WO2022249113A1 - Nouveau composé inhibant la liaison entre aimp2-dx2 et kras, et son utilisation - Google Patents

Nouveau composé inhibant la liaison entre aimp2-dx2 et kras, et son utilisation Download PDF

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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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methyl
carboxamide
fluorophenyl
thiophen
quinoxaline
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PCT/IB2022/054935
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English (en)
Korean (ko)
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이경
김성훈
김민경
김대규
이관식
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주식회사 자이메디
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Priority to KR1020227021003A priority Critical patent/KR20220162116A/ko
Publication of WO2022249113A1 publication Critical patent/WO2022249113A1/fr

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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

La présente invention concerne un nouveau composé ayant une activité pour inhiber la liaison entre AIMP-DX2 et KRAS, et son utilisation. Le composé selon la présente invention est utile pour la prévention ou le traitement de maladies provoquées par une mutation ou une surexpression de KRAS, telles que le cancer.
PCT/IB2022/054935 2021-05-25 2022-05-25 Nouveau composé inhibant la liaison entre aimp2-dx2 et kras, et son utilisation WO2022249113A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54115378A (en) * 1978-02-10 1979-09-07 Bayer Ag Novel nnazolylalkyllhalogenoacetoanilide* its manufacture and herbicidal composition
US20020035136A1 (en) * 2000-08-29 2002-03-21 Gang Liu Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors
WO2004024939A2 (fr) * 2002-09-13 2004-03-25 Georgetown University Ligands du recepteur active de la proliferation des peroxisomes et ses methodes d'utilisation
KR20070085997A (ko) * 2004-11-19 2007-08-27 갈데르마 리써어치 앤드 디벨로프먼트 ＰＰＡＲγ 유형 수용체를 조정하는 화합물, 및 미용 또는약학 조성물에서의 이의 용도
KR101165647B1 (ko) * 2003-06-20 2012-07-17 갈데르마 리써어치 앤드 디벨로프먼트 ＰＰＡＲγ 형 수용체를 조절하는 신규 화합물, 및 미용또는 약학 조성물에서의 이의 용도

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54115378A (en) * 1978-02-10 1979-09-07 Bayer Ag Novel nnazolylalkyllhalogenoacetoanilide* its manufacture and herbicidal composition
US20020035136A1 (en) * 2000-08-29 2002-03-21 Gang Liu Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors
WO2004024939A2 (fr) * 2002-09-13 2004-03-25 Georgetown University Ligands du recepteur active de la proliferation des peroxisomes et ses methodes d'utilisation
KR101165647B1 (ko) * 2003-06-20 2012-07-17 갈데르마 리써어치 앤드 디벨로프먼트 ＰＰＡＲγ 형 수용체를 조절하는 신규 화합물, 및 미용또는 약학 조성물에서의 이의 용도
KR20070085997A (ko) * 2004-11-19 2007-08-27 갈데르마 리써어치 앤드 디벨로프먼트 ＰＰＡＲγ 유형 수용체를 조정하는 화합물, 및 미용 또는약학 조성물에서의 이의 용도

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