lOmM HEPES 배지 (Hyclone) • RPMI + lOmM HEPES Medium (Hyclone)

• 소 태아 혈청 (Fetal Bovine Serum, Hyclone) • Fetal Bovine Serum (Hyclone)

• 페니실린/스트렙토마이신 (Hyclone) • Penicillin/Streptomycin (Hyclone)

• 트립신 (Hyclone) • Trypsin (Hyclone)

• Turbofect (Thermo) • Turbofect (Thermo)

· 디메틸 술폭시드 (Dimethyl Sulphoxide) (DMSO) (Sigma) Dimethyl Sulphoxide (DMSO) (Sigma)

• Nano-Glo 생세포 분석 시스템 키트 (Nanc广 Glo Live Cel 1 Assay System Ki t , Pr omega)• Nano-Glo live cell assay system kit (Nanc广 Glo Live Cel 1 Assay System Kit , Pro omega)

• 플라스미드 미디프렙 키트 (Midi-prep Ki t , Qiagen) • Plasmid Midi-prep Kit (Midi-prep Kit, Qiagen)

• 세포 배양 접시 100 X 15mm (Nunc) • Cell culture dish 100 X 15mm (Nunc)

• 바닥이 평평한 흰색 96 -웰 플레이트 (Corning) • Flat bottom white 96-well plates (Corning)

• CH0-K1 세포주 (ATCC) • CH0-K1 cell line (ATCC)

• Glomax Microplate Reader Discover (Promega) • Glomax Microplate Reader Discover (Promega)

• Countess I I FL 자동세포계수기 (Automated Cel l Counter) (Thermo) • Countess I I FL Automated Cell Counter (Thermo)

• 트리판 블루 염색약 0.4% ( Invi trogen) • Trypan blue dye 0.4% ( Invi trogen)

• LgBiT-AIMP2-DX2 (Biocon)： LgBiT을 함께 발현할 수 있는 AIMP2-DX2 • LgBiT-AIMP2-DX2 (Biocon): AIMP2-DX2 capable of co-expressing LgBiT

• SmBiT-KRAS (Biocon)： SmBiT을 함께 발현할 수 있는 KRAS • SmBiT-KRAS (Biocon): KRAS capable of co-expressing SmBiT

• LgBiT-PRKAR2A (Biocon)： LgBiT을 함께 발현할 수 있는 PRKAR2A • LgBiT-PRKAR2A (Biocon): PRKAR2A capable of co-expressing LgBiT

• SmBiT-PRKACA (Biocon)： SmBiT을 함께 발현할 수 있는 PRKACA 실험예 1. 프로토콜 먼저 2산06개의 010-1(1 세포를 100x15 ■ 세포 배양 접시에 시딩하고 24시간 배양한 2022/249113 ?01/162022/054935

Figure imgf000089_0001
세포에 형질주입시켰다. 형질주입 (transfection) • SmBiT-PRKACA (Biocon): Experimental example of PRKACA capable of co-expressing SmBiT 1. Protocol First, 200 6 pieces of 010-1 (100x15 cells were seeded on a cell culture dish and cultured for 24 hours). 2022/249113 ?01/162022/054935
Figure imgf000089_0001
Cells were transfected. Transfection

1.5 mL 에펜도르프 (E抑 endorf) 튜브를 준비하여 LgBiT-AIMP2-DX2 및 SmBiT-KRAS를 각각 4 y g씩 넣어주었다. 플라스미드가 포함된 튜브에 예열해둔 무혈청 RPMI 배지 600 y L를 첨가한 후 5초간 볼텍싱하여 혼합하였다. 그 다음 16 y L의 Turbofect를 튜브에 첨가하고 5초간 볼텍싱하여 혼합한 후 15분 동안 방치하였다. 반응 튜브를 방치하는 동안 배양 접시에서 배양액을 제거한 후 6mL의 새로운 세포 배양배지를 첨가하였다. 15분 후, 반응 혼합물을 세포 배양 접시에 첨가하고 부드럽게 혼합한 후 C02 배양기에서 4시간 동안 배양하였다. 4시간 후에 배지를 새로운 세포 배양배지로 교환하였다. 24시간 후 세포를 배양 접시에서 분리하여 lOmL의 RPMI 성장 배지에 재현탁시켰다. 세포 현탁액 10 y L에 10y L의 트리판 (trypan) 블루 염색약 0.4%를 첨가한 후 Countess II FL Automated Cel l Counter를 사용하여 세포수를 측정하였다. 측정된 세포수를 기반으로 25, 000개의 형질주입된 세포를 바닥이 평평한 흰색 96웰 플레이트에 시딩하였다. 24시간 배양 후 세포 배양배지를 제거하고 화합물 (3 yM)이 첨가된 무혈청 RPMI 배지 100 y L를 세포 플레이트에 첨가한 후 4시간 동안 배양하였다. 4시간 후 아래와 같이 Glomax Discover Microplate Reader를 사용하여 0.4초/웰의 측정시간 (integration time)으로 나노루시퍼라제 (Nanoluciferase) 활성을 측정하였다. A 1.5 mL Eppendorf tube was prepared and each 4 yg of LgBiT-AIMP2-DX2 and SmBiT-KRAS was added thereto. After adding 600 y L of preheated serum-free RPMI medium to the tube containing the plasmid, the mixture was mixed by vortexing for 5 seconds. 16 y L 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 a cell culture dish, mixed gently, and incubated in a C0 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 lOmL of RPMI growth medium. After adding 0.4% of 10 y L of trypan blue dye to 10 y L 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 y L of serum-free RPMI medium supplemented with the compound (3 yM) 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.

Nano-Glo Live Cell 분석 준비 사용하기 전에 Nano-Glo® LCS 희석 완충액을 녹여 실온으로 평형화시켰다. 준비된 튜브에 LgBiT-AIMP2-DX2 및 SmBiT-KRAS를 각각 4 yg씩 첨가하였다. 1.25 부피의 Nano-Glo® Live Cel l 기질과 23.75 부피의 Nano-Glo® LCS 희석 완충액을 조합하고 볼텍싱에 의해 잘 혼합하여 소정량의 재구성된 Nano-Glo® Live Cel l 시약을 2022/249113 ?01/162022/054935 제조하였다. （장기간 보관하거나 빛에 노출되면 시약 활성에 손실이 발생할 수 있으므로, 각 실험마다 새로운 Nano-Glo® Live Cel l 시약을 준비하였으며 시약 제조 절차는 어두운 조건에서 수행하였다.） Nano-Glo® Live Cel l 시약을 볼텍싱에 의해 잘 혼합하였다. 모든 웰에 제조된 Nano-Glo® Live Cel l 시약을 25 y L씩 첨가한 후 37°C , 5% C02 조건의 가습 배양기에 10분간 배양하였다. 실험예 2. 선택성 확인 Nano-Glo Live Cell Assay Preparation Nano-Glo ® LCS dilution buffer was thawed and allowed to equilibrate to room temperature before use. 4 yg each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. 1.25 volume of Nano-Glo ® Live Cell substrate and 23.75 volume of Nano-Glo ® LCS dilution buffer were combined and mixed well by vortexing to obtain a predetermined amount of reconstituted Nano-Glo ® Live Cell reagent. 2022/249113 -01/162022/054935 was prepared. (Since long-term storage or exposure to light may cause loss of reagent activity, a new Nano-Glo ® Live Cell reagent was prepared for each experiment, and the reagent preparation procedure was performed in the dark.) Nano-Glo ® Live Cell l Reagents were mixed well by vortexing. After adding 25 y L of the prepared Nano-Glo ® Live Cell l reagent to all wells, the cells were incubated for 10 minutes in a humidified incubator at 37 ° C and 5% C0 2 conditions. Experimental Example 2. Confirmation of selectivity

KRAS와 AIMP2-DX2의 결합에 대한 선택적 억제를 확인하기 위해 다음과 같은 실험을 수행하였다. 먼저 2x10® 개의 CH0-K1 세포를 100x15 mm 세포 배양 접시에 시딩하고 24시간 후에 LgBiT-PRKAR2A와 SmBiT-PRKACA를 세포에 형질주입시켰다. 형질주입 In order to confirm the selective inhibition of the binding between KRAS and AIMP2-DX2, the following experiment was performed. First, 2x10 ® 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

1.5 mL 에펜도르프（E抑 endorf） 튜브를 준비하여 LgBiT_PRKAR2A와 SmBiT-PRKACA를 각각 4 y g씩 첨가하였다. 플라스미드가 포함된 튜브에 예열해둔 무혈청 RPMI 배지 600 y L를 첨가한 후 5초간 볼텍싱하여 혼합하였다. 그 다음 16 y L의 Turbofect를 튜브에 첨가하고 5초간 볼텍싱하여 혼합한 후 15분 동안 방치하였다. 반응 튜브를 방치하는 동안 배양 접시에서 배지를 제거한 후 6mL의 새로운 세포 배양배지를 첨가하였다. 15분 후, 반응 혼합물을 세포 배양 접시에 첨가하고 부드럽게 혼합한 후 C02 배양기에서 4시간 동안 배양하였다. 4시간 후에 배지를 새로운 세포 배양배지와 교환하였다. 24시간 후 세포를 배양 접시에서 분리하여 lOmL의 RPMI 성장 배지에 현탁시켰다. 세포 현탁액 10 yL에 10 y L의 트리판 블루 염색약 0.4%를 첨가한 후 Countess II FL Automated Cel l Counter를 사용하여 세포수를 즉정하였다. 측정된 세포수를 기반으로 25, 000개의 형질주입된 세포를 바닥이 평평한 흰색 96- 웰 플레이트에 시딩하였다. 24시간 후 세포 배양배지를 제거하고 화합물（3 yM）이 첨가된 무혈청 RPMI 배지 100 y L를 세포 플레이트에 첨가한 후 4시간 동안 2022/249113 ?01/162022/054935 배양하였다. 4시간 후 아래와 같이 Glomax Discover Microplate Reader를 사용하여 0.4초/웰의 측정시간으로 나노루시퍼라제（Nanoluci ferase） 활성을 측정하였다. A 1.5 mL Eppendorf tube was prepared and 4 yg each of LgBiT_PRKAR2A and SmBiT-PRKACA were added thereto. After adding 600 y L of preheated serum-free RPMI medium to the tube containing the plasmid, the mixture was mixed by vortexing for 5 seconds. 16 y L 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 a cell culture dish, mixed gently, and incubated in a C0 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 lOmL of RPMI growth medium. After adding 10 yL of trypan blue dye 0.4% to 10 yL of the cell suspension, the number of cells was immediately counted using a Countess II FL Automated Cell Counter. Based on the measured cell number, 25,000 transfected cells were seeded in a flat bottom white 96-well plate. After 24 hours, the cell culture medium was removed, and 100 y L of serum-free RPMI medium supplemented with the compound (3 yM) was added to the cell plate for 4 hours. 2022/249113 -01/162022/054935 cultured. After 4 hours, Nanoluci ferase activity was measured at a measurement time of 0.4 seconds/well using the Glomax Discover Microplate Reader as follows.

Nano-Glo 니 0611 분석 준비 사용하기 전에 Nano-Glo® LCS 희석 완충액을 녹여 실온으로 평형화시켰다. 준비된 튜브에 LgBiT-AIMP2-DX2와 SmBiT-KRAS를 각각 4 씩 첨가하였다. 1.25 부피의 Nano-Glo® Live Cel l 기질과 23.75 부피의 Nano-Glo® LCS 희석 완충액을 조합하고 볼텍싱에 의해 잘 혼합하여 소정량의 재구성된 Nano-Glo® Live Cel l 시약을 제조하였다. （장기간 보관하거나 빛에 노출되면 시약 활성에 손실이 발생할 수 있으므로, 각 실험마다 새로운 Nano-Glo® Live Cel l 시약을 준비하였으며 시약 제조 절차는 어두운 조건에서 수행하였다.） Nano-Glo® Live Cel l 시약을 볼텍싱에 의해 잘 혼합하였다. 모든 웰에 제조된 Nano-Glo® Live Cel l 시약을 25 y L씩 첨가한 후 37°C , 5% C02 조건의 가습 배양기에 10분간 배양하였다. 실험예 3： 용량 의존성 확인 Nano-Glo Ni 0611 Assay Preparation Nano-Glo® LCS Dilution Buffer was thawed and allowed to equilibrate to room temperature before use. 4 each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo® Live Cell 1 reagent was prepared by combining 1.25 volumes of Nano-Glo® Live Cell 1 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 l Reagents were mixed well by vortexing. After adding 25 y L of the prepared Nano-Glo® Live Cell l reagent to all wells, it was incubated for 10 minutes in a humidified incubator at 37 ° C and 5% C0 2 conditions. Experimental Example 3: Confirmation of dose dependence

KRAS와 AIMP2-DX2 결합에 대한 용량 의존적 억제를 확인하기 위해 다음과 같은 실험을 수행하였다. 먼저 2x10® 개의 CH0-K1 세포를 100x15 mm 세포 배양 접시에 시딩하고 24시간 후에 LgBiT-AIMP2-DX2와 SmBiT-KRAS, 또는 LgBiT_PRKAR2A와 SmBiT-PRKACA를 세포에 형질주입시켰다. 형질주입 In order to confirm the dose-dependent inhibition of the binding between KRAS and AIMP2-DX2, the following experiment was performed. First, 2x10 ® CH0-K1 cells were seeded in a 100x15 mm cell culture dish, and 24 hours later, cells were transfected with LgBiT-AIMP2-DX2 and SmBiT-KRAS, or LgBiT_PRKAR2A and SmBiT-PRKACA. transfection

1.5 吐 에펜도르프（£；抑（ 此 ） 튜브를 준비하여

Figure imgf000091_0001
또는 ［ 미 구묘 묘요쇼와 ¾1이1니¾1（^쇼를 각각 4 !^씩 첨가하였다. 플라스미드가 포함된 튜브에 예열해둔 무혈청 1¾¾1 배지 600나 를 첨가한 후 5초간 볼텍싱하여 2022/249113 ?01/162022/054935 혼합하였다. 그 다음 16 y L의 Turbofect를 튜브에 첨가하고 5초간 볼텍싱하여 혼합한 후 15분 동안 방치하였다. 반응 튜브를 방치하는 동안 배양 접시에서 배지를 제거한 후 6mL의 새로운 세포 배양배지를 첨가하였다. 15분 후 , 반응 혼합물을 세포 배양 접시에 첨가하고 부드럽게 혼합한 후 C02 배양기에서 4시간 동안 배양하였다. 4시간 후에 배지를 새로운 세포 배양배지와 교환하였다. 24시간 후 세포를 배양 접시에서 분리하여 lOmL의 RPMI 성장 배지에 현탁시켰다. 세포 현탁액 10 에 10 의 트리판 블루 염색약 0.4%를 첨가한 후 Countess I I FL Automated Cel l Counter를 사용하여 세포수를 즉정하였다. 즉정된 세포수를 기반으로 25, 000개의 형질주입된 세포를 바닥이 평평한 흰색 96 -웰 플레이트에 시딩하였다. 24시간 후 세포 배양배지를 제거하고 3배로 연속 희석된 화합물 (0.003- 10, 50 y M)이 첨가된 무혈청 RPMI 배지 100 를 세포 플레이트에 첨가한 후 4시간 동안 배양하였다. 4시간 후 아래와 같이 Glomax Discover Microplate Reader를 사용하여 0.4초/웰의 즉정시간으로 나노루시퍼라제 (Nanoluci ferase) 활성을 측정하였다. 1.5 吐 Eppendorf（£；抑（ 此 ） prepare the tube
Figure imgf000091_0001
Or [Mi Gumyo Myoyosho and ¾1 this 1 Ni ¾1 (^ Sho each 4!^ were added. After adding 600 ml of preheated serum-free 1¾¾1 medium to the tube containing the plasmid, vortex for 5 seconds. 2022/249113 -01/162022/054935 mixed. 16 y L 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 C0 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 lOmL of RPMI growth medium. After adding 0.4% of 10 of trypan blue dye to 10 of the cell suspension, the cell number was immediately counted using a Countess II FL Automated Cell Counter. Based on the pre-determined cell number, 25,000 transfected cells were seeded in white flat-bottom 96-well plates. After 24 hours, the cell culture medium was removed, and serum-free RPMI medium 100 supplemented with three-fold serially diluted compounds (0.003-10, 50 y M) was added to the cell plate, followed by culturing for 4 hours. After 4 hours, Nanoluci ferase activity was measured at an immediate time of 0.4 seconds/well using the Glomax Discover Microplate Reader as follows.

Nano-Glo Live Cell 분석 준비 사용하기 전에 Nano-Glo® LCS 희석 완충액을 녹여 실온으로 평형화시켰다. 준비된 튜브에 LgBiT-AIMP2-DX2와 SmBiT-KRAS를 각각 4 씩 첨가하였다. 1.25 부피의 Nano-Glo® Live Cel l 기질과 23.75 부피의 Nano-Glo® LCS 희석 완충액을 조합하고 볼텍싱에 의해 잘 혼합하여 소정량의 재구성된 Nano-Glo® Live Cel l 시약을 제조하였다. (장기간 보관하거나 빛에 노출되면 시약 활성에 손실이 발생할 수 있으므로, 각 실험마다 새로운 Nano-Glo® Live Cel l 시약을 준비하였으며 시약 제조 절차는 어두운 조건에서 수행하였다. ) Nano-Glo® Live Cel l 시약을 볼텍싱에 의해 잘 혼합하였다. 모든 웰에 제조된 Nano-Glo® Live Cel l 시약을 25 y L씩 첨가한 후 37°C , 5% C02 조건의 가습 배양기에 10분간 배양하였다. 2022/249113 1^（:1^2022/054935 상기 실험 결과를 하기 표 4에 나타내었다.Nano-Glo Live Cell Assay Preparation Nano-Glo ® LCS Dilution Buffer was thawed and allowed to equilibrate to room temperature before use. 4 each of LgBiT-AIMP2-DX2 and SmBiT-KRAS were added to the prepared tube. A predetermined amount of reconstituted Nano-Glo ® Live Cell 1 reagent was prepared by combining 1.25 volumes of Nano-Glo ® Live Cell 1 substrate and 23.75 volumes of Nano-Glo ® LCS dilution buffer and mixing well by vortexing. (Since reagent activity may be lost when stored for a long period of time or exposed to light, a new Nano-Glo ® Live Cell reagent was prepared for each experiment, and the reagent preparation procedure was performed under dark conditions.) Nano-Glo ® Live Cell l Reagents were mixed well by vortexing. After adding 25 y L of the prepared Nano-Glo ® Live Cell l reagent to all wells, the cells were incubated for 10 minutes in a humidified incubator at 37 ° C and 5% C0 2 conditions. 2022/249113 1^（:1^2022/054935 The experimental results are shown in Table 4 below.

【표 4】

Figure imgf000093_0001
2022/249113 ?01/162022/054935
Figure imgf000094_0003
【Table 4】
Figure imgf000093_0001
2022/249113 ?01/162022/054935
Figure imgf000094_0003

ND: not determined의 약어로 IC¥가실험한농도에서 측정되지 않았음을 나타냄 상기 표 4에서

Figure imgf000094_0001
결합에 대한 본 발명 화합물의 억제율을 나타낸다. 1( 는 농도의존적 실험을 통해 사］ 2-0표2와 1¾ 3 결합을 50% 억제할 수 있는본 발명 화합물의 농도를 측정한 것이고,
Figure imgf000094_0002
2022/249113 ?01/162022/054935묘2쇼의 결합 억제를 통해 본 발명 화합물이 다른 결합에는 영향을 주지 않고 사¾032-0표2-1¾쇼3의 결합만 특이적으로 억제할 수 있다는 것을 보여준다. 본 발명에 따른 (3) 화합물 44 및 ( 화합물 48에
Figure imgf000095_0001
결합의 억제효능을 루시퍼라제 활성 측정으로 평가한 결과를 도 1에 나타내었다. 화합물 44 및 화합물
Figure imgf000095_0002
결합에 대해 효과적인 억제 활성을 나타내었다, 특히 , 화합물 44는 3 단일 농도에서
Figure imgf000095_0003
결합에 대해 86.46%의 결합억제율을 보였으며 , 이후 농도실험을 통해 사1?2-¾2-1¾ 3 결합의 50% 저해 농도 (1(：50)가 0.308111로 측정되었으며 ,
Figure imgf000095_0004
실험농도범위에서 比50가 측정되지 않았다어이는 사실에 비추어 볼때 , 화합물 44는
Figure imgf000095_0005
결합만을 특이적으로 저해하는 화합물임을 확인할 수 있다. 전술한 본 발명의 설명은 예시를 위한 것이며 , 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. ND: an abbreviation of not determined, indicating that IC ¥ was not measured at the tested concentration In Table 4 above
Figure imgf000094_0001
Inhibition rate of the compound of the present invention for binding is shown. 1 ( is the concentration of the compound of the present invention capable of inhibiting 50% of the 2-0 Table 2 and 1¾ 3 bond through a concentration-dependent experiment.
Figure imgf000094_0002
2022/249113 ?01/162022/054935 Through inhibition of the binding of myo2show, the compound of the present invention can specifically inhibit only the binding of 4¾0 3 2-0 Table 2-1¾ show 3 without affecting other bonds show what (3) Compound 44 and (Compound 48 according to the present invention
Figure imgf000095_0001
The results of evaluating the binding inhibitory effect by measuring the luciferase activity are shown in FIG. 1 . compound 44 and compound
Figure imgf000095_0002
exhibited effective inhibitory activity against binding, in particular, compound 44 at a single concentration of 3
Figure imgf000095_0003
It showed a binding inhibition rate of 86.46% for the binding, and after concentration experiments, the 50% inhibitory concentration (1(: 50 ) of the four 1?2-¾2-1¾ 3 linkage was measured as 0.308111,
Figure imgf000095_0004
In view of the fact that the ratio of 50 was not measured in the experimental concentration range, compound 44
Figure imgf000095_0005
It can be confirmed that the compound specifically inhibits only binding. 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

2022/249113 ?01/162022/054935 【청구범위】 2022/249113 ?01/162022/054935 【Claims】 【청구항 1] 하기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 : [화학식 1]
Figure imgf000096_0001
상기 식에서, [Claim 1] A compound represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof: [Formula 1]
Figure imgf000096_0001
In the above formula, X 및 는 각각 독립적으로 각각 0 또는 이고; X and are each independently 0 or ; ¾ 은 수소, 할로겐 , 하이드
Figure imgf000096_0002
■2, -0-（：1-6알킬- 0-（：1-6알킬, -0-（：0-5-6원 헤테로아릴, -0-쌨2-（：6-10아릴, 또는 -0 - 0½-（：6，아릴이고, 이때 상기 -6알킬, -6알콕시 , -0-（：0-5-6원 헤테로아릴, -0- 502-06-10 아릴, 및 0-0½-（：6-1（） 아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로 치환될 수 있고, ¾ is hydrogen, halogen, hydride
Figure imgf000096_0002
2, -0-(: 1-6 alkyl-0-(: 1-6 alkyl, -0-(:0-5-6 membered heteroaryl, -0-Xia 2 -(: 6-10 aryl, or -0 - 0½- (: 6 , aryl, wherein - 6 alkyl, - 6 alkoxy , -0- (: 0-5-6 membered heteroaryl, -0- 50 2 -0 6-10 aryl, and 0 -0½-(: 6-1 () aryls may each independently be unsubstituted or substituted with 1 to 3 halogens or 01-6alkyl; ¾ 는 수소, 01-6알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6알킬이거나; 또는 ¾및 는, 이들이 부착된 벤젠 고리와 함께 , 5- 10원 헤테로사이클릴 또는 5 - 10원 헤테로아릴을 형성할 수 있고; ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or ¾ and , together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl; ¾ 는 01-6 알킬 , 03-8 사이클로알킬 , - -6 알킬- ¾-8 사이클로알킬 , 06-10 아릴 , -01-6 알킬- 아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴 또는 - -6 알킬- 5-6원 헤테로사이클릴이고 , 이때 상기 01-6 알킬 , 03-8 사이클로알킬 , -01-6 알킬- ¾-8 사이클로알킬, 06-10 아릴, -01-6 알킬-（:6-10 아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴 및
Figure imgf000096_0003
헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 , ^ -¥（¾, 01-6알킬 , -⑴- 내알킬 또는 -000- 01-6알킬로 치환될 수 있고; 묘4는 -6알킬, -⑴- -6알킬,
Figure imgf000096_0004
헤테로아릴 , 5- 10원 헤테로사이클릴, 또는 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 01 - 2022/249113 ?01/162022/054935 ¾ is 01-6 alkyl, 0 3-8 cycloalkyl, -6 alkyl-¾- 8 cycloalkyl, 0 6-10 aryl, -01-6 alkyl- aryl, 5-6 membered heteroaryl, 5-6 membered Heterocyclyl or - - 6 alkyl- 5-6 membered heterocyclyl, wherein the above 0 1-6 alkyl, 0 3-8 cycloalkyl, -0 1-6 alkyl-¾- 8 cycloalkyl, 0 6 -10 Aryl, -01-6 alkyl- (: 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and
Figure imgf000096_0003
each heterocyclyl may be independently unsubstituted or substituted with 1 to 4 halogens, ^ -¥(¾, 0 1-6 alkyl, -⑴-inalkyl or -000-01-6alkyl; Myo 4 is -6 alkyl, -⑴- -6 alkyl,
Figure imgf000096_0004
heteroaryl , 5-10 membered heterocyclyl, or -5-6 membered heteroaryl-5-6 membered heterocyclyl, wherein the above 0 1 - 2022/249113 ?01/162022/054935 6 알킬, -⑴- -6 알킬, 06-10 아릴, 00 06-10 아릴, 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴 및 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐,
Figure imgf000097_0001
ᅰ02, _¥(¾, 01-6 알킬, 01-6 알콕시 , 또는 - ■-(：0-(：1-6알킬로 치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 지방족 헤테로고리이다. 6 alkyl, -⑴- -6 alkyl, 0 6 -10 aryl, 00 06-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and -5-6 membered heteroaryl- 5-6 membered hetero each cyclyl is independently unsubstituted or contains 1 to 4 halogen;
Figure imgf000097_0001
ᅰ0 2 , _¥(¾, 01-6 alkyl, 01-6 alkoxy , or - ■-(: 0-(: 1-6 alkyl may be substituted; the heteroaryl may be 1 to 1 selected from 0 and £ It is an aromatic heterocycle containing 4 heteroatoms, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. 【청구항 2] 제 1항에 있어서, 상기 화학식 1의 화합물이 하기 화학식 2의 화합물인 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 : [Claim 2] The compound according to claim 1, wherein the compound of Formula 1 is a compound of Formula 2 below, an isomer thereof, or a pharmaceutically acceptable salt thereof: [화학식 到
Figure imgf000097_0002
상기 식에서, [chemical formula 到
Figure imgf000097_0002
In the above formula, ¾ 은 수소, 할로겐 , 하이드록시 , -6알킬 , -6알콕시 , _0~ ⑴ -5-6원 헤테로아릴 , - 0-502_06-10아릴, 또는 -0세½-06-10아릴이고, 이때 상기 01-6알킬, 01-6알콕시 , _0 - 0)-5-6원 헤테로아릴, -0-502-06-10 아릴, 및 0-^2-06-10 아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로 치환될 수 있고,¾ is hydrogen, halogen, hydroxy, -6 alkyl, -6 alkoxy, _0 to ⑴ -5-6 membered heteroaryl, -0-502_06-10 aryl, or -0 ½-06-10 aryl, In this case, the 01-6 alkyl, 01-6 alkoxy, _ 0 - 0) -5-6 membered heteroaryl, -0-502-06-10 aryl, and 0-^2-0 6 -10 aryl are each independently may be unsubstituted or substituted with 1 to 3 halogens or 01-6alkyl; ¾ 는 수소, 01-6알킬, 또는 1 내지 3개의 할로겐으로 치환된 01-6알킬이거나; 또는 ¾및 는, 이들이 부착된 벤젠 고리와 함께 , 5- 10원 헤테로사이클릴 또는 5 - 10원 헤테로아릴을 형성할 수 있고; ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; or ¾ and , together with the benzene ring to which they are attached, may form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl; ¾ 는 03-8사이클로알킬 , -01-6알킬- ¾-8사이클로알킬 , 06-10아릴 , -01-6알킬- 아릴 , 5-6원 헤테로아릴, 또는 5-6원 헤테로사이클릴이고, 이때 상기 ¾-8사이클로알킬, 아릴, 5-6원 헤테로아릴 및 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, 01-6 알킬, 또는 -000-01-6 알킬로 치환될 수 2022/249113 ?01/162022/054935 있고 ; 묘4는 -6알킬 , -⑴- 내알킬 , ，아릴 , -⑴ - ，아릴 , 5- 10원 헤테로아릴 , 5- 10원 헤테로사이클릴, 또는 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 -6알킬 , -⑴- 내알킬 , 아릴 , -⑴ _（〕6，아릴 , 5- 10원 헤테로아릴 , 5- 10원 헤테로사이클릴 및 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐
Figure imgf000098_0001
_炯2, _¥（¾, 01-6알킬, 01-6 알콕시 , 또는 - ■-（：0-（：1-6알킬로치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를포함하는지방족헤테로고리이다. ¾ is 0 3-8 cycloalkyl, -01-6 alkyl-¾- 8 cycloalkyl, 0 6-10 aryl, -01-6 alkyl- aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl Wherein the ¾- 8 cycloalkyl, aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl are each independently unsubstituted, or 1 to 4 halogen, 01-6 alkyl, or -000- may be substituted with 01-6 alkyl 2022/249113 ?01/162022/054935 and ; Key 4 is -6 alkyl, -⑴-internal alkyl, aryl, -⑴-, aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or -5-6 membered heteroaryl-5-6 membered Heterocyclyl, wherein the above -6 alkyl, -⑴-internal alkyl, aryl, -⑴ _(] 6 , aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and -5-6 membered heteroaryl - 5-6 membered heterocyclyls are each independently unsubstituted or contain 1 to 4 halogen atoms
Figure imgf000098_0001
_炯2, _¥（¾, 01-6 alkyl, 01-6 alkoxy , or - ■-(:0-(: 1-6 alkyl; The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. 【청구항 3】 제 2항에 있어서, [Claim 3] The method of claim 2, ¾은 수소, 할로겐, 하이드록시 , -6알킬 , -6알콕시 , -0-¥ -퓨라닐 , -0 02 -페닐 , 또는 -0-抑 2 -페닐이고, 이때 상기 -6알킬, -6알콕시 , -0-0）-퓨라닐, -0-쌨2 -페닐 및 -0-（：¾ -페닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐 또는 01-6알킬로치환될 수 있고, 묘2는수소, 01-6알킬, 또는 1내지 3개의 할로겐으로치환된 01-6알킬이거나; 또는 ¾ 및 묘2는, 이들이 부착된 벤젠 고리와 함께, 벤조디옥솔, 벤즈옥사졸, 벤조퓨란, 디하이드로벤조퓨란, 디옥소이소인돌린 고리를형성할수 있고; 묘3는 03-8사이클로알킬, -0½ 3-8사이클로알킬, 페닐, 벤질, 피리디닐, 피라졸릴, 테트라하이드로피라닐 또는 피페리디닐이고, 이때 상기 ¾-8사이클로알킬, _0½_（：3-8 사이클로알킬 , 페닐 , 벤질 , 피리디닐 , 피라졸릴 , 테트라하이드로피라닐 및 피페리디닐은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, 01-6 알킬 , 또는 -（:⑷- 내알킬로 치환될 수 있고; 묘4는 01-6 알킬 , -⑴- -6 알킬 , 페닐 , 나프틸 , -⑴페닐 , 퓨라닐 , 옥사졸릴 , 이소옥사졸릴 , 티아졸릴 , 피라지닐 , 벤조퓨라닐 , 퀴녹살리닐 , 2022/249113 1^(:1^ 2022/054935 디하이드로벤조디옥시닐 ,
Figure imgf000099_0001
이고, 이때 상기¾ is hydrogen, halogen, hydroxy, -6 alkyl, -6 alkoxy, -0-¥ -furanyl, -0 0 2 -phenyl, or -0-抑2 -phenyl, wherein said -6 alkyl, -6 Alkoxy, -0-0)-furanyl, -0-Xia 2 -phenyl and -0-(:¾-phenyl each independently may be unsubstituted or substituted with 1 to 3 halogens or 01-6 alkyl. 2 is hydrogen, 01-6alkyl, or 01-6alkyl substituted with 1 to 3 halogens; or ¾ and seed 2, together with the benzene ring to which they are attached, can form a benzodioxol, benzoxazole, benzofuran, dihydrobenzofuran, dioxoisoindoline ring; Cat 3 is 0 3 -8 cycloalkyl, -0½ 3-8 cycloalkyl, phenyl, benzyl, pyridinyl, pyrazolyl, tetrahydropyranyl or piperidinyl, wherein the above ¾- 8 cycloalkyl, _0½_ (: 3 -8 cycloalkyl , phenyl , benzyl , pyridinyl , pyrazolyl , tetrahydropyranyl and piperidinyl are each independently unsubstituted, or 1 to 4 halogen, 01-6 alkyl, or -(:⑷- may be substituted with alkyl; Cat 4 is 01-6 alkyl, -⑴- -6 alkyl, phenyl, naphthyl, -⑴ phenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxalinyl, 2022/249113 1^(:1^ 2022/054935 dihydrobenzodioxinyl,
Figure imgf000099_0001
and, at this time, the 01-6 알킬 , -⑴ _（：1-6 알킬 , 페닐 , 나프틸 , -⑴ 페닐 , 퓨라닐 , 옥사졸릴 , 티아졸릴 , 피라지닐 , 벤조퓨라닐 , 퀴녹살리닐 , 디하이드로벤조디옥시닐
Figure imgf000099_0002
Figure imgf000099_0003
독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 , - ■2 , _炯2, _¥（¾, 01-6 알킬 또는 01-6 알콕시로 치환될 수 있는 것인 화합물 , 이의 이성질체 또는 이의 약학적으로 허용가능한 염 . 01-6 alkyl, -⑴ _(:1-6 alkyl, phenyl, naphthyl, -⑴ phenyl, furanyl, oxazolyl, thiazolyl, pyrazinyl, benzofuranyl, quinoxalinyl, dihydrobenzodioxinyl
Figure imgf000099_0002
Figure imgf000099_0003
Compounds that are independently unsubstituted or may be substituted with 1 to 4 halogens, -2, _炯2, _¥(¾, 01-6 alkyl or 01-6 alkoxy, isomers thereof, or pharmaceutical products thereof acceptable salts. 【청구항 4] 제 2항 또는 제 3항에 있어서 , 상기 화합물이 하기로 이루어진 군으로부터 선택되는 어느 하나의 화합물 , 이의 이성질체 또는 이의 약학적으로 허용가능한 염 : [Claim 4] The compound according to claim 2 or 3, wherein the compound is any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof: （1） 於（2 -플루오로페닐）- 於（（5 -페닐티오펜-2 -일）메틸）퀴녹살린-2 -카르복사미드 ;(1) 於(2-fluorophenyl)- 於((5-phenylthiophen-2-yl)methyl)quinoxaline-2-carboxamide; （2）於（2 -플루오로페닐）- （（5 -페닐티오펜-2 -일）메틸）퓨란-2 -카르복사미드 : (2) 於 (2-fluorophenyl)- ((5-phenylthiophen-2-yl) methyl) furan-2-carboxamide: （3） 於（2 -플루오로페닐）-於（（5-細_톨릴）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드 ; (3) 於(2-fluorophenyl)-於((5-細_tolyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （4） 於（2 -플루오로페닐）-於（（5-細_톨릴）티오펜- 2 -일）메틸）퓨란 -2 -카르복사미드 ;(4) 於(2-fluorophenyl)-於((5-細_tolyl)thiophen-2-yl)methyl)furan-2-carboxamide; （5） 於사이클로펜틸-聲（（5-（4 -플루오로페닐）티오펜-2 -일）메틸）퓨란 -2- 카르복사미드 ; 2022/249113 ?01/162022/054935 (5) Cyclopentyl-聲（(5-(4-fluorophenyl)thiophen-2-yl)methyl）furan-2-carboxamide; 2022/249113 ?01/162022/054935 （ 6） 於사이클로핵실-於（（ 5-（ 4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드 ; ( 6) cyclohexyl-於 (( 5-( 4 -fluorophenyl) thiophen- 2 -yl) methyl) furan- 2-carboxamide; （7） 7^（（5 -（4 -플루오로페닐）티오펜- 2 -일）메틸）-7 페닐퓨란- 2 -카르복사미드 ;(7) 7^((5-(4-fluorophenyl)thiophen-2-yl)methyl)-7 phenylfuran-2-carboxamide; （8） （2 -클루오로페닐）- （（5-（4 -클루오로페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드 ; (8) (2-chlorophenyl)-((5-(4-chlorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （ 9） 於（2 -플루오로페닐）-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）옥사졸- 4- 카르복사미드 ; (9) 於(2-fluorophenyl)-於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）oxazole-4-carboxamide; （ 10） （2 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）티아졸- 4- 카르복사미드 ; (10) (2-fluorophenyl)-((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-4-carboxamide; （11） （2 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）티아졸- 2- 카르복사미드 ; (11) (2-fluorophenyl)-((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiazole-2-carboxamide; （ 12） （2 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）피라진- 2- 카르복사미드 ; (12) (2-fluorophenyl)-((5-(4-fluorophenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; （13） 於（（5-（4 -플루오로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (13) 於（(5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl）-於(2-fluorophenyl)quinoxaline-2-carboxamide; （14） 於（（5-（4 -플루오로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（3- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (14) 於((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl)-於(3-fluorophenyl)quinoxaline-2-carboxamide; （15） 於벤질-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2 -카르복사미드 ;(15) 於benzyl-於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）furan-2-carboxamide; （16） 於（（5-（4 -클로로페닐）티오펜- 2 -일）메틸）-聲（2 -플루오로페닐）퓨란 -2- 카르복사미드 ; (16) 於（(5-(4-chlorophenyl)thiophen-2-yl）methyl)-聲(2-fluorophenyl)furan-2-carboxamide; （17） 7^（（5 -（4 -클로로페닐）티오펜- 2 -일）메틸） -聲（3 -플루오로페닐）퓨란- 2- 카르복사미드 ; (17) 7^((5-(4-chlorophenyl)thiophen-2-yl)methyl)-聲(3-fluorophenyl)furan-2-carboxamide; （18） 7^（（5 -（4 -클로로페닐）티오펜- 2 -일）메틸）-聲（ 2 -플루오로페닐）퀴녹살린- 2- 카르복사미드 ; (18) 7^((5-(4-chlorophenyl)thiophen-2-yl)methyl)-聲(2-fluorophenyl)quinoxaline-2-carboxamide; （19） 7^（（5 -（4 -클로로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (19) 7^((5-(4-chloro-3-methylphenyl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935 （20） 7^（（5 -（4 -클로로페닐）티오펜- 2 -일）메틸）-聲（3 -플루오로페닐）퀴녹살린- 2- 카르복사미드; (20) 7^((5-(4-chlorophenyl)thiophen-2-yl)methyl)-聲(3-fluorophenyl)quinoxaline-2-carboxamide; （21） 於（（5-（4 -클로로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（3- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (21) 於（(5-(4-chloro-3-methylphenyl)thiophen-2-yl）methyl）-於(3-fluorophenyl)quinoxaline-2-carboxamide; （22） （3 -플루오로페닐）- （（5-（4 -메틸- 3-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (22) (3-fluorophenyl)-((5-(4-methyl-3-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （23） （2 -플루오로페닐）- （（5-（4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (23) (2-fluorophenyl)-((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （24） （3 -플루오로페닐）- （（5-（4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (24) (3-fluorophenyl)-((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （25） （2 -플루오로페닐）- （（5-（4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (25) (2-fluorophenyl)-((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （26） （3 -플루오로페닐）- （（5-（4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (26) (3-fluorophenyl)-((5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （27） （3 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메틸）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (27) (3-fluorophenyl)-((5-(3-methyl-4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （28） 於벤질-於（（5-（4-（트리플루오로메틸）페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (28) benzyl-於（(5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)methyl）furan-2-carboxamide; （29） （2 -플루오로페닐）-於（（5-（4 -하이드록시페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (29) (2-fluorophenyl)-於（(5-(4-hydroxyphenyl)thiophen-2-yl)methyl）furan-2-carboxamide; （30） （2 -플루오로페닐）- （（5-（4 -하이드록시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (30) (2-fluorophenyl)-((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （31） ^（（5-（3 -에틸- 4 -하이드록시페닐）티오펜- 2 -일）메틸）- （2_ 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (31) ^((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl)-(2_fluorophenyl)quinoxaline-2-carboxamide; （32） （3 -플루오로페닐）- （（5-（4 -하이드록시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (32) (3-fluorophenyl)-((5-(4-hydroxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935 （33） （（5-（3 -에틸- 4 -하이드록시페닐）티오펜- 2 -일）메틸）- （3- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (33) ((5-(3-ethyl-4-hydroxyphenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)quinoxaline-2-carboxamide; （34） （（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）- 페닐퓨란- 2 -카르복사미드 ;(34) ((5-(4-methoxyphenyl)thiophen-2-yl)methyl)-phenylfuran-2-carboxamide; （35） （2 -플루오로페닐）- （（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (35) (2-fluorophenyl)-((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （36） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (36) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （37） 1^（3 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）벤즈아미드; (37) 1^(3-fluorophenyl)-(5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide; （38） 4 -아미노- （3 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）벤즈아미드; (38) 4-amino-(3-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide; （39） 4-（（3 -플루오로페닐）（（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）카바모일）벤조산; (39) 4-((3-fluorophenyl)((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)carbamoyl)benzoic acid; （40） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）피라진_ 2 -카르복사미드 ; (40) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine_2-carboxamide; （41） （2 -플루오로페닐）- 5 -메톡시- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (41) (2-fluorophenyl)-5-methoxy- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; （42） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）- 2- 나프타미드; (42) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-2-naphthamide; （43） 於（2 -플루오로페닐）-於（（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드; (43) 於(2-fluorophenyl)-於（(5-(4-methoxyphenyl)thiophen-2-yl)methyl）quinoxaline-2-carboxamide; （44） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (44) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （45） （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 페닐퀴녹살린- 2- 카르복사미드; (45) ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-phenylquinoxaline-2-carboxamide; （46） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）퀴놀린_ 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (46) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoline_ 2-carboxamide; 2022/249113 ?01/162022/054935 （47） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）벤조퓨란- 2 -카르복사미드 ; (47) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide; （48） （3 -플루오로페닐）- （（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (48) (3-fluorophenyl)-((5-(4-methoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （49） （3 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (49) (3-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （50） 中（3 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）피라진_ 2 -카르복사미드 ; (50) 中（3-fluorophenyl）-（(5-（4-methoxy-3-methylphenyl）thiophen-2-yl）methyl）pyrazine_ 2-carboxamide; （51） 6 -클로로-於（2 -플루오로페닐）-於（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (51) 6-chloro-於(2-fluorophenyl)-於((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; （52） 5 -클로로-於（2 -플루오로페닐）-於（（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (52) 5-chloro-於(2-fluorophenyl)-於((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; （53） ^（3 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (53) ^(3-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （54） ^（4 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (54) ^(4-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （55） 於（（5-（4 -메톡시페닐）티오펜- 2 -일）메틸）-聲（피리딘- 2 -일）퓨란 -2- 카르복사미드; (55) 於（(5-(4-methoxyphenyl)thiophen-2-yl）methyl)-聲(pyridin-2-yl)furan-2-carboxamide; （56） 於벤질-於（（ 5-（ 4 -메톡시페닐）티오펜- 2 -일）메틸）퓨란- 2 -카르복사미드 ;(56) 於benzyl-於（（5-（4-methoxyphenyl）thiophen-2-yl）methyl）furan-2-carboxamide; （57） （2 , 4 -디플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (57) (2,4-difluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （58） （3 , 4 -디플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (58) (3,4-difluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （59） （（5-（4 -에톡시페닐）티오펜- 2 -일）메틸）- （2 -플루오로페닐）퓨란 -2- 카르복사미드; (59) ((5-(4-ethoxyphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)furan-2-carboxamide; （60） （（5-（4 -에톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (60) ((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935 （61） （（5-（4 -에톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- （3- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (61) ((5-(4-ethoxy-3-methylphenyl)thiophen-2-yl)methyl)-(3-fluorophenyl)quinoxaline-2-carboxamide; （62） 於（2 -플루오로페닐）-於（（5-（4 -프로폭시페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (62) 於(2-fluorophenyl)-於（(5-(4-propoxyphenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （63） （2 -플루오로페닐）- （（5-（3 -메틸- 4 -프로폭시페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (63) (2-fluorophenyl)-((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （64） （3 -플루오로페닐）- （（5-（3 -메틸- 4 -프로폭시페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (64) (3-fluorophenyl)-((5-(3-methyl-4-propoxyphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （65） （2 -플루오로페닐）- （（5-（4 -이소프로폭시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (65) (2-fluorophenyl)-((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （66） （3 -플루오로페닐）- （（5-（4 -이소프로폭시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (66) (3-fluorophenyl)-((5-(4-isopropoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （67） （（5-（4-（디플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (67) ((5-(4-(difluoromethoxy)phenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （68） （（5-（4-（디플루오로메톡시）- 3 -메틸페닐）티오펜- 2 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (68) ((5-(4-(difluoromethoxy)-3-methylphenyl)thiophen-2-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （69） （2 -클루오로페닐）- （（5-（4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (69) (2-chlorophenyl)-((5-(4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （70） （3 -클루오로페닐）- （（5-（4_（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (70) (3-chlorophenyl)-((5-(4_(trichloromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （71） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）옥사졸- 5 -카르복사미드 ; (71) (2-fluorophenyl)-((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)oxazole-5-carboxamide; （72） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）이소옥사졸- 5 -카르복사미드 ; (72) (2-fluorophenyl)-((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)isoxazole-5-carboxamide; （73） （2 -플루오로페닐）- 5 -니트로- （（5-（4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (73) (2-fluorophenyl)-5-nitro- ((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide; 2022/249113 ?01/162022/054935 （74） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）피라진- 2 -카르복사미드 ; (74) (2-fluorophenyl)-((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; （ 75） 6 -클로로-於（ 2 -플루오로페닐）-於（（ 5-（ 3 -메틸- 4-( 75) 6-chloro-於 ( 2 -fluorophenyl) -於 ( ( 5- ( 3 -methyl- 4- （트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）피라진- 2 -카르복사미드 ; (trifluoromethoxy)phenyl)thiophen-2-yl)methyl)pyrazine-2-carboxamide; （76） （2 -플루오로페닐）- （（5-（4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (76) (2-fluorophenyl)-((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （77） （3 -플루오로페닐）- （（5-（4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (77) (3-fluorophenyl)-((5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （78） （2 -클루오로페닐）- （（5-（ 3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (78) (2-chlorophenyl)-((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （79） （3 -클루오로페닐）- （（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (79) (3-chlorophenyl)-((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （80） （4 -클루오로페닐）- （（5-（3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (80) (4-chlorophenyl)-((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （81） 4-（5-（（於（3 -클로로페닐）펜탄아미도）메틸）티오펜- 2 -일）페닐 퓨란 -2- 카르복실례이트; (81) 4-(5-((於(3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl furan-2-carboxylate; （82） 4-（5-（（於（3 -클로로페닐）펜탄아미도）메틸）티오펜- 2 -일）페닐 벤젠설포네이트;(82) 4-(5-((於(3-chlorophenyl)pentanamido)methyl)thiophen-2-yl)phenyl benzenesulfonate; （83） 於（（5-（4-（벤질옥시）페닐）티오펜- 2 -일）메틸）-於（3 -클로로페닐）펜탄아미드;(83) 於（(5-(4-(benzyloxy)phenyl)thiophen-2-yl）methyl)-於(3-chlorophenyl)pentanamide; （84） 於（3 -클로로페닐）-於（（5-（4-（（4 -메틸벤질）옥시）페닐）티오펜- 2- 일）메틸）펜탄아미드; (84) 於(3-chlorophenyl)-於（(5-(4-((4-methylbenzyl)oxy)phenyl)thiophen-2-yl)methyl)pentanamide; （85） 於（（5-（벤조［비［1,引디옥솔- 5 -일）티오펜- 2 -일）메틸）-於（2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (85) 於((5-(benzo[bi[1,引dioxol-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide; （86） 於（（5-（벤조［넸옥사졸- 5 -일）티오펜- 2 -일）메틸）-於（2 -플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (86) 於((5-(benzo[nioxazol-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide; （87） 於（（5-（벤조퓨란- 5 -일）티오펜- 2 -일）메틸）-於（2 -플루오로페닐）퀴녹살린- 2- 카르복사미드; 2022/249113 ?01/162022/054935 (87) 於((5-(benzofuran-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935 （88） 於（（5-（벤조퓨란- 5 -일）티오펜- 2 -일）메틸）-於（4 -플루오로페닐）퀴녹살린- 2- 카르복사미드; (88) 於((5-(benzofuran-5-yl)thiophen-2-yl)methyl)-於(4-fluorophenyl)quinoxaline-2-carboxamide; （89） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 5- 모르폴리노피라진- 2 -카르복사미드 ; (89) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-morpholinopyrazine-2-carboxamide; （90） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 5-（4- 메틸피페라진 - 1 -일）피라진 -2 -카르복사미드 ; (90) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperazine-1-yl)pyrazine- 2-carboxamide; （91） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2 -일）메틸）- 5-（4- 메틸피페리딘- 1 -일）피라진- 2 -카르복사미드 ; (91) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-(4-methylpiperidin-1-yl)pyrazine -2-carboxamide; （92） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）퀴녹살린- 6 -카르복사미드 ; (92) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)quinoxaline-6-carboxamide; （93） （2 -클루오로페닐）- （（5-（ 3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）퓨란- 2 -카르복사미드 ; (93) (2-chlorophenyl)-((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （94） （2 -클루오로페닐）- （（5-（ 3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）벤조퓨란- 2 -카르복사미드 ; (94) (2-chlorophenyl)-((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide; （95） 於（（5-（2, 3 -디히드로벤조퓨란- 5 -일）티오펜- 2 -일）메틸）-於（2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (95) 於((5-(2,3-dihydrobenzofuran-5-yl)thiophen-2-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide; （96） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2- 일）메틸）아세타마이드; (96) (2-fluorophenyl)-((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)acetamide; （97） 4 -아세타미도- （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）벤즈아마이드; (97) 4-acetamido-(2-fluorophenyl)-(5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzamide; （98） 於（2 -플루오로페닐）-於（（5-（2 -메틸- 1 , 3 -디옥소이소이돌린- 5 -일）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (98) 於（2-fluorophenyl）-於（(5-(2-methyl-1,3-dioxoisoidoline-5-yl)thiophen-2-yl)methyl）quinoxaline-2-carb duplicating mid; （99） （2 -클루오로페닐）- （（5-（ 3 -메틸- 4-（트리클루오로메특시）페닐）티오펜- 2- 일）메틸）- 2 , 3 -디히드로벤조 [비 [ 1 , 4]디옥신- 2 -카르복사미드 ; (99) (2-chlorophenyl)- ((5-(3-methyl-4-(trichloromethoxy)phenyl)thiophen-2-yl)methyl)-2,3-dihydrobenzo [B [1,4]dioxin-2-carboxamide; （100） 中（3 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드; 2022/249113 ?01/162022/054935 (100) medium (3-fluorophenyl)- ((5- (4-fluorophenyl) thiophen- 2 -yl) methyl) furan- 2-carboxamide; 2022/249113 ?01/162022/054935 （101） （4 -플루오로페닐）- （（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란- 2- 카르복사미드; (101) (4-fluorophenyl)-((5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （102） 於（2 -브로모페닐）-於（（5-（4 -플루오로페닐）티오펜- 2 -일）메틸）퓨란 -2- 카르복사미드; (102) 於(2-bromophenyl)-於（(5-(4-fluorophenyl)thiophen-2-yl)methyl)furan-2-carboxamide; （103） 於（（ 5-（4 -플루오로페닐）티오펜- 2 -일）메틸）-於（ 0 -톨릴）퓨란- 2 -카르복사미드 ;(103) 於（(5-(4-fluorophenyl)thiophen-2-yl)methyl）-於(0-tolyl)furan-2-carboxamide; （104） （2 -플루오로페닐）- 5 -메톡시- （（5-（3 -메틸- 4-(104) (2-fluorophenyl)-5-methoxy- (5-(3-methyl-4- （트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）벤조퓨란- 2 -카르복사미드 ; (trifluoromethoxy)phenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide; （ 105） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）- 5 -니트로퓨란 -2 -카르복사미드 ; (105) (2-fluorophenyl)- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-5-nitrofuran-2-carboxamide ; （ 106） （2 -플루오로페닐）- （（5-（4 -메톡시 -3 -메틸페닐）티오펜- 2 -일）메틸）- 5- 니트로벤조퓨란- 2 -카르복사미드 ; (106) (2-fluorophenyl)- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)-5-nitrobenzofuran-2-carboxamide; （107） （2 -플루오로페닐）- 5 -메톡시- （（5-（4 -메톡시- 3 -메틸페닐）티오펜- 2- 일）메틸）벤조퓨란- 2 -카르복사미드 ; (107) (2-fluorophenyl)-5-methoxy- ((5-(4-methoxy-3-methylphenyl)thiophen-2-yl)methyl)benzofuran-2-carboxamide; （ 108） 사이클로부틸- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; ( 108) cyclobutyl- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （ 109） 사이클로펜틸- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; ( 109) cyclopentyl- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （110） 於사이클로핵실-於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (110) 於cyclohexyl-於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl）quinoxaline-2-carboxamide; （111） 於（사이클로핵실메틸）-於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (111) 於(cyclohexylmethyl)-於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)quinoxaline-2-carboxamide; （112） 於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）퀴녹살린- 2- 카르복사미드; (112) 於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl）quinoxaline-2-carboxamide; （113） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （테트라히드로- 211-피란- 4 -일）퀴녹살린- 2 -카르복사미드 ; (113) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-(tetrahydro-211-pyran-4-yl)quinoxaline-2-carb duplicating mid; （114） 打-부틸 4-（於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2- 일）메틸）퀴녹살린- 2 -카르복사미도）피퍼리딘- 1 -카르복시레이트; 2022/249113 ?01/162022/054935 (114) 打-butyl 4-（於（（5-（3 -methyl- 4-（trifluoromethoxy）phenyl）thiophen- 2-yl）methyl）quinoxaline- 2-carboxamido）piperidine- 1-carboxylate; 2022/249113 ?01/162022/054935 （115） 於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）-於（피퍼리딘-(115) 於（(5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl）-於（piperidine- 4 -일）퀴녹살린- 2 -카르복사미드 ; 4-yl）quinoxaline-2-carboxamide; （116） 於（（5-（4 -플루오로- 3 -메틸페닐）티오펜- 2 -일）메틸）-於（2- 플루오로페닐 1）퀴녹살린- 2 -카르복사미드 ; (116) 於((5-(4-fluoro-3-methylphenyl)thiophen-2-yl)methyl)-於(2-fluorophenyl 1)quinoxaline-2-carboxamide; （117） 於（（5-（3 -에틸- 4 -플루오로페닐）티오펜- 2 -일）메틸）-於（2- 플루오로페닐 1）퀴녹살린- 2 -카르복사미드 ; (117) 於((5-(3-ethyl-4-fluorophenyl)thiophen-2-yl)methyl)-於(2-fluorophenyl 1)quinoxaline-2-carboxamide; （118） 於（（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）-於（피라진- 2- 일）퀴녹살린- 2 -카르복사미드 ; (118) 於((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)-於(pyrazin-2-yl)quinoxaline-2-carboxamide; （119） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （피리미딘-(119) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophen-2-yl)methyl)- (pyrimidine- 5 -일）퀴녹살린- 2 -카르복사미드; 및 5-day）quinoxaline-2-carboxamide; and （120） （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）티오펜- 2 -일）메틸）- （내- 피라졸- 4 -일）퀴녹살린- 2 -카르복사미드 . (120) ((5-(3-methyl-4-(trifluoromethoxy)phenyl)thiophene-2-yl)methyl)-(in-pyrazol-4-yl)quinoxaline-2-carboxamide . 【청구항 5】 제 1항에 있어서 , 상기 화학식 1의 화합물이 하기 화학식 3의 화합물인 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 : [Claim 5] The compound according to claim 1, wherein the compound of Formula 1 is a compound of Formula 3 below, an isomer thereof, or a pharmaceutically acceptable salt thereof: ［화학식 到
Figure imgf000108_0001
상기 식에서 , [chemical formula 到
Figure imgf000108_0001
In the above formula, ¾ 은 수소, 할로겐 , 하이드록시 , 01-6 알킬 , 01-6 알콕시 , 01-6 알킬-
Figure imgf000108_0002
■2, 또는 -에내 알킬 -0-^-6 알킬이고, 이때 상기 01-6 알킬 및 01-6 알콕시는 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐으로 치환될 수 있고; 묘2는 수소, 01-6 알킬 , 또는 1 내지 3개의 할로겐으로 치환된 01-6 알킬이며 ; 묘3는 01-6 알킬 , 03-8 사이클로알킬 , 06-10 아릴 , 5-6원 헤테로아릴 , 5-6원 2022/249113 ?01/162022/054935 헤테로사이클릴,
Figure imgf000109_0001
알킬- 5-6원 헤테로사이클릴이고, 이때 상기 01-6알킬, ¾-8사이클로알킬,
Figure imgf000109_0002
아릴, 5-6원 헤테로아릴, 5-6원 헤테로사이클릴 및 -01-6 알킬- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐,
Figure imgf000109_0003
치환될 수 있고; 묘4는 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴, 또는 -5-6원 헤테로아릴- 5-6원 헤테로사이클릴이고, 이때 상기 5- 10원 헤테로아릴, 5- 10원 헤테로사이클릴 및 -5- 6원 헤테로아릴- 5-6원 헤테로사이클릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6알킬로치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이고, 상기 헤테로사이클릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를포함하는지방족헤테로고리이다. ¾ is hydrogen, halogen, hydroxy, 01-6 alkyl, 01-6 alkoxy, 01-6 alkyl-
Figure imgf000108_0002
■2, or -in alkyl -0-^-6 alkyl, wherein the 01-6 alkyl and 01-6 alkoxy each independently may be unsubstituted or substituted with 1 to 3 halogens; parent 2 is hydrogen, 01-6 alkyl, or 01-6 alkyl substituted with 1 to 3 halogens; Cat 3 is 01-6 alkyl, 0 3-8 cycloalkyl, 0 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered 2022/249113 ?01/162022/054935 heterocyclyl;
Figure imgf000109_0001
Alkyl-5-6 membered heterocyclyl, wherein said 0 1-6 alkyl, ¾- 8 cycloalkyl,
Figure imgf000109_0002
Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and -0 1-6 alkyl-5-6 membered heterocyclyl are each independently unsubstituted or 1 to 4 halogen;
Figure imgf000109_0003
can be substituted; Catalyst 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 01-6 alkyl; The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. 【청구항 6】 제 5항에 있어서, 묘3는 01-6 알킬, 사이클로프로필, 페닐, 피리디닐, 피리미디닐, 또는 모르폴리노에틸이고, 이때 상기 01-6 알킬, 사이클로프로필, 페닐, 피리디닐, 피리미디닐 및 모르폴리노에틸은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐, ^ - 000\\, 01-6알킬 또는 -00-01-6알킬로 치환될 수 있고; [Claim 6] The method of claim 5, wherein the parent 3 is 01-6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl, or morpholinoethyl, wherein the 0 1-6 alkyl, cyclopropyl, phenyl, pyridinyl, pyrimidinyl and morpholinoethyl may each independently be unsubstituted or substituted with 1 to 4 halogens, ^ - 000\\, 01-6alkyl or -00-01-6alkyl; ，.公 4 ，.公 4 1 One ¾는 피리디닐, 피라지닐, 퀴녹살리닐, 디하이드로벤조디옥시닐, 또는¾ is pyridinyl, pyrazinyl, quinoxalinyl, dihydrobenzodioxinyl, or 0 入 ᄂ 이고, 이때 상기 피리디닐, 피라지닐, 퀴녹살리닐, 2022/249113 1^(:1^ 2022/054935 디하이드로벤조디옥시닐，
Figure imgf000110_0001
각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6 알킬로 치환될 수 있는 것인 화합물 , 이의 이성질체 또는 이의 약학적으로 허용가능한 염 . 0 入 ᄂ, wherein the pyridinyl, pyrazinyl, quinoxalinyl, 2022/249113 1^(:1^ 2022/054935 dihydrobenzodioxinyl,
Figure imgf000110_0001
A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, each of which is independently unsubstituted or may be substituted with 1 to 4 halogen or 01-6 alkyl. 【청구항 7] 제 5항 또는 제 6항에 있어서 , 상기 화합물이 하기로 이루어진 군으로부터 선택되는 어느 하나의 화합물 , 이의 이성질체 또는 이의 약학적으로 허용가능한 염 : [Claim 7] The compound according to claim 5 or 6, wherein the compound is any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof: （121） 7^（（2 -（4 -플루오로- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (121) 7^((2-(4-fluoro-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （122） 7^（（2-（4 -클로로- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (122) 7^((2-(4-chloro-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （123） （ 2 -플루오로페닐）- （（ 2-（4 -메톡시 - 3 -메틸페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (123) (2-fluorophenyl)-((2-(4-methoxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （124） （（2-（4-（디플루오로메톡시）페닐）티아졸- 5 -일）메틸）- （2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (124) ((2-(4-(difluoromethoxy)phenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （125） （（ 2-（4-（디플루오로메톡시）- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (125) ((2-(4-(difluoromethoxy)-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （ 126） 6 -클로로- （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）피라진- 2 -카르복사미드 ; (126) 6-chloro- (2-fluorophenyl)- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)pyrazine-2-carboxamide; （ 127） 於（2 -플루오로페닐）- 6 -모르폴리노-聲（（2-（4 -( 127) 於（2-fluorophenyl）-6-morpholino-聲（（2-（4 - （트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）피라진- 2 -카르복사미드 ; (trifluoromethoxy)phenyl)thiazol-5-yl)methyl)pyrazine-2-carboxamide; （ 128） （2 -플루오로페닐）- （（2-（3 -메틸- 4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; 2022/249113 ?01/162022/054935 (128) (2-fluorophenyl)-((2-(3-methyl-4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; 2022/249113 ?01/162022/054935 （ 129） （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (129) (2-fluorophenyl)-(2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （130） 中（4 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (130) of (4-fluorophenyl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （131） （3 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (131) (3-fluorophenyl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （ 132） （4 -플루오로페닐）- （（2-（3 -메틸- 4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (132) (4-fluorophenyl)-((2-(3-methyl-4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （133） （피리딘- 2 -일）- （（ 2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (133) (pyridin-2-yl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （134） （피리딘- 3 -일）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (134) (pyridin-3-yl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （135） 에틸- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드 ; (135) ethyl- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （ 136） （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）피페리딘- 1 -일）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (136) (2-fluorophenyl)-((2-(4-(trifluoromethoxy)piperidin-1-yl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （137） （피리딘- 3 -일）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (137) (pyridin-3-yl)-((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （138） 3-（於（（2-（4-（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미도）피리딘- 1 -이움 클로라이드 ; (138) 3-(於((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamido)pyridin-1-ium chloride; （139） （2 -플루오로페닐）- （（2-（4-（트리플루오로메톡시）페닐）티아졸- 5 -일）메틸）_ 2 , 3 -디하이드로벤조比] [ 1 , 4]디옥신- 2 -카르복사미드 ; (139) (2-fluorophenyl)- ((2-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methyl)_ 2,3-dihydrobenzo] [1,4] dioxin-2-carboxamide; （140） （4 -플루오로페닐）- （（2-（4-（메톡시메톡시）- 3 -메틸페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (140) (4-fluorophenyl)-((2-(4-(methoxymethoxy)-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （141） （4 -플루오로페닐）- （（2-（4 -히드록시 -3 -메틸페닐）티아졸- 5- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (141) (4-fluorophenyl)-((2-(4-hydroxy-3-methylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （142） （（2-（4 -메톡시페닐）티아졸- 5 -일）메틸）- （3 -메틸피리딘- 2 -일）퀴녹살린- 2 - 2022/249113 ?01/162022/054935 카르복사미드 ; (142) ((2-(4-methoxyphenyl)thiazol-5-yl)methyl)- (3-methylpyridin-2-yl)quinoxaline-2- 2022/249113 ?01/162022/054935 Carboxamide; （143） 於（（ 2-（4 -메톡시페닐）티아졸- 5 -일）메틸）-聲（피리미딘- 2 -일）퀴녹살린- 2- 카르복사미드 ; (143) 於（(2-(4-methoxyphenyl)thiazol-5-yl）methyl)-聲(pyrimidin-2-yl)quinoxaline-2-carboxamide; （144） （2 -플루오로페닐）- （（2-（4 -메톡시페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드 ; (144) (2-fluorophenyl)-((2-(4-methoxyphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; （145） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸） -聲사이클로프로필퀴녹살린- 2- 카르복사미드 ; (145) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲cyclopropylquinoxaline-2-carboxamide; （146） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸）-聲（ 2 -플루오로페닐）피콜린아미드 ;(146) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲(2-fluorophenyl)picolinamide; （147） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸）-聲（4 -시아노페닐）퀴녹살린- 2- 카르복사미드 ; (147) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲(4-cyanophenyl)quinoxaline-2-carboxamide; （148） 7^（（2 -（4 -클로로페닐）티아졸- 5 -일）메틸）-聲（ 2 -모르폴리노에틸）퀴녹살린- 2- 카르복사미드 ; (148) 7^((2-(4-chlorophenyl)thiazol-5-yl)methyl)-聲(2-morpholinoethyl)quinoxaline-2-carboxamide; （ 149） （2-（4 -클로로페닐）티아졸- 5 -일）메틸）퀴녹살린- 2 -카르복사미드）벤조산 ;(149) (2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide)benzoic acid; （150） （（ 2-（4-（아미노메틸）페닐）티아졸- 5 -일）메틸）-於（ 2 -플루오로페닐）퀴녹살린_ 2 -카르복사미드 ; (150) (( 2-(4-(aminomethyl)phenyl)thiazol-5-yl)methyl)-於(2-fluorophenyl)quinoxaline_ 2-carboxamide; （151） 7^（（2 -（4 -카바모일페닐）티아졸- 5 -일）메틸）-於（ 2 -플루오로페닐）퀴녹살린- 2- 카르복사미드 ; (151) 7^((2-(4-carbamoylphenyl)thiazol-5-yl)methyl)-於(2-fluorophenyl)quinoxaline-2-carboxamide; （152） 7^（（2 -（4 -카바모일- 3 -메틸페닐）티아졸- 5 -일）메틸）- （ 2- 플루오로페닐）퀴녹살린- 2 -카르복사미드 ; (152) 7^((2-(4-carbamoyl-3-methylphenyl)thiazol-5-yl)methyl)-(2-fluorophenyl)quinoxaline-2-carboxamide; （ 153） （2 -플루오로페닐）- （（2-（4 -설퍼모일페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드 ; 및 (153) (2-fluorophenyl)-((2-(4-sulfurmoylphenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide; and （154） （3 -아세틸페닐）- （（2-（4 -클로로페닐）티아졸- 5 -일）메틸）퀴녹살린- 2- 카르복사미드 . (154) (3-acetylphenyl)-((2-(4-chlorophenyl)thiazol-5-yl)methyl)quinoxaline-2-carboxamide. 【청구항 8】 제 1항에 있어서 , 상기 화학식 1의 화합물이 하기 화학식 4의 화합물인 화합물 , 이의 이성질체 또는 2022/249113 ?01/162022/054935 이의 약학적으로 허용가능한 염 : [화학식 4]
Figure imgf000113_0001
상기 식에서, [Claim 8] The compound according to claim 1, wherein the compound of Formula 1 is a compound of Formula 4 below, an isomer thereof, or 2022/249113 ?01/162022/054935 A pharmaceutically acceptable salt thereof: [Formula 4]
Figure imgf000113_0001
In the above formula, ¾ 은 수소, 할로겐, 하이드록시, 01-6 알킬, 또는 01-6 알콕시이고, 이때 상기 01-6 알킬 및 01-6 알콕시는 각각 독립적으로 치환되지 않거나, 또는 1 내지 3개의 할로겐으로 치환될 수 있고; ¾ is hydrogen, halogen, hydroxy, 0 1-6 alkyl, or 0 1-6 alkoxy, wherein the 0 1-6 alkyl and 0 1-6 alkoxy are each independently unsubstituted or with 1 to 3 halogen can be substituted; ¾ 는 수소, 01-6알킬, 또는 1내지 3개의 할로겐으로 치환된 01-6알킬이며; 묘3는 06-10 아릴 또는 5-6원 헤테로아릴이고, 이때 상기 06-10 아릴 및 5-6원 헤테로아릴은 각각 독립적으로 치환되지 않거나, 또는 1 내지 4개의 할로겐 또는 01-6알킬로 치환될 수 있고; 묘4는 5-10원 헤테로아릴이고, 이때 상기 5-10원 헤테로아릴은 각각 독립적으로 치환되지 않거나, 또는 1내지 4개의 할로겐 또는 01-6알킬로 치환될 수 있고; 상기 헤테로아릴은 0 및 £로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 방향족 헤테로고리이다. ¾ is hydrogen, 0 1-6 alkyl, or 0 1-6 alkyl substituted with 1 to 3 halogens; Cat 3 is 0 6-10 aryl or 5-6 membered heteroaryl, wherein the 0 6-10 aryl and 5-6 membered heteroaryl are each independently unsubstituted, or 1 to 4 halogen or 01-6 alkyl may be substituted with; parent 4 is a 5-10 membered heteroaryl, wherein each of the 5-10 membered heteroaryls may be independently unsubstituted or substituted with 1 to 4 halogen or 01-6 alkyl; The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from 0 and £. 【청구항 9】 제 8항에 있어서, 묘3는 페닐 또는 피리디닐이고, 이때 상기 페닐 및 피리디닐은 각각 독립적으로 치환되지 않거나, 또는 1내지 4개의 할로겐 또는 01-6알킬로 치환될 수 있고; [Claim 9] The method of claim 8, wherein the moiety 3 is phenyl or pyridinyl, wherein the phenyl and pyridinyl are each independently unsubstituted or may be substituted with 1 to 4 halogen or 01-6 alkyl; ¾ 는 피라지닐 또는 퀴녹살리닐이고, 이때 상기 피라지닐 및 퀴녹살리닐은 각각 독립적으로 치환되지 않거나, 또는 1내지 4개의 할로겐 또는 01-6알킬로 치환될 수 있는 것인 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 . ¾ is pyrazinyl or quinoxalinyl, wherein the pyrazinyl and quinoxalinyl are each independently unsubstituted or may be substituted with 1 to 4 halogens or 0 1-6 alkyl compounds, isomers thereof, or A pharmaceutically acceptable salt thereof. 【청구항 10】 2022/249113 ?01/162022/054935 제 8항 또는 제 9항에 있어서 , 상기 화합물이 하기로 이루어진 군으로부터 선택되는 어느 하나의 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 : 【Claim 10】 2022/249113 ?01/162022/054935 The compound according to claim 8 or 9, wherein the compound is any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof: （ 155） （2 -플루오로페닐）- （（5-（4 -메톡시- 3 -메틸페닐）- 1 , 3 , 4 -티아디아졸- 2- 일）메틸）퀴녹살린- 2 -카르복사미드 ; (155) (2-Fluorophenyl)- (5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2-carboxamide ; （ 156） （2 -플루오로페닐）- （（5-（3 -메틸- 4-（트리플루오로메톡시）페닐）- 1 , 3 , 4- 티아디아졸- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 ; 및 (156) (2-Fluorophenyl)- ((5-(3-methyl-4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline- 2-carboxamide; and （157） （2 -플루오로페닐）- （（5-（4-（트리플루오로메톡시）페닐）- 1,3, 4 -티아디아졸- 2 -일）메틸）퀴녹살린- 2 -카르복사미드 . (157) (2-fluorophenyl)- ((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)quinoxaline-2-carboxyl mid . 【청구항 11】 제 1항 내지 제 10항 중 어느 한 항에 따른 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 , 및 약학적으로 허용가능한 담체를 포함하는, 1¾ 3 돌연변이나 과발현으로 인한 질환을 예방 또는 치료하기 위한 약학 조성물. [Claim 11] Diseases caused by 1¾ 3 mutation or overexpression, including 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 A pharmaceutical composition for prevention or treatment. 【청구항 12】 제 11항에 있어서 , [Claim 12] The method of claim 11, 1¾ 3 돌연변이나 과발현으로 인한 질환이 암인 약학 조성물. A pharmaceutical composition wherein a disease caused by 1¾ 3 mutation or overexpression is cancer. 【청구항 13】 제 11항 또는 제 12항에 있어서 , 상기 암이 암종 (carcinoma) , 림프종 (lymphoma) , 모세포종 (blastoma) , 육종 (sarcoma) , 지방육종 ( 1 iposarcoma) , 신경내분비종 (neuroendocrine tumor) ,중피종 (mesothel ioma) , 신경초종 (schwanoma) , 수막종 (meningioma) , 샘암종 (adenocarcinoma) , 폭색종 (melanoma) , 백혈병 (leukemia) , 악성 림프종 ( lympho i dma 1 i gnancy ) , 편평세포암종 (squamous cel l cancer) , 편평상피세포암 (epithel ial squamous cel l cancer) , 폐암 ( lung cancer) , 소세포폐암 (smal卜 cel l 2022/249113 1^(:1^ 2022/054935 lungcancer)， 비소세포폐암 (non-small cell lungcancer)， 폐샘암종[Claim 13] The method of claim 11 or 12, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, liposarcoma (1 iposarcoma), neuroendocrine tumor ) , mesothelial ioma , schwanoma , meningioma , adenocarcinoma , melanoma , leukemia , lymphoma 1 i gnancy , squamous cell carcinoma cell cancer), epithelial squamous cell cancer, lung cancer, small cell lung cancer 2022/249113 1^(:1^ 2022/054935 lungcancer), non-small cell lung cancer, lung adenocarcinoma (adenocarcinoma of the lung), 폐편평암종 (squamous carcinoma of the lung),복막종 (cancer of the peritoneum),간세포성종 (hepatocellular cancer), 위암종 (gastric or stomach cancer),위장관종 (gastrointestinal cancer), 췌장암(pancreatic cancer),뇌암 (brain cancer),아교모세포종 (glioblastoma), 자궁경부암 (cervical cancer),난소암 (ovarian cancer),간암 (liver cancer), 방광암 (bladder cancer),간암 (hepatoma),유방암 (breast cancer),결장암 (colon cancer),직장암 (rectal cancer),결장직장암 (colorectal cancer), 자궁내막 또는 자궁암 (endometrial or uterine carcinoma),침샘암 (salivary gland carcinoma),신장암 (kidney andrenalcancer),전립선암 (prostatecancer), 외음암 (vulvalcancer),갑상선암 (thyroid cancer),간암종 (hepatic carcinoma), 항문암종 (anal carcinoma),음경암종 (penile carcinoma),고환암 (testicular cancer), 식도정맥류암 (esophageal cancer), 담도암 (biliary tract), 대장암(colorectal cancer)및 두경부암 (head and neck cancer)으로 이루어진 군으로부터 선택되는 어느 하나인， 약학 조성물. (adenocarcinoma of the lung), 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 (breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, Prostate cancer, vulvalcancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer cancer), biliary tract, colorectal cancer, and head and neck cancer, any one selected from the group consisting of, a pharmaceutical composition. 【청구항 14】 제1항 내지 제10항 중 어느 한 항에 따른 화합물， 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 대상에게 투여하는 것을 포함하는， KRAS돌연변이나 과발현으로 인한 질환을 예방 또는 치료하는 방법. [Claim 14] Preventing or treating diseases caused by KRAS mutation or overexpression, including administering the compound according to any one of claims 1 to 10, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject Way. 【청구항 15】 【Claim 15】 KRAS돌연변이나 과발현으로 인한 질환을 예방 또는 치료하기 위한 제1항 내지 제10항 중 어느 한 항에 따른 화합물， 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도. 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.
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