WO2017183927A1 - Nouveau composé hétérocyclique, procédé de préparation de celui-ci et composition pharmaceutique contenant celui-ci en tant que principe actif pour la prévention ou le traitement du cancer - Google Patents

Nouveau composé hétérocyclique, procédé de préparation de celui-ci et composition pharmaceutique contenant celui-ci en tant que principe actif pour la prévention ou le traitement du cancer Download PDF

Info

Publication number
WO2017183927A1
WO2017183927A1 PCT/KR2017/004246 KR2017004246W WO2017183927A1 WO 2017183927 A1 WO2017183927 A1 WO 2017183927A1 KR 2017004246 W KR2017004246 W KR 2017004246W WO 2017183927 A1 WO2017183927 A1 WO 2017183927A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
substituted
amino
carbonyl
indole
Prior art date
Application number
PCT/KR2017/004246
Other languages
English (en)
Korean (ko)
Inventor
박성준
허정녕
김광록
김성수
임환정
이혁
장성연
김범태
윤은영
임병호
Original Assignee
한국화학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국화학연구원 filed Critical 한국화학연구원
Publication of WO2017183927A1 publication Critical patent/WO2017183927A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention

Definitions

  • the present invention relates to a novel heterocyclic compound, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • Ubls Post-translational modification of proteins by ubiquitin-like molecules (ubls) is an important intracellular regulatory process that plays an important role in regulating many biological processes, including cell division, cell signaling and immune responses.
  • Ubl is a small protein covalently bound to lysine on the target protein via isopeptide binding of ubl to the C terminal glycine.
  • Ubiquitin-like molecules can alter the molecular surface of the target protein and influence properties such as protein-protein interactions, enzymatic activity, stability, and intracellular localization of the target.
  • Ubiquitin and other ubls are activated by specific El enzymes that catalyze the formation of acyl-adenylate intermediates of ubl with the C-terminal glycine.
  • the activated ubl molecule is then delivered to the catalytic cysteine residue in the El enzyme through the formation of a thioester binding intermediate.
  • E1-ubl intermediate and E2 are associated to cause thioester exchange, where ubl is delivered to the active site cysteine of E2.
  • the ubl is then conjugated to the target protein, either directly or in combination with an E3 ligase, through the formation of an isopeptide bond with the amino group of the lysine side chain in the target protein.
  • Ubiquitin is its target via an enzyme cascade comprising its specific E1 activating enzyme, Uba1 (ubiquitin activating enzyme, UAE), a conjugation enzyme from the family of E2 and a ubiquitin ligase from any of the rings or HECT classes of E3. Conjugated to protein.
  • target specificity is determined by a specific combination of each of at least 40 E2 proteins and at least 100 E3 proteins.
  • ubiquitin there are ten ubiquitin-like proteins, each of which is thought to be activated by a specific El activating enzyme and processed through a similar but distinct downconjugation pathway.
  • Ubls for which E1 activating enzymes have been identified include NEDD8 (APPBP1-Uba3), ISG15 (UBE1L), and SUMO family (Aos1-Uba2).
  • NEDD8 is activated by the heterodimeric NEDD8-activating enzyme (APPBP1-Uba3) (NAE) and delivered to a single E2 (Ubc12), which is eventually ligated to the cullin protein.
  • APPBP1-Uba3 heterodimeric NEDD8-activating enzyme
  • Ubc12 E2
  • the action of neddylation induces the activation of the cholinergic ubiquitin ligase involved in ubiquitination and thus changes in cell signaling proteins and many cell cycles, including p27 and I- ⁇ B.
  • SUMO relies on ATP to have an activation mechanism through the SUMO Activating Enzyme (SAE) enzyme, which is transferred from E1 to the cysteine residue of E2 (SUMO Conjugating Enzyme, Ubc9), and the SUMO protein is located on the target protein.
  • SAE SUMO Activating Enzyme
  • SUMO binds to the target protein either directly or through conjugation with the E3 ligase to the target protein, via the epsilon amino group of the pseudopeptide bond. It plays a role in regulating position and function, complexation and stability of matrix protein.
  • SUMO binding since SUMO binding is initiated by the SAE enzyme, it may be inhibited or regulated to regulate cell metabolism, cell regulation, transcriptional regulation, preservation of genetic information, chromosome fraction, and the like.
  • gene expression and growth regulation pathways of cancer cells are regulated through SUMO binding, cancer and tumor cells can be suppressed and killed through the development of drugs for treating cancer or tumors targeting SAE enzymes.
  • E1 activating enzymes act in the first stage of the ubl conjugation pathway, such that inhibition of E1 activating enzymes specifically regulates the down biological consequences of ubl modification. Inhibition of this activating enzyme and the inhibition of the resulting downward effect of ubl conjugation represent a method that interferes with the integrity of some aspects of cell division, cell signaling and cell physiology that are important in disease mechanisms.
  • El enzymes such as UAE, NAE and SAE, which are modulators of various cellular actions, are potentially important therapeutic targets for the identification of new approaches to the treatment of diseases and disorders.
  • UPP ubiquitin-proteasome pathway
  • the functional UPP pathways described above are required for the maintenance of normal cells, which play a pivotal role in the transformation of many important regulatory proteins involved in transcription, cell cycle progression and apoptosis, all of which are important for disease states, including tumor cells. do.
  • cell proliferation is particularly sensitive to the inhibition of UPP, and the role of the UPP pathway in carcinogenesis may be a method of potential anticancer therapy by inhibiting proteasomes.
  • VELCADE® botezomib
  • proteins which down-regulate NAE and UAE activity whose levels are regulated by the cullinic ubiquitin ligase include CDK inhibitors, p27Kip1 and inhibitors of NF ⁇ B and I ⁇ B. Inhibition of degradation of p27 is expected to block the cell cycle through the G1 and S phases of the cell cycle, and the disruption of I ⁇ B degradation is due to nuclear localization of NF- ⁇ B, transcription of various NF- ⁇ B-dependent genes associated with malignant phenotypes. And prevents resistance to standard cytotoxic therapeutics. In addition, NF- ⁇ B plays an important role in the expression of several proinflammatory mediators, suggesting the role of such inhibitors in inflammatory diseases.
  • inhibition of UPP through inhibition of NAE and UAE activity may include, for example, inflammatory diseases including rheumatoid arthritis, asthma, multiple sclerosis, psoriasis and reperfusion injury; Neurodegenerative diseases including, for example, Parkinson's disease, Alzheimer's disease, three-way code repeat disease; Neuropathic pain; Ischemic diseases such as stroke, infarction, kidney disease; And a useful target for treatment in diseases such as cachexia.
  • inflammatory diseases including rheumatoid arthritis, asthma, multiple sclerosis, psoriasis and reperfusion injury
  • Neurodegenerative diseases including, for example, Parkinson's disease, Alzheimer's disease, three-way code repeat disease
  • Neuropathic pain Ischemic diseases such as stroke, infarction, kidney disease
  • a useful target for treatment in diseases such as cachexia.
  • NAE NEDD8-activating enzyme
  • the present inventors are trying to develop an effective cancer therapeutic agent from a novel compound exhibiting inhibitory activity against NAE and SAE, and the novel heterocyclic compounds according to the present invention are NAE (NEDD8-Activating Enzyme) and SAE (Sumo Activating Enzyme).
  • NAE NEDD8-Activating Enzyme
  • SAE Sudo Activating Enzyme
  • Another object of the present invention is to provide a method for preparing the heterocyclic compound.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease related to NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) containing the heterocyclic compound as an active ingredient.
  • NAE NEDD8-Activating Enzyme
  • SAE Stumo Activating Enzyme
  • Another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer containing the heterocyclic compound as an active ingredient.
  • Still another object of the present invention is to provide a nutraceutical composition for preventing or improving a disease related to NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) containing the heterocyclic compound as an active ingredient.
  • NAE NEDD8-Activating Enzyme
  • SAE Stumo Activating Enzyme
  • Another object of the present invention is to administer to the subject a therapeutically effective amount of the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, to a subject (NEDD8-Activating Enzyme) or SAE (Sumo Activating). Enzyme) to provide a method for treating a related disease.
  • the present invention provides a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are independently —H, —OH, halogen, amine, nitro, cyano, C 1-10 straight or branched alkyl, or C 1-10 straight or branched alkoxy;
  • R 3 is -H, -OH, halogen, amine, nitro, cyano, substituted or unsubstituted alkyl of straight or branched chain of the C 1-10 ring, a substituted or unsubstituted alkoxy group of a linear or branched unsubstituted C 1-10 , Unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted C 3-10 cycloalkyl-C 1-10 alkyl, unsubstituted or substituted 3 to 10 heterocyclic alkyl, unsubstituted or substituted Substituted heterocycloalkyl-C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl-C 1-10 alkyl, N, O and 5 to 10 each ring unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from the group consisting of
  • substituted heterocycloalkyl may be substituted with one or more -OH;
  • substituted phenyl and substituted heteroaryl are independently —H, —OH, halogen, —BnO, amine, nitro, cyano, C 1-10 straight or branched chain alkyl, and C 1-10
  • substituents selected from the group consisting of straight or branched alkoxy may be substituted
  • X is CH or N.
  • the present invention is to prevent or treat a disease represented by the formula (1), its stereoisomers or pharmaceutically acceptable salts thereof NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases It provides a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is to prevent or improve the disease represented by the formula (1), its stereoisomers or pharmaceutically acceptable salts thereof NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases It provides a health functional food composition for.
  • the present invention comprises administering to the subject a therapeutically effective amount of the compound, its stereoisomer or pharmaceutically acceptable salt thereof to the subject (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme). ) Provides a method of treating related diseases.
  • the heterocyclic compound according to the present invention can inhibit NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) at a concentration of nanomolar units excellent, and NAE (NEDD8-Activating Enzyme) containing it as an active ingredient or Sumo Activating Enzyme (SAE) -related diseases, for example, can be usefully used as a pharmaceutical composition for the prevention or treatment of cancer.
  • NAE NEDD8-Activating Enzyme
  • SAE Sumo Activating Enzyme
  • the present invention provides a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are independently —H, —OH, halogen, amine, nitro, cyano, C 1-10 straight or branched alkyl, or C 1-10 straight or branched alkoxy;
  • R 3 is —H, —OH, halogen, amine, nitro, cyano, substituted or unsubstituted C 1-10 straight or branched alkyl, substituted or unsubstituted C 1-10 straight or branched alkoxy , Unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted C 3-10 cycloalkyl-C 1-10 alkyl, unsubstituted or substituted 3 to 10 heterocyclic alkyl, unsubstituted or substituted Substituted heterocycloalkyl-C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl-C 1-10 alkyl, N, O and 5 to 10 each ring unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from the group consisting of S, or 5 to 5 or more comprising one or more heteroatoms selected from
  • substituted heterocycloalkyl may be substituted with one or more -OH;
  • substituted phenyl and substituted heteroaryl are independently —H, —OH, halogen, —BnO, amine, nitro, cyano, C 1-10 straight or branched chain alkyl, and C 1-10
  • substituents selected from the group consisting of straight or branched alkoxy may be substituted
  • X is CH or N.
  • R 1 and R 2 are each independently -H, -OH, or halogen.
  • R 3 is -H, -OH, halogen, amine, nitro, cyano, substituted or unsubstituted C 1-10 linear or branched alkyl, substituted or unsubstituted C 1-10 linear or branched Alkoxy, unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted C 3-10 cycloalkyl-C 1-2 alkyl, unsubstituted or substituted 3 to 10 each ring heterocycloalkyl, unsubstituted or Substituted 3-10 heterocyclic heterocycloalkyl-C 1-2 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl-C 1-2 alkyl, N, O And 5 to 10-membered unsubstituted or substituted heteroaryl including one or more hetero atoms selected from the group consisting of S, or 5 comprising one or more hetero atoms
  • substituted heterocycloalkyl may be substituted with one or more —OH.
  • R 3 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • the compound represented by Chemical Formula 1 is any one compound selected from the following compound groups.
  • the compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloride
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid.
  • the solvent may be prepared by filtration and drying, or by distillation under reduced pressure of the solvent and excess acid, followed by drying and crystallization in an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.
  • Step 3 Preparing a compound represented by Chemical Formula 7 from the compound represented by Chemical Formula 6 prepared in Step 2 (Step 3);
  • It provides a method for producing a compound represented by the formula (1) comprising the step (step 6) of preparing a compound represented by the formula (1) from the compound represented by the formula (11) prepared in step 5.
  • R 1 , R 2 , R 3 , And X is as defined in Formula 1 above;
  • the PT is -Boc.
  • step 1 is a step of preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 to be.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably dimethylform Amides (DMF) can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out between the boiling point of the solvent at -10 to 10 °C, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours
  • the present invention is not limited thereto, but step 1 may be performed as in step 1 of Example 1 below.
  • Step 2 is represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 To prepare a compound.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably dimethylform Amides (DMF) can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out between the boiling point of the solvent at -10 to 10 °C, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours
  • step 2 may be performed as in step 2 of Example 1 below.
  • Step 3 is a step of preparing a compound represented by Chemical Formula 7 from the compound represented by Chemical Formula 6 prepared in Step 2.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably methylene chloride Can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-20 hours
  • the production method of the present invention Although not limited thereto, Step 2 may be most preferably performed as Step 3 of Example 1 below.
  • Step 4 is represented by Chemical Formula 9 by reacting the compound represented by Chemical Formula 7 prepared in Step 3 with the compound represented by Chemical Formula 8 To prepare a compound.
  • the solvent used in the step is dimethylformamide (DMF), H 2 O, methanol, ethanol, t-butanol (t-BuOH), n-butanol (n-BuOH), tetrahydrofuran (THF), Methylene chloride, toluene, acetonitrile and the like can be used, and preferably n-butanol (n-BuOH) can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 90 to 120 °C
  • reaction time is not particularly limited
  • the reaction is preferably for 0.5-20 hours
  • the production method of the present invention Although not limited thereto, Step 2 may be most preferably performed as Step 4 of Example 1 below.
  • Step 5 is represented by Chemical Formula 11 by reacting the compound represented by Chemical Formula 9 and the compound represented by Chemical Formula 10 prepared in Step 4 To prepare a compound.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably dimethylform Amides can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-40 hours
  • Step 2 may be most preferably performed as Step 5 of Example 1 below.
  • Step 6 is a step of preparing a compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 11 prepared in Step 5.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably tetrahydro Furan can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-20 hours
  • Step 2 may be performed as in Step 6 of Example 1 below.
  • Step 3 Preparing a compound represented by Chemical Formula 7 'from the compound represented by Chemical Formula 6' prepared in Step 2 (Step 3);
  • Step 5 Preparing a compound represented by Chemical Formula 12 from the compound represented by Chemical Formula 9 'prepared in Step 4 (Step 5);
  • Step 6 Preparing a compound represented by Chemical Formula 13 from the compound represented by Chemical Formula 12 prepared in Step 5 (Step 6);
  • step 8 It provides a method of producing a compound represented by Formula 1 of claim 1 comprising the step (step 8) of preparing a compound represented by Formula 1 from the compound represented by Formula 14 prepared in step 7.
  • R 1 , R 2 , R 3 , And X is as defined in formula 1 of claim 1;
  • the PT, PT 1 and PT 2 are each an independent protecting group.
  • Step 1 is a step of preparing a compound represented by Chemical Formula 4 ′ from the compound represented by Chemical Formula 2.
  • step 1 of Scheme 2 may be understood as introducing a protecting group (-PT 1 ) at the N-position of the compound.
  • the protecting group (-PT 1 ) to be introduced is not particularly limited, but is preferably -Boc as long as it does not hinder the method of preparing the compound of Formula 1 of the present invention.
  • the protecting group (-PT 1 ) of step 1 is included in the present invention as a whole range of protecting groups that can be easily changed or modified by those skilled in the art, that is, not impeded to perform the manufacturing method.
  • the protecting group introduced in step 1 is subsequently removed in step 6 of scheme 2 and in step 7 by introducing a substituent of -R 3 into the N-position.
  • the compound represented by Formula 2, (Boc) 2 O, DMAP, and TEA may be reacted in DMF.
  • the solvent used in step 1 of Scheme 2 may be preferably DMF as an example, but the solvent usable in the step is dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF ), Methylene chloride, toluene, acetonitrile and the like can be used.
  • DMF dimethylformamide
  • H 2 O methanol
  • ethanol ethanol
  • Methylene chloride toluene
  • acetonitrile acetonitrile
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours.
  • Step 2 is represented by Chemical Formula 6 'by reacting the compound represented by Chemical Formula 4' prepared in Step 1 with the compound represented by Chemical Formula 5 To prepare a compound.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably tetrahydro Furan (THF) can be used.
  • reaction temperature in the above step is not particularly limited, but preferably can be reacted while increasing the temperature to -80 to 10 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-20 hours, of the present invention
  • the compound represented by Formula 4 ', n-BuLi, and the compound represented by Formula 5 may be reacted in THF.
  • Step 3 is a step of preparing a compound represented by Chemical Formula 7 'from the compound represented by Chemical Formula 6' prepared in Step 2.
  • the step may be understood as an oxidation step, if the compound represented by the formula (7 ') is included in the production method of the present invention without limitation if the oxidation step is prepared.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, methylene chloride toluene, acetonitrile, and the like may be used as the solvent usable in the above step.
  • Methylene chloride can be used as the solvent usable in the above step.
  • Step 2 may be performed by, for example, reacting a compound represented by Chemical Formula 6 ', MnO 2 in methylene chloride.
  • Step 4 is a compound represented by Chemical Formula 9 'by reacting the compound represented by Chemical Formula 7' prepared in Step 3 with the compound represented by Chemical Formula 8 It is a step of preparing a compound represented by.
  • the -O-PT group of the compound represented by the formula (8 ') when one of R1 and R2 is -OH group, or when the substituent can be introduced may be protected with a separate protecting group, or
  • the -PT group of the -O-PT group may be a protecting group which simultaneously protects one substituent of R1 and R2.
  • the PT (protecting group) may be a protecting group protected by only one PT (protecting group), such as -O-PT-O-.
  • solvents usable in the above steps include dimethylformamide (DMF), H 2 O, methanol, ethanol, t-butanol (t-BuOH), n-butanol (n-BuOH), tetrahydrofuran (THF), Methylene chloride, toluene, acetonitrile and the like can be used, and preferably n-butanol (n-BuOH) can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 50 to 120 °C
  • reaction time is not particularly limited, it is preferable to react for 0.5-20 hours
  • the production method of the present invention although not limited thereto, for example, the compound represented by Formula 7 ', the compound represented by Formula 8, and DIPEA may be performed by reacting n-butanol.
  • step 5 is a step of preparing a compound represented by Formula 12 from the compound represented by Formula 9 'prepared in Step 4.
  • the step may be understood as introducing a protecting group (-PT 2 ) to the -OH group of the cyclopentyl moiety -CH 2 -OH, where the protecting group (-PT 2 ) can be used without particular limitation, but an example And tert-butyldimethylsilyl).
  • the same protecting group can be used, and the compound represented by the formula (12) can be prepared, and if the protecting group in the range that does not hinder in performing the method for preparing the compound represented by the formula (1) finally without limitation to the present invention Included.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, and the like may be used, preferably methylene.
  • Chloride can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-40 hours
  • the production method of the present invention the compound represented by Chemical Formula 9 ', TBSCl, and imidazole may be performed by reacting with methylene chloride.
  • step 6 is a step of preparing a compound represented by Chemical Formula 13 from the compound represented by Chemical Formula 12 prepared in Step 5.
  • step 6 may be understood as removing the protecting group PT 1 of the indole N-position introduced in step 1.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably Preferably isopropanol.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 50 to 90 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-20 hours
  • the production method of the present invention although not limited thereto, for example, the compound represented by Formula 12, K 3 PO 4 may be performed by reacting in isopropanol.
  • Step 7 is represented by Chemical Formula 14 by reacting the compound represented by Chemical Formula 13 prepared in Step 6 with the compound represented by Chemical Formula 3 Preparing a compound.
  • step 7 may be understood as introducing a -R 3 substituent, and may be understood to be performed in the same manner as in Step 1 of Scheme 1.
  • dimethylformamide (DMF), H 2 O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, and the like may be used.
  • DMF dimethylformamide
  • H 2 O methanol, ethanol, propanol, isopropanol
  • THF tetrahydrofuran
  • methylene chloride toluene
  • acetonitrile acetonitrile
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C
  • reaction time is not particularly limited, the reaction is preferably for 0.5-20 hours
  • the production method of the present invention although not limited thereto, for example, the compound represented by Chemical Formula 13, the compound represented by Chemical Formula 3, and Cs 2 CO 3 may be performed by reacting in DMF.
  • Step 8 is a step of preparing a compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 14 prepared in Step 7.
  • step 8 is a step of removing all of the protecting groups of the cyclopropyl moiety, and in particular, introduces a substituent of -O-SO 2 -NH 2 by introducing NH 2 SO 2 Cl in the -OH part to the part protected with TBS. It includes a step.
  • the solvent used in the step is not particularly limited, but preferably DMF, dimethylformamide (DMF), H 2 O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, Toluene, acetonitrile and the like can be used.
  • reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 °C
  • reaction time is not particularly limited, it is preferable to react over 0.5-20 hours or 1 to 3 days.
  • the present invention is not limited thereto, but, for example, step 8 may be performed in three steps. First, the compound represented by Formula 14, TASF, is reacted in DMF, and then, NH 2 SO 2 Cl may be reacted in DMF, overnight or overnight, and finally overnight in TfOH: H 2 O (9: 1) in methanol.
  • the above-described manufacturing method of the present invention can be carried out by changing or modifying, such as inverting each step in consideration of the desired compound, the achieved yield, etc. If it is possible to change or modify in the manufacturing method of the invention will be easily understood that it is included in the present invention.
  • the present invention is to prevent or treat a disease represented by the formula (1), its stereoisomers or pharmaceutically acceptable salts thereof NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases It provides a pharmaceutical composition.
  • the NEDD8-Activating Enzyme (NAE) or Sumo Activating Enzyme (SAE) -related disease is correlated with the NEDD8-Activating Enzyme (NAE) or Sumo Activating Enzyme (SAE) to date, as in the background of the present invention described above. It refers to all diseases identified as having, for example, NEDD8-Activating Enzyme (NAE) or Sum Activating Enzyme (SAE) -related diseases include cancer, inflammation, cardiovascular disease, nerves. Neurodegenerative diseases, and the like.
  • the cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myxocarcinoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B cell lymphoma Cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, non-Hodgkin lymphoma, tongue cancer, astrocytoma,
  • the cancer may preferably be at least one selected from breast cancer, colon cancer, colon cancer, lung cancer, prostate cancer, esophageal cancer, bladder cancer, and head and neck cancer.
  • the cancer is acute myeloid leukemia (AML); Chronic myeloid leukemia (CML); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Waldenstrom megaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocyte lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome may be one or more selected from the group consisting of.
  • AML acute myeloid leukemia
  • CML Chronic myeloid leukemia
  • ALL Acute lymphoblastic leukemia
  • CLL Chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL Non-Hodgkin's lymphoma
  • NAE-related disease is not limited thereto, but refers to any disease that may be expressed from a phenomenon other than normal activity such as abnormality, modification, overexpression, etc. of NAE.
  • one example of NAE-related diseases is cancer, where the compounds of the present invention, their stereoisomers and acceptable salts thereof, may result from NAE activity when they result from abnormal activity of NAE in connection with cell proliferation of cancer cells. It can be effectively suppressed in molar units, and can be usefully used for ameliorating, preventing or treating diseases referred to as the NAE-related diseases.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof may be characterized by inhibiting NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) to prevent or treat cancer.
  • NAE NEDD8-Activating Enzyme
  • SAE Sudo Activating Enzyme
  • Pseudomyxoma intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myeloma sarcoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, Ovarian germ cell cancer, breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia
  • the cancer may preferably be at least one selected from breast cancer, colon cancer, colon cancer, lung cancer, prostate cancer, esophageal cancer, bladder cancer, and head and neck cancer.
  • the cancer is acute myeloid leukemia (AML); Chronic myeloid leukemia (CML); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Waldenstrom megaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocyte lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome may be one or more selected from the group consisting of.
  • AML acute myeloid leukemia
  • CML Chronic myeloid leukemia
  • ALL Acute lymphoblastic leukemia
  • CLL Chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL Non-Hodgkin's lymphoma
  • cancer refers to unregulated or overregulated cell proliferation, reduced cellular differentiation, inadequate ability to invade surrounding tissue, and / or to establish new growth at an ectopic site. Cellular disorders characterized by the ability to do so.
  • the term “cancer” includes, but is not limited to, solid tumors and blood mediated tumors (blood malignancies).
  • cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels.
  • cancer further includes primary and metastatic cancers.
  • the solid tumor is pancreatic cancer; Bladder cancer, including invasive bladder cancer; Colorectal cancer; Breast cancer including thyroid cancer, gastric cancer, metastatic breast cancer; Prostate cancer, including androgen-dependent and androgen-independent prostate cancer; Kidney cancer, including, for example, metastatic renal cell carcinoma; Liver cancers including, for example, hepatocellular carcinoma and intrahepatic bile ducts; Lung and bronchial cancers including non-small cell lung cancer (NSCLC), squamous epithelial lung cancer, bronchoalveolar alveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer (SCLC); Ovarian cancer, including, for example, advanced epithelial or primary peritoneal cancer; Cervical cancer; Uterine cancer including, for example, the uterine body and cervix; Endometrial cancer; Stomach cancer; Esophageal cancer; Head and neck cancers including, for example, squamous cell carcinoma of the head
  • the hematologic malignancy includes acute myeloid leukemia (AML); Chronic myeloid leukemia (CML) (including accelerated CML and CML subcellular phases (CML-BP)); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL) (including follicular lymphoma and mantle cell lymphoma); B-cell lymphoma (including immature large B-cell lymphoma (DLBCL)); T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Waldenstrom megaglobulinemia; Myelodysplastic syndrome (MDS) (including anemia of refractory anemia (RA), intractable anemia with coronary blasts (RARS) (anemia of refractory with hyperblasts (RAEB), and transformation-associated RAEB (RAEB-T))) ; Small lymph
  • the present invention is to prevent or improve the disease represented by the formula (1), its stereoisomers or pharmaceutically acceptable salts thereof NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases It provides a health functional food composition for.
  • the NEDD8-Activating Enzyme (NAE) or Sumo Activating Enzyme (SAE) -related diseases may include cancer, inflammation, cardiovascular disease, neurodegenerative diseases, and the like. And preferably cancer.
  • the cancer may include pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycelial sarcoma, acute myeloid leukemia, acute lymphocytic leukemia, and basal cells.
  • ovarian epithelial cancer ovarian germ cell cancer, breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma, Batterous swollen cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, non-Hodgkin lymphoma, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer , Glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma
  • the cancer may preferably be at least one selected from breast cancer, colon cancer, colon cancer, lung cancer, prostate cancer, esophageal cancer, bladder cancer, and head and neck cancer.
  • the cancer is acute myeloid leukemia (AML); Chronic myeloid leukemia (CML); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Waldenstrom megaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocyte lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome may be one or more selected from the group consisting of.
  • AML acute myeloid leukemia
  • CML Chronic myeloid leukemia
  • ALL Acute lymphoblastic leukemia
  • CLL Chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL Non-Hodgkin's lymphoma
  • the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, orally and parenterally, during clinical administration.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be performed by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, and it is an ampule or vial unit dosage form. It can be prepared by.
  • the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • Lactose 1 g
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • an injection was prepared by containing the above components in the contents shown.
  • the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the subject, Based on an adult subject of 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and is divided once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist. It may also be administered.
  • compositions of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy and biological response modifiers for the prevention or treatment of diseases caused by eurotensin-II receptor overactivity. have.
  • the present invention comprises administering to the subject a therapeutically effective amount of the compound, its stereoisomer or pharmaceutically acceptable salt thereof to the subject (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme). ) Provides a method of treating related diseases.
  • NAE NEDD8-Activating Enzyme
  • SAE Sudo Activating Enzyme
  • a disease that can be treated preferably cancer.
  • the cancer also includes all of the cancers described above.
  • the therapeutically effective amount refers to an amount that can improve the symptoms or condition of the subject when administered into the body, depending on the method of administration.
  • the amount may be different depending on the weight, age, sex, condition, family history of the subject to be administered, and in the present invention, the treatment method may determine a different amount of dosage according to different conditions for each subject.
  • an "effective amount” is an amount useful for treating proliferative, inflammatory, infectious, neurological or cardiovascular disorders, or an amount effective for treating cancer.
  • an "effective amount” of a compound is an amount that inhibits binding of NAE or SAE.
  • the compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration effective for treating a disease.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dose unit form refers to physically discrete units of the formulation appropriate for the subject to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment.
  • the particular effective dosage level for any particular subject or organism will depend on a variety of factors, including the following.
  • the disease to be treated and the severity of the disease The activity of the specific compound employed; The specific composition employed; Age, weight, general health, sex and diet of the subject; Time of administration, route of administration, and rate of excretion of the specific compound employed; Duration of treatment; Drugs used with or concurrent with the specific compound employed, and factors well known in, for example, medical techniques.
  • subject refers to an animal, eg a mammal, such as a human.
  • compositions of the present invention can be administered orally, rectally, parenterally, intranasally, vaginally, intraperitoneally, topically (powders, ointments, lotions, plasters, or drops) to humans and other animals depending on the severity of the infection to be treated. ), Orally, orally or as a nasal spray, and the like.
  • a compound of the invention is administered in an amount of about 0.01 mg / kg to about 50 mg / kg, eg, about 1 mg / kg to about 25 mg / kg body weight per day, once, to achieve the desired therapeutic effect. It may be administered orally or parenterally at a dosage level of more than / 1 day.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain the following inert diluents conventionally used in the art: water or other solvents, solubilizers, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, peanuts, corn, bacteria, olives, casters, and sesame oils), glycerol, tetrahydro Fatty acid esters of furfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof.
  • oral compositions may also include adjuvants, tetrahydro Fatty acid esters of
  • Injectable preparations for example, sterile injectable aqueous or lipogenic suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, for example solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or dispersion medium. Any blended fixed oil may be used for this purpose and includes synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations may be sterilized, for example, by incorporating a tangerine in the presence of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use, for example, by filtration through a bacteria-fixed filter. have.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissue.
  • compositions for rectal or vaginal administration are suppositories, which can be prepared, for example, by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository waxes, which suppositories are solid ambient temperatures Solid at, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository waxes, which suppositories are solid ambient temperatures Solid at, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) filler or extender such as starch, lactose , Sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants Agar-agar-agar, calcium nitrate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, Cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.
  • Tablets, dragees, capsules, pills, and granules in solid dosage forms can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. It may optionally contain an opaque agent and may also be a composition which releases only the active ingredient (s), eg, in certain parts of the intestine, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.
  • the active compound may also be in micro-encapsulated form with one or more excipients as described above.
  • Tablets, dragees, capsules, pills, and granules in solid dosage forms can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulation art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also include additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as in normal practice.
  • the dosage form may also comprise a buffer. It may be a composition which may optionally contain an opacifying agent and which also releases only the active ingredient (s), for example in certain parts of the intestine, optionally, in a delayed manner.
  • a buffer may be a composition which may optionally contain an opacifying agent and which also releases only the active ingredient (s), for example in certain parts of the intestine, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active ingredient is mixed with a pharmaceutically acceptable carrier and any necessary preservatives or buffers under sterile conditions as required.
  • Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches having the added advantage of providing controlled cleavage of the compound into the body.
  • Such dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption accelerators can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a compound of the invention or a pharmaceutical composition thereof is administered with an anticancer agent.
  • anticancer agent refers to any agent administered to a subject with cancer to treat cancer.
  • Combination therapy includes the administration of therapeutic agents either concurrently or sequentially.
  • the therapeutic agent may be combined in one composition administered to the subject.
  • the compounds of the present invention are used in combination with other therapeutic agents.
  • the additional therapeutic agent is selected from inhibitors of other SAEs.
  • the compound of the present invention is administered with a therapeutic agent selected from the group consisting of cytotoxic drugs, radiotherapy, and immunotherapy.
  • the compounds of the present invention may be used with chemotherapeutic regimens for the treatment of relapsed / refractory non-Hodgkin's lymphoma, including DLBCL and CLL.
  • Chemotherapy regimens include, but are not limited to, R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), R-DHAP (rituximab, dexamethasone, high-dose cyta Lavigne and cisplatin), and R-GDP (rituximab, gemcitabine, cisplatin and dexamethasone). It is understood that other combinations may be undertaken within the scope of the present invention.
  • R-ICE rituximab, ifosfamide, carboplatin, and etoposide
  • R-DHAP rituximab, dexamethasone, high-dose cyta Lavigne and cisplatin
  • R-GDP rituximab, gemcitabine, cisplatin and dexamethasone
  • Additional agents may be administered separately from the combination therapy provided as part of a multiple dosage regimen.
  • the agents may be part of a single dosage form mixed with a compound of the present invention. If administered as part of a combination therapy, the two therapeutic agents may be provided simultaneously, sequentially, or intermittently.
  • Combination therapy can be used for any of the therapeutic indications described herein.
  • the combination therapy is for treating a proliferative disorder (eg, cancer) in a subject.
  • the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myeloid leukemia or acute lymphoblastic leukemia.
  • Another aspect of the invention relates to inhibiting SAE activity in a biological sample or subject, the method comprising administering to or contacting a compound represented by Formula 1, or a composition comprising the compound, or contacting the biological sample It includes.
  • biological sample generally includes in vivo, in vitro, and ex vivo materials, and also includes, but is not limited to, cell cultures or extracts thereof; Biopsied material obtained from a mammal or extracts thereof; And blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • kits comprising a separate container in a single package, wherein the compounds or pharmaceutical compositions and / or salts thereof disclosed herein comprise one or more disorders, symptoms in which SAE plays a role. And one or more pharmaceutically acceptable carriers for use in treating the disease.
  • Compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to the present invention may inhibit the activity of NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) to prevent NAE (NEDD8-Activating Enzyme) or SAE (Sumo). Activating Enzyme) It was confirmed through experiments that there is a useful effect in the improvement, prevention or treatment of diseases.
  • the experiment was performed on human-derived breast cancer cells (HCT-116, THP-1) purchased from ATCC, Example 1 according to the present invention
  • HCT-116, THP-1 human-derived breast cancer cells
  • the -45 compound has been found to inhibit cancer cell growth excellently at a unit concentration of micromolar or nanomolar relative to human-derived breast cancer cells (HCT-116, THP-1), the heterocyclic compound according to the present invention can prevent cancer Or it was confirmed that it can be usefully used as an active ingredient of the therapeutic pharmaceutical composition (see Experimental Example 1).
  • Example 1-45 compound according to the present invention is excellent in SAE at a concentration of micromolar or nanomolar units And it was confirmed that can inhibit the activity of NAE, it was confirmed that it can be usefully used as a pharmaceutical composition for the prevention and treatment of cancer containing the same (see Experimental Example 2 and Experimental Example 3).
  • Step 2 Preparation of (1- (3-bromobenzyl) -1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanol
  • Step 3 Preparation of (1- (3-bromobenzyl) -1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone
  • Step 4 (1- (3-bromobenzyl) -1H-indol-3-yl) (4-(((3aR, 4R, 6R, 6aS) -6- (hydroxymethyl-2,2-dimethyltetra Preparation of hydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrimidin-5-yl) methanone
  • reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step 5 ((3aS, 4R, 6R, 6aR) -6-((5- (1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- Preparation of 2,2-dimethyltetrohydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate
  • reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step 6 ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- Preparation of 2,3-dihydrooxycyclopentyl) methyl sulfamate
  • reaction mixture was stirred at room temperature for 2 hours, the reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • the target compound was prepared in the same manner as in Example 1, except that 1H-indazole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1 ( LC / MS M + H: 616.1).
  • the target compound was prepared in the same manner as in Example 1, except that 3-fluorobenzyl bromide was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H). : 556.2).
  • the target compound was prepared in the same manner as in Example 1, except that 3-chloro-4-fluorobenzyl bromide was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H: 590.1).
  • the target compound was prepared in the same manner as in Example 1, except that 2,5-dichlorobenzyl bromide was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H: 606.1).
  • the target compound was prepared in the same manner as in Example 1, except that 2-fluorobenzyl bromide was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H). : 556.2).
  • a target compound was prepared in the same manner as in Example 1 except that 4-trifluoromethylthiobenzyl bromide was used (LC / MS M + H: 674.1).
  • a target compound was prepared in the same manner as in Example 1 except that 4- (bromomethyl) -1,1′-biphenyl was used (LC / MS M + H: 614.20).
  • a target compound was prepared in the same manner as in Example 1 except that 2- (bromomethyl) -6-methylpyridine was used (LC / MS M + H: 553.2).
  • Example 1 was carried out in the same manner as in Example 1, except that 2- (bromomethyl) -5- (trifluoromethyl) furan was used in place of 3-bromobenzyl bromide used in Step 1 of Example 1 Compounds were prepared (LC / MS M + H: 596.1).
  • the target compound was prepared in the same manner as in Example 1, except that 3- (bromomethyl) -5-methylisoxazole was used in place of the 3-bromobenzyl bromide used in Step 1 of Example 1. (LC / MS M + H: 543.2).
  • the target compound was prepared by the same method as Example 1, except that 5-methyl-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1. (LC / MS M + H: 630.1).
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1. Prepared (LC / MS M + H: 634.1).
  • Example 1 was carried out in the same manner as in Example 1, except that 5- (benzyloxy) -1H-indole-3-carbaldehyde was used in place of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1 Compounds were prepared (LC / MS M + H: 722.1).
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1. Prepared (LC / MS M + H: 614.2).
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1.
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1.
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1.
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1. Prepared (LC / MS M + H: 604.2).
  • the target compound was prepared in the same manner as in Example 1, except that 5-fluoro-1H-indole-3-carbaldehyde was used instead of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1. Prepared (LC / MS M + H: 682.1).
  • Step 1 (1-benzyl-1H-indol-3-yl) (4-(((1R, 3R, 4S) -3- (hydroxymethyl) -4-((triisoprosilylyl) oxy) cyclo Synthesis of pentyl) amino) pyrimidin-5-yl) methanone
  • reaction was confirmed by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO 4, and the solvent was removed under reduced pressure.
  • Step 1 (1-benzyl-1H-indol-3-yl) (4-(((1R, 2R, 3R, 4R) -2-fluoro-3-hydroxy-4- (hydroxymethyl) cyclopentyl Preparation of Amino) pyrimidin-5-yl) methanone
  • Step 2 (1-benzyll-1H-indol-3-yl) (4-(((1R, 2R, 3R, 4R) -3-((tert-butyldimethylsilyl) oxy) -4- (talt Preparation of -butyldimethylsilyl) oxy) methyl) 2-fluorocyclopentyl) amino) pyrimidin-5-yl) methanone
  • Step 3 (1-benzyl-1H-indol-3-yl) (4-(((1R, 2R, 3R, 4R) -3-((talt-butyldimethylsilyl) oxy) -2-fluoro- Preparation of 4- (hydromethylmethyl) cyclopentyl) amino) pyrimidin-5-yl) methanone
  • Step 4 ((1R, 2R, 3R, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -3-fluoro-2 Preparation of -Hydroxycyclopentyl) methyl sulfamet
  • Step 1 (1- (2-Butyn-1-yl) -5-fluoro-1H-indol-3-yl) (3-(((3aS, 4R, 6R, 6aR) -6-(((Talt -Butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrazin-2-yl) methanone Produce
  • Step 2 (1- (2-Butyn-1-yl) -5-fluoro-1H-indol-3-yl) (3-(((3aS, 4R, 6R, 6aR) -6-hydromethylmethyl- Preparation of 2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrazin-2-yl) methanone
  • Step 3 ((3aR, 4R, 6R, 6aS) -6-((3- (1- (2-butyn-1yl) 5-fluoro-1H-indol-3-carbonyl) pyrazin-2-yl Preparation of Amino) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate
  • Step 4 ((1R, 2R, 3S, 4R) -4-((3- (1- (2-butyn-1yl) 5-fluoro-1H-indol-3-carbonyl) pyrazin-2-yl Preparation of Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
  • reaction was terminated with NaHCO3, extracted with ethyl acetate, and dried over MgSO4.
  • Step 1 Preparation of 1- (2-butyn-1-yl) -1H-indole-3-carbaldehyde
  • Step 2 Preparation of ((4-chloropyrimidin-5-yl) (1-isobutyl-1H-indol-3-yl) methanol
  • reaction was terminated using saturated NH 4 Cl, extracted using EA, and dried using MgSO 4 .
  • Step 4 (4-(((3aS, 4S, 6R, 6aR) -6- (hydroxymethyl) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol- Preparation of 4-yl) amino) pyrimidin-5-yl) (1-isobutyl-1H-indol-3-yl) methanone
  • Step 5 ((3aR, 4R, 6S, 6aS) -6-((5- (1- (2-butyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,2 Preparation of -dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate
  • Step 6 ((1R, 2R, 3S, 4S) -2,3-dihydroxy-4-((5- (1-isobutyl-1H-indole-3-carbonyl) pyrimidin-4-yl) Preparation of amino) cyclopentyl) methyl sulfamate
  • a target compound was prepared in the same manner as in Example 36, except that 4- (2-chloroethyl) morpholine was used instead of 1-bromo-2-methylpropane used in Step 1 of Example 36. It was.
  • a target compound was prepared in the same manner as in Example 33, except that 4- (3- (chloromethyl) phenyl) morpholine was used instead of 1-bromo-2-butyne used in Step 1 of Example 33. Was prepared.
  • Example 33 except for using 5- (chloromethyl) -2- (1H-pyrazol-1-yl) pyridine in place of the 1-bromo-2-butyne used in step 1 of Example 33 above In the same manner as in the title compound was prepared.
  • Example 33 The same procedure as in Example 33 was carried out except that N- (3- (chloromethyl) phenyl) methanesulfonamide was used instead of 1-bromo-2-butyne used in Step 1 of Example 33. Compounds were prepared (LC / MS M + H: 649.1).
  • Example 33 except for using 1- (chloromethyl) -2-methyl-3- (trifluoromethyl) benzene in place of the 1-bromo-2-butyne used in Step 1 of Example 33 above In the same manner as in the title compound was prepared.
  • Table 1 below shows the chemical structural formulas of the compounds prepared in Examples 1-45.
  • Example constitutional formula Example constitutional formula One 24 2 25 3 26 4 27 5 28 6 29 7 30 8 31 9 32 10 33 11 34 12 35 13 36 14 37 15 38 16 39 17 40 18 41 19 42 20 43 21 44 22 45 23
  • human-derived breast cancer cells purchased from ATCC were cultured in RPMI medium containing 10% fetal bovine serum. Cultured breast cancer cells were separated from the container with 2% trypsin to make individual cells, and the number of cells per ml was measured by a cell count. Cells are injected in a clear 96 well in an amount of 3,000 cells / well / 100 ul and incubated for 18 hours to stabilize.
  • Example compounds of the present invention dissolved in DMSO were treated with 20 uM, 10 uM, 5 uM, 2.5 uM, 1.25 uM, 0.625 uM, 0.3125 uM.
  • the concentration of DMSO was not more than 0.1% of the cell medium.
  • Samples treated with DMSO only at the same rate were used as controls.
  • the Example compound was treated with cells for 48 hours, after 48 hours, the existing culture solution was removed and dissolved in DMSO at a concentration of 20 mM, 10 mM, 5 mM, 2.5 mM, 1.25 mM, 0.625 mM, 0.3125 mM.
  • Compounds were diluted 1000-fold in culture medium and injected into the wells at 200 ul. Further incubation for 24 hours, cell growth was measured. Cell growth was measured using cell count kit-8 (Dojindo, CK04-13). After adding 10 ul of CCK-8 solution to the cells and reacting at 37 ° C. for 2 hours, the absorbance was measured at 450 nm using an absorbance measuring instrument. At this time, the cell growth inhibition formula is as follows.
  • Example LD 50 ( ⁇ M) HCT116 THP1 One 0.934 0.223 3 0.2277 ⁇ 0.03 4 0.7897 0.6002 5 0.4557 ⁇ 0.03 6 1.237 1.284 7 0.4306 ⁇ 0.03 8 1.801 1.426 9 0.6429 0.6619 10 2.276 1.808 11 1.481 1.557 12 0.587 0.163 13 15.131 13.171 14 3.121 1.002 15 4.121 2.781 18 0.4134 0.0553 19 2.014 0.813 22 1.009 0.896 24 2.014 0.813
  • the compounds of Examples 1-45 according to the present invention are all in the unit concentration of micromolar or nanomolar with respect to human-derived breast cancer cells (HCT-116, THP-1) It is confirmed to inhibit cancer cell growth.
  • the heterocyclic compound according to the present invention can be usefully used as a pharmaceutical composition for improving, preventing or treating cancer, or as a nutraceutical composition, since it can be confirmed that the heterocyclic compound can inhibit the growth of cancer cells.
  • In vivo sumoylation assay kit (SA-001) and sumo-1 His-tag (Enzo, BML-UW9195) were used.
  • SA-001 In vivo sumoylation assay kit
  • Reagent A 2 ul, sumo-1 His-tag 1 ug and Reagent C 1 ul were adjusted to a total of 20 ul in DW.
  • Positive control and samples were adjusted to a total of 19 ul of Reagent A 2 ul, sumo-1 His-tag 1 ug, Reagent C 1 ul and Reagent D 1 ul in DW.
  • the positive control group was injected with 1 ul of DW and 1 ul of 20 X samples (diluted in DW) in the treated group and reacted at 37 ° C. for 2 hours.
  • anti 6HIS-Eu cryptate cisbio, 61HI2KLA
  • anti GST-d2 cisbio, 61GSTDLA
  • a solution prepared by injecting 0.1% BSA and 0.5% Tween 20 into PBS was injected into the wells, and 0.2 ul of anti 6HIS-Eu and 0.2 ul of anti GST-d2 were injected into a white 384 well. After reacting for 1 hour at 37 ° C., the reaction solution was repeatedly injected for 3 wells by 1 ul, and HTRF was measured using I3 (molecular device), an HRTRF measuring instrument. 3 is shown.
  • Example SAE [IC 50 ( ⁇ M)] One 0.10 2 1.70 3 0.12 4 0.46 5 1.65 6 3.18 7 0.04 8 1.60 10 3.48 11 0.03 12 0.47 14 2.88 18 2.21 19 1.29 22 0.53 24 0.661 27 0.68 28 1.72 31 0.56 32 1.84 34 1.86 37 1.65 39 > 10 45 0.99
  • the heterocyclic compound according to the present invention can inhibit SAE activity at a concentration of micromolar or nanomolar units well
  • the compound of the present invention is a pharmaceutical composition for improving, preventing or treating cancer, or health function It can be usefully used as a food composition.
  • NAE enzyme activity is measured using a time-resolved fluorescence energy transfer assay. 10 nM Ubc12 in 50 ⁇ l enzyme reaction (50 mM HEPES (Sigma), pH7.5, 0.05% BSA (Sigma), 5 mM MgCl 2 (Sigma), 20 uM ATP (Sigma), 250 uM glutathione (Sigma)) -GST (Ubiquigent), 75 nM NEDD8-Flag (Bostonbiochem) and 0.3 nM NAE enzyme (Enzo) were added to a 384 well plate for 90 minutes at room temperature, followed by 25 ul stop solution (0.1 M HEPES (Sigma)).
  • Example NAE [IC 50 ( ⁇ M)] 3 0.005 4 0.019 5 0.091 6 0.012 7 0.022 9 0.037 10 0.02 11 0.008 22 0.0009 26 0.141 28 0.015 30 0.010 31 0.0006 39 0.013 45 0.112
  • the heterocyclic compound according to the present invention can inhibit NAE activity at a concentration of micromolar or nanomolar units well
  • the compound of the present invention is a pharmaceutical composition for improving, preventing or treating cancer, or health function It can be usefully used as a food composition.
  • the heterocyclic compound according to the present invention can excellently inhibit NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) at a concentration of nanomolar units, thereby improving, preventing or preventing NAE or SAE-related diseases such as cancer. It can be used as a pharmaceutical composition or nutraceutical composition for treatment, and also has a useful effect, such as providing a method of treatment comprising administering to a subject in need thereof an effective amount.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé hétérocyclique, son procédé de préparation, et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer. Le composé hétérocyclique selon la présente invention peut inhiber de manière significative l'enzyme d'activation de NEDD8 (NAE) ou l'enzyme d'activation de Sumo (SAE) jusqu'à une concentration nanomolaire, et par conséquent, peut être avantageusement utilisé en tant que principe actif dans une composition pharmaceutique pour prévenir ou traiter le cancer, par exemple, une maladie associée à une enzyme d'activation de NEDD8 (NAE) ou à une enzyme d'activation de Sumo (SAE).
PCT/KR2017/004246 2016-04-20 2017-04-20 Nouveau composé hétérocyclique, procédé de préparation de celui-ci et composition pharmaceutique contenant celui-ci en tant que principe actif pour la prévention ou le traitement du cancer WO2017183927A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20160048433 2016-04-20
KR10-2016-0048433 2016-04-20

Publications (1)

Publication Number Publication Date
WO2017183927A1 true WO2017183927A1 (fr) 2017-10-26

Family

ID=60116230

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/004246 WO2017183927A1 (fr) 2016-04-20 2017-04-20 Nouveau composé hétérocyclique, procédé de préparation de celui-ci et composition pharmaceutique contenant celui-ci en tant que principe actif pour la prévention ou le traitement du cancer

Country Status (2)

Country Link
KR (1) KR101927375B1 (fr)
WO (1) WO2017183927A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024099438A1 (fr) * 2022-11-11 2024-05-16 微境生物医药科技(上海)有限公司 Composés utilisés en tant qu'inhibiteurs de l'enzyme d'activation de sumo

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080051404A1 (en) * 2006-08-08 2008-02-28 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US20120258927A1 (en) * 2006-02-02 2012-10-11 Millenium Pharmaceuticals, Inc. Inhibitors of e1 activating enzymes
US20130150388A1 (en) * 2011-08-24 2013-06-13 Millennium Pharmaceuticals, Inc. Inhibitors of nedd8-activating enzyme
WO2015002994A2 (fr) * 2013-07-02 2015-01-08 Millennium Pharmaceuticals, Inc. Composés hétéroaryliques pouvant être utilisés en tant qu'inhibiteurs de l'enzyme sae

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120258927A1 (en) * 2006-02-02 2012-10-11 Millenium Pharmaceuticals, Inc. Inhibitors of e1 activating enzymes
US20080051404A1 (en) * 2006-08-08 2008-02-28 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US20130150388A1 (en) * 2011-08-24 2013-06-13 Millennium Pharmaceuticals, Inc. Inhibitors of nedd8-activating enzyme
WO2015002994A2 (fr) * 2013-07-02 2015-01-08 Millennium Pharmaceuticals, Inc. Composés hétéroaryliques pouvant être utilisés en tant qu'inhibiteurs de l'enzyme sae

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MILHOLLEN, M. A. ET AL.: "MLN4924, a NEDD8-activating Enzyme Inhibitor, is Active in Diffuse Large B- cell Lymphoma Models: Rationale for Treatment of NF- kappa B-dependent Lymphoma", BLOOD, vol. 116, no. 9, 2010, pages 1515 - 1523, XP002723587 *

Also Published As

Publication number Publication date
KR20170120521A (ko) 2017-10-31
KR101927375B1 (ko) 2018-12-11

Similar Documents

Publication Publication Date Title
WO2017204445A2 (fr) Composition pharmaceutique induisant la décomposition de la protéine alk, et composition pharmaceutique pour la prévention ou le traitement du cancer la contenant en tant que composant actif
WO2010093191A2 (fr) Nouveaux composés efficaces en tant qu'inhibiteurs de xanthine oxydase, leur procédé de préparation et composition pharmaceutique les contenant
WO2020171499A1 (fr) Nouveau dérivé de pyrido[3,4-d]pyrimidin-8-one ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique pour prévenir, soulager ou traiter le cancer, comprenant celui-ci
WO2015030514A1 (fr) Dérivé de tétrahydrocyclopentapyrrole et son procédé de préparation
WO2013073875A1 (fr) Dérivé antiviral inédit de pyrrolopyridine et son procédé de production
WO2019078522A1 (fr) Composé induisant la dégradation de la protéine céréblon, procédé de préparation associé, et composition pharmaceutique pour la prévention ou le traitement du cancer le contenant en tant que principe actif
WO2020149723A1 (fr) Dérivé de pyrrolopyrimidine et composition pharmaceutique pour la prévention ou le traitement d'une maladie liée à la protéine kinase le comprenant en tant que principe actif
WO2021145521A1 (fr) Dérivé de pyrido[3,4-d]pyrimidine et composition pharmaceutique thérapeutique le comprenant
WO2021145520A1 (fr) Dérivé de 7-amino-3,4-dihydropyrimidopyrimidin-2-one ayant une activité inhibitrice vis-à-vis des protéines kinases et composition pharmaceutique thérapeutique comprenant celui-ci
WO2020149553A1 (fr) Dérivé d'aryle ou d'hétéroaryle, et composition pharmaceutique le comprenant en tant que principe actif pour le traitement d'une maladie associée à une kinase
WO2022035303A1 (fr) Nouveaux dérivés de dioxoloisoquinolinone et leur utilisation
WO2015102426A1 (fr) Nouveau composé dérivé d'indole et composition pharmaceutique contenant ce dérivé
WO2011162562A2 (fr) Bicycles fusionnés [6+5] en tant qu'antagonistes de la thrombine, procédé de préparation de ceux-ci et compositions pharmaceutiques contenant les bicycles
WO2021162493A1 (fr) Composé induisant la dégradation de protéines kinases et son utilisation
AU2021226297B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2021086069A1 (fr) Composé comprenant un inhibiteur d'ezh2 et un liant de ligase e3 et composition pharmaceutique pour prévenir ou traiter une maladie associée à ezh2 comprenant celui-ci en tant que principe actif
WO2010036000A2 (fr) Nouveaux dérivés d'oxazolidinone avec une amidoxime cyclique ou une amidrazone cyclique et compositions pharmaceutiques les comprenant
WO2018048261A1 (fr) Nouveau composé dérivé de spiroquinone, son procédé de production, et composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter des troubles neurologiques
WO2016006974A2 (fr) Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation
WO2023153748A1 (fr) Inhibiteur de sos1 et dérivé de celui-ci
WO2017183927A1 (fr) Nouveau composé hétérocyclique, procédé de préparation de celui-ci et composition pharmaceutique contenant celui-ci en tant que principe actif pour la prévention ou le traitement du cancer
WO2018044136A1 (fr) Nouveau composé, son procédé de préparation et composition pharmaceutique le contenant en tant que principe actif pour la prévention ou le traitement de maladies associées à la poly (adp-ribose) polymérase -1 (parp -1)
AU2019344240B2 (en) Novel thiazole derivatives and pharmaceutically acceptable salts thereof
WO2017164705A1 (fr) Nouveau dérivé de pyridine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter une maladie liée à fgfr contenant ledit dérivé comme principe actif
WO2021040422A1 (fr) Nouveau dérivé de pyrimido[4,5-d]pyrimidine-2-one ayant une activité inhibitrice de protéine kinase

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17786195

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17786195

Country of ref document: EP

Kind code of ref document: A1