WO2017183927A1 - Novel heterocyclic compound, method for preparing same, and pharmaceutical composition comprising same as active ingredient for preventing or treating cancer - Google Patents

Novel heterocyclic compound, method for preparing same, and pharmaceutical composition comprising same as active ingredient for preventing or treating cancer Download PDF

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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
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cancer
substituted
amino
carbonyl
indole
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PCT/KR2017/004246
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French (fr)
Korean (ko)
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박성준
허정녕
김광록
김성수
임환정
이혁
장성연
김범태
윤은영
임병호
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한국화학연구원
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Publication of WO2017183927A1 publication Critical patent/WO2017183927A1/en

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    • 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.

Abstract

The present invention relates to a novel heterocyclic compound, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient for preventing or treating cancer. The heterocyclic compound according to the present invention can significantly inhibit NEDD8-activating enzyme (NAE) or Sumo activating enzyme (SAE) at a concentration in a nanomolar unit, and thus the heterocyclic compound can be favorably used for a pharmaceutical composition containing the same as an active ingredient for preventing or treating cancer, for example, a disease associated with NEDD8-activating enzyme (NAE) or Sumo activating enzyme (SAE).

Description

신규한 헤테로고리 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물Novel heterocyclic compounds, preparation methods thereof and pharmaceutical compositions for the prevention or treatment of cancer containing the same as an active ingredient
본 발명은 신규한 헤테로고리 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.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.
유비퀴틴 유사 분자(ubiquitin-like molecule: ubl)에 의한 단백질의 번역 후 변형은 세포 분열, 세포 신호전달 및 면역 반응을 비롯한 많은 생물학적 과정을 조절하는 데 있어서 중요한 역할을 하는 세포 내 중요한 조절 과정이다. Ubl은 ubl의 C 말단 글라이신과의 이소펩티드 결합을 통해 표적 단백질 위의 라이신에 공유 결합된 작은 단백질이다. 유비퀴틴 유사 분자는 표적 단백질의 분자 표면을 바꾸고 단백질-단백질 상호작용, 효소활성, 안정성 및 표적의 세포내 편재화와 같은 특성에 영향을 미칠 수 있다.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.
유비퀴틴 및 여타 ubl은 ubl의 C 말단 글라이신과의 아실-아데닐레이트 중간체의 형성을 촉매화하는 특이적 E1 효소에 의해 활성화된다. 이후, 활성화된 ubl 분자는 티오에스터 결합 중간체의 형성을 통해 E1 효소 내의 촉매 시스테인 잔기로 전달된다. E1-ubl 중간체 및 E2는 회합되어 티오에스터 교환을 발생시키고, 여기서 ubl은 E2의 활성 부위 시스테인으로 전달된다. 이후, ubl은 표적 단백질에서 라이신 측쇄의 아미노기와의 이소펩티드 결합 형성을 통해, 직접 또는 E3 리가제와 함께, 표적 단백질에 접합된다.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.
ubl 변형의 생물학적 결과는 해당 표적에 따라 달라진다. 유비퀴틴화의 변형의 결과는 26S 프로테아좀(proteasome)에 의한 폴리-유비퀴틴화 단백질의 분해이다. 유비퀴틴은 이의 특이적 E1 활성화 효소, Uba1(유비퀴틴 활성화 효소, UAE), E2의 패밀리 유래의 접합 효소 및 E3의 고리 또는 HECT 클래스 중 어느 하나의 유래의 유비퀴틴 리가제를 포함하는 효소 캐스케이드를 통해 이의 표적 단백질에 접합된다.The biological consequences of the ubl modification depend on the target in question. The result of the modification of ubiquitination is the degradation of poly-ubiquitated proteins by 26S proteasomes. 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.
현재 알려진 바로는, 40개 이상의 E2 단백질 및 100개 이상의 E3 단백질 각각의 특정 조합에 의해 표적 특이성이 결정된다. 유비퀴틴 이외에, 10개의 유비퀴틴 유사 단백질이 존재하고, 각각은 특이적 E1 활성화 효소에 의해 활성화되고 유사하지만 구별되는 하향 접합 경로를 통해 프로세싱되는 것으로 생각된다. E1 활성화 효소가 확인된 ubl로는 NEDD8(APPBP1-Uba3), ISG15(UBE1L) 및 SUMO 패밀리(Aos1-Uba2)를 들 수 있다.As currently known, target specificity is determined by a specific combination of each of at least 40 E2 proteins and at least 100 E3 proteins. In addition to 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).
이중, NEDD8은 이종이합체 NEDD8-활성화 효소(APPBP1-Uba3)(NAE)에 의해 활성화되고 단일 E2(Ubc12)로 전달되어, 결국에는 컬린(cullin) 단백질에 결찰된다. 네딜화(neddylation)의 작용은 유비퀴틴화에 관여하는 컬린계 유비퀴틴 리가제의 활성화 및 이에 따른 p27 및 I-κB를 포함하는 세포 신호전달 단백질 및 많은 세포주기의 변화를 유도한다.Of these, 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. 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-κB.
한편, SUMO는 ATP에 의존하여 SAE(SUMO Activating Enzyme) 효소를 통한 활성화 기전을 갖는데, SUMO는 E1에서 E2(SUMO Conjugating Enzyme, Ubc9)의 시스테인 잔기로 이동되고, SUMO 단백질은 표적 단백질에 위치한 리신 측쇄의 엡실론 아미노기와 유사펩티드 결합을 통해, 표적 단백질에 직접적으로 또는 E3 리가제(ligase)와 컨쥬게이션 한 후, 표적 단백질에 결합하고, 상기 표적 단백질과 SUMO의 결합을 통해, SUMO는 세포 내 소기관의 위치와 기능, 기질 단백질의 복합체 형성 및 안정성을 조절하는 역할을 수행하게 된다.On the other hand, 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. 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.
따라서, SAE 효소에 의해 SUMO 결합이 시작되기 때문에, 이를 저해하거나 조절하여 세포 대사, 세포 조절, 전사 조절, 유전 정보의 보존, 염색체 분획, 등을 조절할 수 있다. 특히, SUMO 결합을 통해 암세포의 유전자 발현 및 성장 조절 경로가 조절되기 때문에, SAE 효소를 표적한 암 또는 종양 치료용 약물 개발을 통해 암, 종양 세포의 억제와 사멸이 가능해진다.Therefore, 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. In particular, since 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.
최근, 다발성 골수증, 유방암 등이 SAE 변형 발현과 연관되어 있음을 확인하였고, SAE 활성 저해와 암의 상관관계가 규명되어(Driscoll et al.Blood. 2010;. 115(14):2827-2834.) SAE 효소를 표적한 약물은 암과 같은 증식 장애의 치료 수단의 일환으로 유용하게 사용될 수 있음이 더욱 분명해졌다. 또한, SAE 저해제는 종양 외의 질병을 치료하는데 유효할 수 있고, 신경병성 질환, 염증, 바이러스성 감염 등의 치료에도 사용될 수 있음이 확인되었으나, 아직까지 분명한 약효를 수반한 치료제가 개발되지 않고 있어 지속적인 연구와 노력이 요구되고 있다.Recently, it has been confirmed that multiple myeloma, breast cancer, etc. are associated with the expression of SAE modification, and the correlation between the inhibition of SAE activity and cancer has been identified (Driscoll et al. Blood. 2010 ;. 115 (14): 2827-2834. Drugs targeting SAE enzymes have become more apparent as useful as a means of treatment for proliferative disorders such as cancer. In addition, SAE inhibitors may be effective for treating diseases other than tumors and may be used for the treatment of neuropathic diseases, inflammations, viral infections, etc., but therapeutic agents with obvious medicinal effects have not been developed. Research and effort are required.
이처럼 E1 활성화 효소의 표적화는 세포 신호전달 및 세포 분열의 완전성을 유지하는 데 중요한 다양한 생화학 경로를 방해하는 독특한 기회를 제공한다. E1 활성화 효소는 ubl 접합 경로의 제1단계에서 작용하여, E1 활성화 효소의 억제는 ubl 변형의 하향 생물학적 결과를 특이적으로 조절한다. 이 활성화 효소의 억제 및 그 결과로 생긴 ubl 접합의 하향 효과의 억제는 질환 기전에 중요한 세포 분열, 세포 신호전달 및 세포 생리학의 몇몇 양태의 완전성을 방해하는 방법을 나타낸다. 따라서, 다양한 세포 작용의 조절물질인 UAE, NAE 및 SAE와 같은 E1 효소는 질환 및 장애의 치료에 대한 새로운 접근법의 확인을 위한 잠재적으로 중요한 치료학적 표적이다.This targeting of E1 activating enzymes offers a unique opportunity to disrupt various biochemical pathways that are important for maintaining cell signaling and cell division integrity. 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. Thus, 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.
E1 활성화 효소 활성을 통해 조절되는 중요한 특정 경로는 유비퀴틴-프로테아좀 경로(ubiquitin-proteasome pathway: UPP)가 있는데, UAE 및 NAE는 유비퀴틴화 캐스케이드에서의 상이한 단계에서 UPP를 조절한다. UAE는 캐스케이드의 제1단계에서 유비퀴틴을 활성화하는 반면, NAE는 NEDD8의 활성화를 통해 컬린계 리가제를 활성화하고, 결국 특정한 표적 단백질에 유비퀴틴을 최종적으로 전달한다.A particular important pathway regulated through El activating enzyme activity is the ubiquitin-proteasome pathway (UPP), where UAE and NAE regulate UPP at different stages in the ubiquitination cascade. UAE activates ubiquitin in the first phase of the cascade, while NAE activates cullin-based ligase through activation of NEDD8, which ultimately delivers ubiquitin to specific target proteins.
이처럼, 정상 세포의 유지에 상술된 기능적 UPP 경로가 필요한데, UPP는 전사, 세포주기 진행 및 아폽토시스(이들 모두 종양 세포를 비롯한 질환 상태에 중요함)에 관여하는 많은 중요한 조절 단백질의 변화에 중추적 역할을 한다. 예를 들면, 세포 증식은 UPP의 억제에 특히 민감하고, 발암에서의 UPP 경로의 역할은 프로테아좀 억제하는 것으로 잠재적 항암 치료의 방법이 될 수 있다. 예를 들면, 벨케이드(VELCADE)(등록상표)(보르테조밉)에 의한 26S 프로테아좀의 억제로부터 UPP 경로의 조절은 특정 암에서 효과적인 치료인 것으로 입증되었고, 다발성 골수종 및 외투 세포 림프종 대상의 치료에서 승인된 바 있다.As such, 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. For example, 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. For example, regulation of the UPP pathway from inhibition of 26S proteasomes by VELCADE® (bortezomib) has proven to be an effective treatment in certain cancers and in the treatment of multiple myeloma and mantle cell lymphoma subjects. It has been approved.
또한, 컬린계 유비퀴틴 리가제에 의해 수치가 조절되는 NAE 및 UAE 활성을 하향 조절하는 단백질의 예로는 CDK 억제제, p27Kip1 및 NFκB, IκB의 억제제를 들 수 있다. p27의 분해 억제는 세포주기의 G1상 및 S상을 통해 세포의 주기를 차단하는 것으로 예상되고, IκB의 분해 방해는 NF-κB의 핵 편재화, 악성 표현형과 관련된 다양한 NF-κB 의존적 유전자의 전사를 억제하고, 표준 세포독성 치료제에 대한 내성을 방지하는 기능을 한다. 추가로, NF-κB는 여러 전염증성 중재자의 발현에 중요한 역할을 하며, 이는 염증성 질환에서 상기 억제제의 역할을 시사한다.In addition, examples of proteins which down-regulate NAE and UAE activity whose levels are regulated by the cullinic ubiquitin ligase include CDK inhibitors, p27Kip1 and inhibitors of NFκB and IκB. 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 IκB degradation is due to nuclear localization of NF-κB, transcription of various NF-κB-dependent genes associated with malignant phenotypes. And prevents resistance to standard cytotoxic therapeutics. In addition, NF-κB plays an important role in the expression of several proinflammatory mediators, suggesting the role of such inhibitors in inflammatory diseases.
더욱이, NAE 및 UAE 활성 억제를 통한 UPP의 억제는 예를 들면, 류마티스성 관절염, 천식, 다발성 경화증, 건선 및 재관류 손상을 포함하는 염증성 질환; 예를 들면, 파킨슨병, 알츠하이머병, 3자 암호 반복 질환을 포함하는 신경퇴행성 질환; 신경병증 통증; 허혈 질환, 예를 들면 뇌졸중, 경색증, 신장 질환; 및 악액질과 같은 질환에서의 치료에 유용한 표적이 된다.Moreover, 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.
구체적으로 NAE와 암 질환의 관계에 있어서, NEDD8-활성화 효소(NAE)의 억제는 이종 이식 모델(xenograft model)에서 암 세포의 사멸을 유발하고 종양의 성장을 억제하는 것으로 규명되었고(T.A. Soucy et al., Nature, 2009, 458, 732-737), 이에 신규 NAE의 억제제를 사용한 암 질환의 치료제 개발이 이루어지고 있으나(미국 특허 출원 제11/346,469호(공개 번호 제2006/0189636호, 특허 제7,951,810호)), 아직까지 신규 NAE 억제제에 대한 공급이 많지 않고, 치료제로 승인받은 바는 더욱 없어, 여전히 효과적인 암 치료제에 대한 지속적인 요구가 있다.Specifically, in relation to NAE and cancer disease, inhibition of NEDD8-activating enzyme (NAE) has been shown to induce cancer cell death and inhibit tumor growth in xenograft model (TA Soucy et al. ., Nature, 2009, 458, 732-737, but there is a development of a therapeutic agent for cancer diseases using a novel inhibitor of NAE (US Patent Application No. 11 / 346,469 (Publication No. 2006/0189636, Patent No. 7,951,810). There is still a short supply of new NAE inhibitors, and few have been approved for treatment, and there is still a continuing need for effective cancer treatments.
한편, 상술된 NAE와 같이, SAE에 대한 표적으로 다발성 골수증, 유방암 등이 SAE 변형 발현과 연관되어 있음을 확인하였고, SAE 활성 저해와 암의 상관관계가 규명되어 SAE 효소를 표적한 약물은 암과 같은 증식 장애의 치료 수단의 일환으로 유용하게 사용될 수 있음이 더욱 분명해졌다. 또한, SAE 저해제는 종양 외의 질병을 치료하는데 유효할 수 있고, 신경병성 질환, 염증, 바이러스성 감염 등의 치료에도 사용될 수 있음이 확인되었으나, 아직까지 분명한 약효를 수반한 치료제가 개발되지 않고 있어 지속적인 연구와 노력이 요구되고 있다.On the other hand, as described above, it was confirmed that multiple myelosis, breast cancer, and the like are related to SAE modification expression as targets for SAE, and the correlation between SAE activity inhibition and cancer has been identified, and thus, drugs targeting SAE enzyme are known as cancers. It has become more apparent that it can be usefully used as a means of treatment for proliferative disorders. In addition, SAE inhibitors may be effective for treating diseases other than tumors and may be used for the treatment of neuropathic diseases, inflammations, viral infections, etc., but therapeutic agents with obvious medicinal effects have not been developed. Research and effort are required.
이에, 본 발명자들은 NAE 및 SAE에 대한 억제활성을 나타내는 신규 화합물로부터 효과적인 암 치료제를 개발하기 위해 노력하던 중, 본 발명에 따른 신규 헤테로고리 화합물이 NAE(NEDD8-Activating Enzyme) 및 SAE(Sumo Activating Enzyme)의 활성을 나노몰의 단위로 우수하게 저해할 수 있고, 이로부터 암세포 증식을 현저하게 억제할 수 있음을 확인한 바, 본 발명을 완성하였다.Therefore, 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). The present invention was completed by confirming that the activity of) can be excellently inhibited in nanomolar units, and cancer cell proliferation can be remarkably suppressed therefrom.
본 발명의 목적은 신규한 헤테로고리 화합물을 제공하는 것이다.It is an object of the present invention to provide novel heterocyclic compounds.
본 발명의 다른 목적은 상기 헤테로고리 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the heterocyclic compound.
본 발명의 또 다른 목적은 상기 헤테로고리 화합물을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 상기 헤테로고리 화합물을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer containing the heterocyclic compound as an active ingredient.
본 발명의 또 다른 목적은 상기 헤테로고리 화합물을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 치료 방법을 제공하는 것이다.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.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2017004246-appb-I000001
Figure PCTKR2017004246-appb-I000001
상기 화학식 1에서,In Chemical Formula 1,
R1 및 R2는 독립적으로 -H, -OH, 할로겐, 아민, 나이트로, 시아노, C1-10의 직쇄 또는 측쇄의 알킬, 또는 C1-10의 직쇄 또는 측쇄의 알콕시이고;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;
R3은 -H, -OH, 할로겐, 아민, 나이트로, 시아노, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알킬, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 치환된 C3-10의 사이클로알킬, 비치환 또는 치환된 C3-10사이클로알킬-C1-10알킬, 비치환 또는 치환된 3 내지 10각 환의 헤테로사이클로알킬, 비치환 또는 치환된 3-10각 환의 헤테로사이클로알킬-C1-10알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴-C1-10알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴-C1-10알킬이고,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 S, or 5 to 5 or more comprising one or more heteroatoms selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl-C 1-10 alkyl in ten rings,
여기서, 상기 치환된 알킬 및 치환된 알콕시의 C-C 단일결합은 각각 독립적으로 하나 이상의 이중결합(C=C) 또는 삼중결합(C≡C)으로 치환될 수 있고,Here, the C-C single bond of the substituted alkyl and substituted alkoxy may be independently substituted with one or more double bonds (C = C) or triple bonds (C≡C),
상기 치환된 알킬, 치환된 알콕시, 치환된 사이클로알킬, 치환된 사이클로알킬-알킬, 치환된 헤테로사이클로알킬, 치환된 헤테로사이클로알킬-알킬, 치환된 아릴, 치환된 아릴-알킬, 치환된 헤테로아릴 및 치환된 헤테로아릴-알킬은 각각 독립적으로 -OH, -SCF3, -SF5, -SO2-C1-10알킬, -NH-SO2-C1-10알킬, -SO2-NH-C1-10알킬, -(C=O)-O-C1-10알킬, 할로겐, 아민, 나이트로, 시아노, 옥소(oxo), 비치환 또는 하나 이상의 할로겐 또는 하나 이상의 -OH가 치환된 C1-10의 직쇄 또는 측쇄의 알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 하나 이상의 할로겐이 치환된 C2-10의 직쇄 또는 측쇄의 알키닐(alkynyl), C1-10의 직쇄 또는 측쇄의 트리알킬실릴(trialkylsilyl), C3-10의 사이클로 알킬, C6-10의 아릴, N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 헤테로아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3 내지 8각 환의 비치환 또는 치환된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환되거나; 비치환 또는 하나 이상의 할로겐이 치환된 페닐, 또는 하나 이상의 N을 포함하는 비치환된 5 내지 6각 환의 헤테로아릴이 융합(fused)될 수 있고,Substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted cycloalkyl-alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl and Substituted heteroaryl-alkyl are each independently -OH, -SCF 3 , -SF 5 , -SO 2 -C 1-10 alkyl, -NH-SO 2 -C 1-10 alkyl, -SO 2 -NH-C 1-10 alkyl,-(C = O) -OC 1-10 alkyl, halogen, amine, nitro, cyano, oxo, unsubstituted or one or more halogen or one or more -OH substituted C 1- 10 linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C 1-10 is substituted C 2-10 carbonyl (alkynyl ), made of a tree of a straight or branched C 1-10 alkylsilyl (trialkylsilyl) aryl-cycloalkyl, C 6-10 of 3-10 C, N, O and S Unsubstituted or substituted heterocyclo of a 5 to 10-membered ring containing at least one hetero atom selected from 3 to 8-membered ring containing at least one hetero atom selected from the group consisting of N, O and S At least one substituent selected from the group consisting of alkyl is substituted; Unsubstituted or substituted at least one halogen may be fused, or unsubstituted 5- to 6-membered heteroaryl containing at least one N,
다시 여기서, 상기 치환된 헤테로사이클로알킬에는 하나 이상의 -OH가 치환될 수 있고;Here again, the substituted heterocycloalkyl may be substituted with one or more -OH;
Figure PCTKR2017004246-appb-I000002
은 비치환 또는 치환된 페닐, N을 1-2개 포함하는 6각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로원자를 포함하는 5각 환의 비치환 또는 치환된 헤테로아릴이고,
Figure PCTKR2017004246-appb-I000002
Is an unsubstituted or substituted phenyl, a hexagonal ring containing 1 to 2 N, or an unsubstituted or substituted heteroaryl, or a pentagonal ring containing one or more heteroatoms selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl,
여기서, 상기 치환된 페닐 및 치환된 헤테로아릴은 독립적으로 -H, -OH, 할로겐, -BnO, 아민, 나이트로, 시아노, C1-10의 직쇄 또는 측쇄의 알킬, 및 C1-10의 직쇄 또는 측쇄의 알콕시로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환될 수 있고; 및Wherein the 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 One or more substituents selected from the group consisting of straight or branched alkoxy may be substituted; And
X는 CH 또는 N이다.X is CH or N.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, 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.
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.Furthermore, 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.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, 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.
나아가, 본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 치료 방법을 제공한다.Furthermore, 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.
본 발명에 따른 헤테로고리 화합물은 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme)를 나노몰 단위의 농도로 우수하게 저해할 수 있어, 이를 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환 예를 들어, 암의 예방 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.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.
이하, 본 발명을 하기와 같이 상세히 설명한다. 단, 하기 설명은 본 발명의 이해를 돕기 위해 제시되는 것일 뿐, 본 발명의 범주 및 사상이 하기의 설명으로 제한되는 것은 아니다.Hereinafter, the present invention will be described in detail as follows. However, the following description is provided only to assist in understanding the present invention, and the scope and spirit of the present invention are not limited to the following description.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2017004246-appb-I000003
Figure PCTKR2017004246-appb-I000003
상기 화학식 1에서,In Chemical Formula 1,
R1 및 R2는 독립적으로 -H, -OH, 할로겐, 아민, 나이트로, 시아노, C1-10의 직쇄 또는 측쇄의 알킬, 또는 C1-10의 직쇄 또는 측쇄의 알콕시이고;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;
R3은 -H, -OH, 할로겐, 아민, 나이트로, 시아노, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알킬, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 치환된 C3-10의 사이클로알킬, 비치환 또는 치환된 C3-10사이클로알킬-C1-10알킬, 비치환 또는 치환된 3 내지 10각 환의 헤테로사이클로알킬, 비치환 또는 치환된 3-10각 환의 헤테로사이클로알킬-C1-10알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴-C1-10알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴-C1-10알킬이고,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 the group consisting of N, O and S Unsubstituted or substituted heteroaryl-C 1-10 alkyl in ten rings,
여기서, 상기 치환된 알킬 및 치환된 알콕시의 C-C 단일결합은 각각 독립적으로 하나 이상의 이중결합(C=C) 또는 삼중결합(C≡C)으로 치환될 수 있고,Here, the C-C single bond of the substituted alkyl and substituted alkoxy may be independently substituted with one or more double bonds (C = C) or triple bonds (C≡C),
상기 치환된 알킬, 치환된 알콕시, 치환된 사이클로알킬, 치환된 사이클로알킬-알킬, 치환된 헤테로사이클로알킬, 치환된 헤테로사이클로알킬-알킬, 치환된 아릴, 치환된 아릴-알킬, 치환된 헤테로아릴 및 치환된 헤테로아릴-알킬은 각각 독립적으로 -OH, -SCF3, -SF5, -SO2-C1-10알킬, -NH-SO2-C1-10알킬, -SO2-NH-C1-10알킬, -(C=O)-O-C1-10알킬, 할로겐, 아민, 나이트로, 시아노, 옥소(oxo), 비치환 또는 하나 이상의 할로겐 또는 하나 이상의 -OH가 치환된 C1-10의 직쇄 또는 측쇄의 알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 하나 이상의 할로겐이 치환된 C2-10의 직쇄 또는 측쇄의 알키닐(alkynyl), C1-10의 직쇄 또는 측쇄의 트리알킬실릴(trialkylsilyl), C3-10의 사이클로 알킬, C6-10의 아릴, N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 헤테로아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3 내지 8각 환의 비치환 또는 치환된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환되거나; 비치환 또는 하나 이상의 할로겐이 치환된 페닐, 또는 하나 이상의 N을 포함하는 비치환된 5 내지 6각 환의 헤테로아릴이 융합(fused)될 수 있고,Substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted cycloalkyl-alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl and Substituted heteroaryl-alkyl are each independently -OH, -SCF 3 , -SF 5 , -SO 2 -C 1-10 alkyl, -NH-SO 2 -C 1-10 alkyl, -SO 2 -NH-C 1-10 alkyl,-(C = O) -OC 1-10 alkyl, halogen, amine, nitro, cyano, oxo, unsubstituted or one or more halogen or one or more -OH substituted C 1- 10 linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C 1-10 is substituted C 2-10 carbonyl (alkynyl ), made of a tree of a straight or branched C 1-10 alkylsilyl (trialkylsilyl) aryl-cycloalkyl, C 6-10 of 3-10 C, N, O and S Unsubstituted or substituted heterocyclo of a 5 to 10-membered ring containing at least one hetero atom selected from 3 to 8-membered ring containing at least one hetero atom selected from the group consisting of N, O and S At least one substituent selected from the group consisting of alkyl is substituted; Unsubstituted or substituted at least one halogen may be fused, or unsubstituted 5- to 6-membered heteroaryl containing at least one N,
다시 여기서, 상기 치환된 헤테로사이클로알킬에는 하나 이상의 -OH가 치환될 수 있고;Here again, the substituted heterocycloalkyl may be substituted with one or more -OH;
Figure PCTKR2017004246-appb-I000004
은 비치환 또는 치환된 페닐, N을 1-2개 포함하는 6각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로원자를 포함하는 5각 환의 비치환 또는 치환된 헤테로아릴이고,
Figure PCTKR2017004246-appb-I000004
Is an unsubstituted or substituted phenyl, a hexagonal ring containing 1 to 2 N, or an unsubstituted or substituted heteroaryl, or a pentagonal ring containing one or more heteroatoms selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl,
여기서, 상기 치환된 페닐 및 치환된 헤테로아릴은 독립적으로 -H, -OH, 할로겐, -BnO, 아민, 나이트로, 시아노, C1-10의 직쇄 또는 측쇄의 알킬, 및 C1-10의 직쇄 또는 측쇄의 알콕시로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환될 수 있고; 및Wherein the 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 One or more substituents selected from the group consisting of straight or branched alkoxy may be substituted; And
X는 CH 또는 N이다.X is CH or N.
바람직하게,Preferably,
상기 R1 및 R2는 각각 독립적으로 -H, -OH, 또는 할로겐이다.R 1 and R 2 are each independently -H, -OH, or halogen.
바람직하게,Preferably,
상기 R3은 -H, -OH, 할로겐, 아민, 나이트로, 시아노, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알킬, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 치환된 C3-10의 사이클로알킬, 비치환 또는 치환된 C3-10사이클로알킬-C1-2알킬, 비치환 또는 치환된 3 내지 10각 환의 헤테로사이클로알킬, 비치환 또는 치환된 3-10각 환의 헤테로사이클로알킬-C1-2알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴-C1-2알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴-C1-2알킬이고,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 selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl-C 1-2 alkyl of 10 to 10 rings,
여기서, 상기 치환된 알킬 및 치환된 알콕시의 C-C 단일결합은 각각 독립적으로 하나 이상의 이중결합(C=C) 또는 삼중결합(C≡C)으로 치환될 수 있고,Here, the C-C single bond of the substituted alkyl and substituted alkoxy may be independently substituted with one or more double bonds (C = C) or triple bonds (C≡C),
상기 치환된 알킬, 치환된 알콕시, 치환된 사이클로알킬, 치환된 사이클로알킬-알킬, 치환된 헤테로사이클로알킬, 치환된 헤테로사이클로알킬-알킬, 치환된 아릴, 치환된 아릴-알킬, 치환된 헤테로아릴 및 치환된 헤테로아릴-알킬은 각각 독립적으로 -OH, -SCF3, -SF5, -SO2-C1-2알킬, -NH-SO2-C1-2알킬, -SO2-NH-C1-2알킬, -(C=O)-O-C1-2알킬, 할로겐, 아민, 나이트로, 시아노, 옥소(oxo), 비치환 또는 하나 이상의 할로겐 또는 하나 이상의 -OH가 치환된 C1-10의 직쇄 또는 측쇄의 알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 하나 이상의 할로겐이 치환된 C2-10의 직쇄 또는 측쇄의 알키닐(alkynyl), C1-10의 직쇄 또는 측쇄의 트리알킬실릴(trialkylsilyl), C3-10의 사이클로 알킬, C6-10의 아릴, N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 헤테로아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3 내지 8각 환의 비치환 또는 치환된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환되거나; 비치환 또는 하나 이상의 할로겐이 치환된 페닐, 또는 하나 이상의 N을 포함하는 비치환된 5 내지 6각 환의 헤테로아릴이 융합(fused)될 수 있고,Substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted cycloalkyl-alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl and Substituted heteroaryl-alkyl are each independently -OH, -SCF 3 , -SF 5 , -SO 2 -C 1-2 alkyl, -NH-SO 2 -C 1-2 alkyl, -SO 2 -NH-C 1-2 alkyl,-(C = O) -OC 1-2 alkyl, halogen, amine, nitro, cyano, oxo, unsubstituted or at least one halogen or at least one -OH substituted C 1- 10 linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C 1-10 is substituted C 2-10 carbonyl (alkynyl ), C 1-10 straight or branched trialkylsilyl, C 3-10 cycloalkyl, C 6-10 aryl, N, O and S Unsubstituted or substituted heterocyclo of 5 to 10-membered rings containing at least one hetero atom selected from 3 to 8-membered rings containing at least one hetero atom selected from the group consisting of N, O and S At least one substituent selected from the group consisting of alkyl is substituted; Unsubstituted or substituted at least one halogen may be fused, or unsubstituted 5- to 6-membered heteroaryl containing at least one N,
다시 여기서, 상기 치환된 헤테로사이클로알킬에는 하나 이상의 -OH가 치환될 수 있다.Here again, the substituted heterocycloalkyl may be substituted with one or more —OH.
바람직하게,Preferably,
상기
Figure PCTKR2017004246-appb-I000005
는 비치환된 페닐, 또는 -CH3, -F 또는 -BnOr로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환된 페닐 또는 하나의 N 원자를 포함하는 6각 환의 비치환된 헤테로아릴이다.remind
Figure PCTKR2017004246-appb-I000005
Is unsubstituted phenyl or phenyl substituted with one or more substituents selected from the group consisting of -CH 3 , -F or -BnOr or a hexagonal ring unsubstituted heteroaryl containing one N atom.
더욱 바람직하게,More preferably,
R3은
Figure PCTKR2017004246-appb-I000006
,
Figure PCTKR2017004246-appb-I000007
,
Figure PCTKR2017004246-appb-I000008
,
Figure PCTKR2017004246-appb-I000009
,
Figure PCTKR2017004246-appb-I000010
,
Figure PCTKR2017004246-appb-I000011
,
Figure PCTKR2017004246-appb-I000012
,
Figure PCTKR2017004246-appb-I000013
,
Figure PCTKR2017004246-appb-I000014
,
Figure PCTKR2017004246-appb-I000015
,
Figure PCTKR2017004246-appb-I000016
,
Figure PCTKR2017004246-appb-I000017
,
Figure PCTKR2017004246-appb-I000018
,
Figure PCTKR2017004246-appb-I000019
,
Figure PCTKR2017004246-appb-I000020
,
Figure PCTKR2017004246-appb-I000021
,
Figure PCTKR2017004246-appb-I000022
,
Figure PCTKR2017004246-appb-I000023
,
Figure PCTKR2017004246-appb-I000024
,
Figure PCTKR2017004246-appb-I000025
,
Figure PCTKR2017004246-appb-I000026
,
Figure PCTKR2017004246-appb-I000027
,
Figure PCTKR2017004246-appb-I000028
,
Figure PCTKR2017004246-appb-I000029
,
Figure PCTKR2017004246-appb-I000030
,
Figure PCTKR2017004246-appb-I000031
,
Figure PCTKR2017004246-appb-I000032
,
Figure PCTKR2017004246-appb-I000033
,
Figure PCTKR2017004246-appb-I000034
,
Figure PCTKR2017004246-appb-I000035
,
Figure PCTKR2017004246-appb-I000036
,
Figure PCTKR2017004246-appb-I000037
,
Figure PCTKR2017004246-appb-I000038
,
Figure PCTKR2017004246-appb-I000039
,
Figure PCTKR2017004246-appb-I000040
,
Figure PCTKR2017004246-appb-I000041
,
Figure PCTKR2017004246-appb-I000042
, 또는
Figure PCTKR2017004246-appb-I000043
이다.R 3 is
Figure PCTKR2017004246-appb-I000006
,
Figure PCTKR2017004246-appb-I000007
,
Figure PCTKR2017004246-appb-I000008
,
Figure PCTKR2017004246-appb-I000009
,
Figure PCTKR2017004246-appb-I000010
,
Figure PCTKR2017004246-appb-I000011
,
Figure PCTKR2017004246-appb-I000012
,
Figure PCTKR2017004246-appb-I000013
,
Figure PCTKR2017004246-appb-I000014
,
Figure PCTKR2017004246-appb-I000015
,
Figure PCTKR2017004246-appb-I000016
,
Figure PCTKR2017004246-appb-I000017
,
Figure PCTKR2017004246-appb-I000018
,
Figure PCTKR2017004246-appb-I000019
,
Figure PCTKR2017004246-appb-I000020
,
Figure PCTKR2017004246-appb-I000021
,
Figure PCTKR2017004246-appb-I000022
,
Figure PCTKR2017004246-appb-I000023
,
Figure PCTKR2017004246-appb-I000024
,
Figure PCTKR2017004246-appb-I000025
,
Figure PCTKR2017004246-appb-I000026
,
Figure PCTKR2017004246-appb-I000027
,
Figure PCTKR2017004246-appb-I000028
,
Figure PCTKR2017004246-appb-I000029
,
Figure PCTKR2017004246-appb-I000030
,
Figure PCTKR2017004246-appb-I000031
,
Figure PCTKR2017004246-appb-I000032
,
Figure PCTKR2017004246-appb-I000033
,
Figure PCTKR2017004246-appb-I000034
,
Figure PCTKR2017004246-appb-I000035
,
Figure PCTKR2017004246-appb-I000036
,
Figure PCTKR2017004246-appb-I000037
,
Figure PCTKR2017004246-appb-I000038
,
Figure PCTKR2017004246-appb-I000039
,
Figure PCTKR2017004246-appb-I000040
,
Figure PCTKR2017004246-appb-I000041
,
Figure PCTKR2017004246-appb-I000042
, or
Figure PCTKR2017004246-appb-I000043
to be.
가장 바람직하게,Most preferably,
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나의 화합물이다.The compound represented by Chemical Formula 1 is any one compound selected from the following compound groups.
(1) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드로옥시사이클로펜틸)메틸 설파메이트;(1) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydrooxycyclopentyl) methyl sulfamate;
(2) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-인다졸-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(2) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-indazol-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(3) ((1R,2R,3S,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(3) ((1R, 2R, 3S, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydro Oxycyclopentyl) methyl sulfamate;
(4) ((1R,2R,3S,4R)-4-((5-(1-(3-클로로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(4) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-chlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2 , 3-dihydroxycyclopentyl) methyl sulfamate;
(5) ((1R,2R,3S,4R)-4-((5-(1-(3-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(5) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-fluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydroxycyclopentyl) methyl sulfamate;
(6) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-(3-(트리플루오로)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(6) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3- (trifluoro) benzyl) -1H-indole-3-carbonyl ) Pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(7) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-(3-메톡시벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(7) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3-methoxybenzyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
(8) ((1R,2R,3S,4R)-4-((5-(1-(3-클로로-4-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(8) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-chloro-4-fluorobenzyl) -1H-indol-3-carbonyl) pyrimidin-4-yl ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(9) ((1R,2R,3S,4R)-4-((5-(1-(2,5-디클로로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(9) ((1R, 2R, 3S, 4R) -4-((5- (1- (2,5-dichlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(10) ((1R,2R,3S,4R)-4-((5-(1-(3,4-디플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(10) ((1R, 2R, 3S, 4R) -4-((5- (1- (3,4-difluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(11) ((1R,2R,3S,4R)-4-((5-(1-(2,4-디플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(11) ((1R, 2R, 3S, 4R) -4-((5- (1- (2,4-difluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(12) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-(3-아이오도벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(12) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3-iodobenzyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
(13) ((1R,2R,3S,4R)-4-((5-(1-(3-시아노벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(13) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-cyanobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydroxycyclopentyl) methyl sulfamate;
(14) ((1R,2R,3S,4R)-4-((5-(1-(2-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(14) ((1R, 2R, 3S, 4R) -4-((5- (1- (2-fluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydroxycyclopentyl) methyl sulfamate;
(15) ((1R,2R,3S,4R)-4-((5-(1-(3,5-비스(트리플루오로메틸)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(15) ((1R, 2R, 3S, 4R) -4-((5- (1- (3,5-bis (trifluoromethyl) benzyl) -1H-indole-3-carbonyl) pyrimidine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(16) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((트리플루오로메틸)싸이오)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(16) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((trifluoromethyl) thio) benzyl) -1H-indole-3-carbonyl) pyrimidine-4 -Yl) amino) cyclopentyl) methyl sulfamate;
(17) ((1R,2R,3S,4R)-4-((5-(1-([1,1'-바이페닐]-4-일메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(17) ((1R, 2R, 3S, 4R) -4-((5- (1-([1,1'-biphenyl] -4-ylmethyl) -1H-indole-3-carbonyl) pyridine Midin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(18) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-((6-메틸피리딘-2-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(18) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1-((6-methylpyridin-2-yl) methyl) -1H-indole-3 -Carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(19) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-((5-(트리플루오로메틸)퓨란_2-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(19) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1-((5- (trifluoromethyl) furan_2-yl) methyl)- 1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(20) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-((5-메틸이소옥사졸-3-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(20) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1-((5-methylisoxazol-3-yl) methyl) -1H-indole- 3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(21) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-5-메틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(21) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -5-methyl-1H-indol-3-carbonyl) pyrimidin-4-yl ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(22) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(22) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -5-fluoro-1H-indole-3-carbonyl) pyrimidine-4- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(23) ((1R,2R,3S,4R)-4-((5-(5-(벤질옥시)-1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(23) ((1R, 2R, 3S, 4R) -4-((5- (5- (benzyloxy) -1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(24) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-피롤로[2,3-b]피리딘-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(24) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) pyrid Midin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(25) 메틸 3-((3-(4-(((1R,2S,3R,4R)-2,3-디하이드록시-4-((설파모일록시)메틸)사이클로펜틸)아미노)피리미딘-5-카보닐)-5-플루오로-1H-인돌-1-일)메틸)벤조에이트;(25) Methyl 3-((3- (4-(((1R, 2S, 3R, 4R) -2,3-dihydroxy-4-((sulfamoyloxy) methyl) cyclopentyl) amino) pyrimidine -5-carbonyl) -5-fluoro-1H-indol-1-yl) methyl) benzoate;
(26) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(나프탈렌-2-일메틸)-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(26) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (naphthalen-2-ylmethyl) -1H-indole-3-carbonyl) pyridine-4- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(27) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(3-메틸벤질)-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(27) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (3-methylbenzyl) -1H-indol-3-carbonyl) pyridin-4-yl) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(28) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-플루오로-3-메틸벤질)-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(28) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4-fluoro-3-methylbenzyl) -1H-indole-3-carbonyl) pyridine -4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(29) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-플루오로-3-메톡시벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(29) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4-fluoro-3-methoxybenzyl) -1H-indole-3-carbonyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(30) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(펜타플루오로-l6-설파닐)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(30) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (pentafluoro-16-sulfanyl) benzyl) -1H-indole-3- Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(31) ((1R,2S,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2-하이드로시싸이클로펜틸)메틸 설파메이트;(31) ((1R, 2S, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2-hydrocyclocyclopentyl) methyl Sulfamate;
(32) ((1R,2R,3R,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-yl)아미노)-3-플루오로-2-하이드로시싸이클로펜틸)메틸 설파메이트;(32) ((1R, 2R, 3R, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -3-fluoro-2 Hydrocyclocyclopentyl) methyl sulfamate;
(33) ((1R,2R,3S,4R)-4-((5-(1-(2-뷰틴-1-일)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-다이하이드로시싸이클로펜틸) 메틸 설파메이트;(33) ((1R, 2R, 3S, 4R) -4-((5- (1- (2-butyn-1-yl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino ) -2,3-dihydrocyclocyclopentyl) methyl sulfamate;
(34) ((1R,2R,3S,4S)-4-((5-(1-((E)-2-뷰텐-1-일)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-다이하이드로시싸이클로펜틸)메틸 설파메이트;(34) ((1R, 2R, 3S, 4S) -4-((5- (1-((E) -2-buten-1-yl) -1H-indole-3-carbonyl) pyrimidine-4 -Yl) amino) -2,3-dihydrocyclocyclopentyl) methyl sulfamate;
(35) ((1R,2R,3S,4R)-2,3-다이하이드록시-4-((5-(1-(2-메톡시에틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(35) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (2-methoxyethyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
(36) ((1R,2R,3S,4S)-2,3-다이하이드록시-4-((5-(1-아이소뷰틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(36) ((1R, 2R, 3S, 4S) -2,3-dihydroxy-4-((5- (1-isobutyl-1H-indole-3-carbonyl) pyrimidin-4-yl) Amino) cyclopentyl) methyl sulfamate;
(37) ((1R,2R,3S,4R)-4-((5-(1-(싸이클로헥실메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-다이하이드록시싸이클로펜틸)메틸 설파메이트;(37) ((1R, 2R, 3S, 4R) -4-((5- (1- (cyclohexylmethyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2, 3-dihydroxycyclopentyl) methyl sulfamate;
(38) ((1R,2R,3S,4R)-2,3-다이하이드록시-4-((5-(1-(몰포리노에틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(38) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (morpholinoethyl) -1H-indole-3-carbonyl) pyrimidine-4 -Yl) amino) cyclopentyl) methyl sulfamate;
(39) ((1R,2R,3S,4R)-2,3-다이하이드록시-4-((5-(1-(3-몰포리노벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(39) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3-morpholinobenzyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
(40) ((1R,2R,3S,4R)-4-((5-(1-((6-(1H-피라졸-1-일)피리딘-3-일)메틸)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(40) ((1R, 2R, 3S, 4R) -4-((5- (1-((6- (1H-pyrazol-1-yl) pyridin-3-yl) methyl) -5-fluoro -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(41) ((1R,2R,3S,4R)-4-((5-(1-((6-브로모벤조퓨란-3-일)메틸)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(41) ((1R, 2R, 3S, 4R) -4-((5- (1-((6-bromobenzofuran-3-yl) methyl) -5-fluoro-1H-indole-3- Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(42) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(메틸설포닐)-3-니트로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(42) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (methylsulfonyl) -3-nitrobenzyl) -1H-indole-3-carbo Yl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(43) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(3-(메틸설폰아미도)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(43) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (3- (methylsulfonamido) benzyl) -1H-indole-3-carbonyl) pyrid Midin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(44) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(N-메틸설파모일)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트; 및(44) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (N-methylsulfamoyl) benzyl) -1H-indole-3-carbonyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate; And
(45) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(2-메틸-3-(트리플루오로메틸)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3,-다이하이드로시싸이클로펜틸)메틸 설파메이트.(45) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (2-methyl-3- (trifluoromethyl) benzyl) -1H-indole-3- Carbonyl) pyrimidin-4-yl) amino) -2,3, -dihydrocyclocyclopentyl) methyl sulfamate.
본 발명의 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.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. It is obtained from 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. Examples of 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, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, mandelate and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜셔 제조할 수 있다. 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.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.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).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용 가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 입체 이성질체, 수화물 등을 모두 포함한다.Furthermore, 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.
또한, 본 발명은 또한, 본 발명은 하기 반응식 1에 나타난 바와 같이,In addition, the present invention also, the present invention as shown in Scheme 1,
화학식 2로 표시되는 화합물과, 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1);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 (step 1);
상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과, 화학식 5로 표시되는 화합물을 반응시켜 화학식 6으로 표시되는 화합물을 제조하는 단계(단계 2);Preparing a compound 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 (step 2);
상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물로부터 화학식 7로 표시되는 화합물을 제조하는 단계(단계 3);Preparing a compound represented by Chemical Formula 7 from the compound represented by Chemical Formula 6 prepared in Step 2 (Step 3);
상기 단계 3에서 제조한 화학식 7로 표시되는 화합물을 화학식 8로 표시되는 화합물과 반응시켜 화학식 9로 표시되는 화합물을 제조하는 단계(단계 4);Preparing 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 (step 4);
상기 단계 4에서 제조한 화학식 9로 표시되는 화합물을 화학식 10으로 표시되는 화합물과 반응시켜 화학식 11로 표시되는 화합물을 제조하는 단계(단계 5); 및Preparing a compound represented by Chemical Formula 11 by reacting the compound represented by Chemical Formula 9 prepared in Step 4 with the compound represented by Chemical Formula 10 (step 5); And
상기 단계 5에서 제조한 화학식 11로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계(단계 6);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.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.
[반응식 1]Scheme 1
Figure PCTKR2017004246-appb-I000044
Figure PCTKR2017004246-appb-I000044
상기 반응식 1에서,In Scheme 1,
상기 R1, R2, R3,
Figure PCTKR2017004246-appb-I000045
및 X는 상기 화학식 1에서 정의한 바와 같고; 및R 1 , R 2 , R 3 ,
Figure PCTKR2017004246-appb-I000045
And X is as defined in Formula 1 above; And
상기 PT는 -Boc이다.The PT is -Boc.
이하, 본 발명에 따른 상기 반응식 1의 화학식 1로 표시되는 화합물의 제조방법을 단계별로 상세히 설명한다.Hereinafter, a method for preparing a compound represented by Chemical Formula 1 of Scheme 1 according to the present invention will be described in detail step by step.
본 발명에 따른 반응식 1의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 1은 화학식 2로 표시되는 화합물과, 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 1, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 디메틸포름아미드(DMF)을 사용할 수 있다.In this case, as the solvent usable in the step, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 -10 내지 10℃에서 용매의 비등점 사이에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 1은 가장 바람직하게 하기 실시예 1의 단계 1과 같이 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out between the boiling point of the solvent at -10 to 10 ℃, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours In the manufacturing method of the present invention, the present invention is not limited thereto, but step 1 may be performed as in step 1 of Example 1 below.
본 발명에 따른 반응식 1의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과, 화학식 5로 표시되는 화합물을 반응시켜 화학식 6으로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 1 according to the present invention, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 디메틸포름아미드(DMF)를 사용할 수 있다.In this case, as the solvent usable in the step, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 -10 내지 10℃에서 용매의 비등점 사이에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 2는 가장 바람직하게 하기 실시예 1의 단계 2와 같이 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out between the boiling point of the solvent at -10 to 10 ℃, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours In the manufacturing method of the present invention, the present invention is not limited thereto, but step 2 may be performed as in step 2 of Example 1 below.
본 발명에 따른 반응식 1의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 3은 상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물로부터 화학식 7로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 1 according to the present invention, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 메틸렌클로라이드를 사용할 수 있다.In this case, as the solvent usable in the step, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 2는 가장 바람직하게 하기 실시예 1의 단계 3과 같이 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the 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.
본 발명에 따른 반응식 1의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 4는 상기 단계 3에서 제조한 화학식 7로 표시되는 화합물과, 화학식 8로 표시되는 화합물을 반응시켜 화학식 9로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 1 according to the present invention, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, t-부탄올(t-BuOH), n-부탄올(n-BuOH), 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 n-부탄올(n-BuOH)을 사용할 수 있다.At this time, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 90 내지 120℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 2는 가장 바람직하게 하기 실시예 1의 단계 4와 같이 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 90 to 120 ℃, the 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.
본 발명에 따른 반응식 1의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 5는 상기 단계 4에서 제조한 화학식 9로 표시되는 화합물과 화학식 10으로 표시되는 화합물을 반응시켜, 화학식 11로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 1 according to the present invention, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 디메틸포름아미드를 사용할 수 있다.In this case, as the solvent usable in the step, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-40시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 2는 가장 바람직하게 하기 실시예 1의 단계 5와 같이 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the reaction time is not particularly limited, the reaction is preferably for 0.5-40 hours, the production method of the present invention Although not limited thereto, Step 2 may be most preferably performed as Step 5 of Example 1 below.
본 발명에 따른 반응식 1의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 6은 상기 단계 5에서 제조한 화학식 11로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 1 according to the present invention, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 테트라하이드로퓨란을 사용할 수 있다.In this case, as the solvent usable in the step, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 2는 가장 바람직하게 하기 실시예 1의 단계 6과 같이 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the 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 performed as in Step 6 of Example 1 below.
나아가, 본 발명은 하기 반응식 2에 나타난 바와 같이,Furthermore, the present invention, as shown in Scheme 2 below,
화학식 2로 표시되는 화합물로부터 화학식 4'로 표시되는 화합물을 제조하는 단계(단계 1);Preparing a compound represented by Chemical Formula 4 'from the compound represented by Chemical Formula 2 (Step 1);
상기 단계 1에서 제조한 화학식 4'로 표시되는 화합물과, 화학식 5로 표시되는 화합물을 반응시켜 화학식 6'로 표시되는 화합물을 제조하는 단계(단계 2);Preparing a compound 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 (step 2);
상기 단계 2에서 제조한 화학식 6'로 표시되는 화합물로부터 화학식 7'로 표시되는 화합물을 제조하는 단계(단계 3);Preparing a compound represented by Chemical Formula 7 'from the compound represented by Chemical Formula 6' prepared in Step 2 (Step 3);
상기 단계 3에서 제조한 화학식 7'로 표시되는 화합물을 화학식 8로 표시되는 화합물과 반응시켜 화학식 9'로 표시되는 화합물을 제조하는 단계(단계 4);Preparing 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 (step 4);
상기 단계 4에서 제조한 화학식 9'로 표시되는 화합물로부터 화학식 12로 표시되는 화합물을 제조하는 단계(단계 5);Preparing a compound represented by Chemical Formula 12 from the compound represented by Chemical Formula 9 'prepared in Step 4 (Step 5);
상기 단계 5에서 제조한 화학식 12로 표시되는 화합물로부터 화학식 13으로 표시되는 화합물을 제조하는 단계(단계 6);Preparing a compound represented by Chemical Formula 13 from the compound represented by Chemical Formula 12 prepared in Step 5 (Step 6);
상기 단계 6에서 제조한 화학식 13으로 표시되는 화합물을 화학식 3으로 표시되는 화합물과 반응시켜 화학식 14로 표시되는 화합물을 제조하는 단계(단계 7); 및Preparing a compound 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 (step 7); And
상기 단계 7에서 제조한 화학식 14로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계(단계 8);를 포함하는 제1항의 화학식 1로 표시되는 화합물의 제조방법을 제공한다.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.
[반응식 2]Scheme 2
Figure PCTKR2017004246-appb-I000046
Figure PCTKR2017004246-appb-I000046
상기 반응식 2에서,In Scheme 2,
상기 R1, R2, R3,
Figure PCTKR2017004246-appb-I000047
및 X는 제1항의 화학식 1에서 정의한 바와 같고; 및R 1 , R 2 , R 3 ,
Figure PCTKR2017004246-appb-I000047
And X is as defined in formula 1 of claim 1; And
상기 PT, PT1 및 PT2는 각각 독립적인 보호기(protecting group)이다.The PT, PT 1 and PT 2 are each an independent protecting group.
이하, 본 발명에 따른 상기 반응식 2의 화학식 1로 표시되는 화합물의 제조방법을 단계별로 상세히 설명한다.Hereinafter, a method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention will be described in detail step by step.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 1은 화학식 2로 표시되는 화합물로부터 화학식 4'로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, Step 1 is a step of preparing a compound represented by Chemical Formula 4 ′ from the compound represented by Chemical Formula 2.
이때, 상기 반응식 2의 단계 1은 화합물의 N-위치에 보호기(-PT1)를 도입하는 단계로 이해할 수 있다.In this case, step 1 of Scheme 2 may be understood as introducing a protecting group (-PT 1 ) at the N-position of the compound.
여기서, 상기 도입되는 보호기(-PT1)는 본 발명 화학식 1 화합물의 제조방법을 수행하는데 장애가 되지 않는다면, 크게 제한되지는 않으나, 바람직하게 -Boc이다. 단계 1의 보호기(-PT1)는 당 분야의 기술자가 용이하게 변경 또는 수정하여 적용할 수 있는 것이라면, 즉 제조방법 수행에 장애가 되지 않는 모든 범위의 보호기로 본 발명에 포함된다. 단계 1에서 도입된 보호기는 추후 반응식 2의 단계 6에서 제거되고 단계 7에서 N-위치로 -R3의 치환기를 도입하는 단계로 수행된다. 상기 반응식 1에서는 반응식 2와 다르게 N-위치에 보호기의 도입 없이 바로 -R3의 치환기를 도입하는 단계로 수행되었는데, 이는 목적하는 화합물에 따라, 제조되는 수율에 따라 선호되는 방법으로 변경 또는 수정되어 본 발명의 화학식 1로 표시되는 화합물이 제조될 수 있음을 나타낸다. 따라서, 본 명세서에 기재된 반응식 1 및 반응식 2의 제조방법과 하기 실시예 화합물의 제조방법 각 단계를 목적 화합물 및 수율 등의 조건을 고려하여 당해 분야의 통상의 기술자라면 용이하게 변경 또는 수정할 수 있을 것임을 이해할 수 있다. 이에, 변경 또는 수정 가능한 범위더라도 본 발명에서 제시하는 화학식 1로 표시되는 화합물을 제조할 수 있는 방법이라면 본 발명에 모두 포함되는 것으로 이해되어야 한다.Herein, 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. In Scheme 1, unlike Scheme 2, a step of introducing a substituent of -R 3 without introducing a protecting group in the N-position is performed, which is changed or modified in a preferred method according to the yield prepared according to the desired compound. Indicates that the compound represented by Formula 1 of the present invention can be prepared. Accordingly, it will be appreciated that those skilled in the art will readily be able to change or modify the preparation methods of Schemes 1 and 2 and the methods of preparing the compounds of the following Examples in consideration of conditions such as the target compound and yield. I can understand. Thus, even if it is possible to change or modify the scope of the present invention if it is a method for producing a compound represented by the formula (1) it is to be understood that all included in the present invention.
한편, 상기 반응식 2의 단계 1을 수행하는데 있어, 하나의 구체예로 상기 화학식 2로 표시되는 화합물, (Boc)2O, DMAP, TEA를 DMF에서 반응시켜 수행할 수 있다.Meanwhile, in performing Step 1 of Scheme 2, in one embodiment, the compound represented by Formula 2, (Boc) 2 O, DMAP, and TEA may be reacted in DMF.
또한, 상기 반응식 2의 단계 1에 사용되는 용매는 바람직하게 한 예로 DMF일 수 있으나, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있다.In addition, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 2는 단계 1에서 제조된 화학식 4'로 표시되는 화합물을 화학식 5로 표시되는 화합물과 반응시켜 화학식 6'로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, 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.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 테트라하이드로퓨란(THF)를 사용할 수 있다.In this case, as the solvent usable in the step, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 -80 내지 10℃로 승온하면서 반응할 수 있고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 일례로, 화하식 4'로 표시되는 화합물, n-BuLi, 화학식 5로 표시되는 화합물을 THF에서 반응시켜 수행될 수 있다.In addition, the reaction temperature in the above step is not particularly limited, but preferably can be reacted while increasing the temperature to -80 to 10 ℃, the reaction time is not particularly limited, the reaction is preferably for 0.5-20 hours, of the present invention Although not limited thereto, the compound represented by Formula 4 ', n-BuLi, and the compound represented by Formula 5 may be reacted in THF.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 3은 상기 단계 2에서 제조한 화학식 6'으로 표시되는 화합물로부터 화학식 7'로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, 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.
이때, 상기 단계는 산화단계로 이해할 수 있는데, 화학식 7'로 표시되는 화합물이 제조되는 산화단계라면 제한없이 본 발명의 제조방법에 포함된다.At this time, 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.
한편, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 메틸렌클로라이드 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 메틸렌클로라이드을 사용할 수 있다.Meanwhile, as the solvent usable in the above step, dimethylformamide (DMF), H 2 O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, methylene chloride toluene, acetonitrile, and the like may be used. Methylene chloride can be used.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 상기 단계 2는 일례로, 화학식 6'로 표시되는 화합물, MnO2를 메틸렌클로라이드에서 반응시켜 수행될 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the 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 performed by, for example, reacting a compound represented by Chemical Formula 6 ', MnO 2 in methylene chloride.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 4는 상기 단계 3에서 제조한 화학식 7'로 표시되는 화합물과, 화학식 8로 표시되는 화합물을 반응시켜 화학식 9'로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, 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.
이때, 화학식 8'로 표시되는 화합물의 -O-PT 기는 R1 및 R2 중 하나가 -OH기인 경우, 또는 보호기가 도입될 수 있는 치환기인 경우, 별도의 보호기로 보호된 상태일 수 있으며, 또는 상기 -O-PT기의 -PT기가 R1 및 R2 중 하나의 치환기를 동시에 보호하는 보호기일 수 있다. 예를 들어, R1 및 R2 중 하나가 -OH기인 경우, 상기 PT(보호기)는 -O-PT-O-와 같이, 하나의 PT(보호기)만으로 보호되는 보호기일 수 있는 것이다.At this time, 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. For example, when one of R1 and R2 is an -OH group, the PT (protecting group) may be a protecting group protected by only one PT (protecting group), such as -O-PT-O-.
한편, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, t-부탄올(t-BuOH), n-부탄올(n-BuOH), 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 n-부탄올(n-BuOH)을 사용할 수 있다.Meanwhile, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 50 내지 120℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 일례로, 화학식 7'로 표시되는 화합물, 화학식 8로 표시되는 화합물, DIPEA를 n-부탄올에서 반응시켜 수행될 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 50 to 120 ℃, the 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.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 5는 상기 단계 4에서 제조한 화학식 9'로 표시되는 화합물로부터 화학식 12로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Formula 1 of Scheme 2, step 5 is a step of preparing a compound represented by Formula 12 from the compound represented by Formula 9 'prepared in Step 4.
이때, 상기 단계는 사이클로펜틸 부분 -CH2-OH의 -OH기에 보호기(-PT2)를 도입하는 단계로 이해될 수 있고, 여기서, 보호기(-PT2)는 특별한 제한없이 사용할 수 있으나, 일례로 TBS(tert-부틸디메틸실일)일 수 있다. 또한, 이와 상등한 보호기를 사용할 수 있고, 화학식 12로 표시도는 화합물이 제조될 수 있고, 최종적으로 화학식 1로 표시되는 화합물의 제조방법을 수행하는데 장애가 되지 않는 범위의 보호기라면 본 발명에 제한없이 포함된다.In this case, 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). In addition, 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.
한편, 상기 단계 5에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 메틸렌클로라이드를 사용할 수 있다.Meanwhile, as the solvent usable in step 5, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-40시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 일례로 화학식 9'로 표시되는 화합물, TBSCl, 이미다졸을 메틸렌클로라이드에서 반응시켜 수행할 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the reaction time is not particularly limited, the reaction is preferably for 0.5-40 hours, the production method of the present invention Although not limited thereto, the compound represented by Chemical Formula 9 ', TBSCl, and imidazole may be performed by reacting with methylene chloride.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 6은 상기 단계 5에서 제조한 화학식 12로 표시되는 화합물로부터 화학식 13으로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, 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.
이때, 상기 단계 6은 상기 단계 1에서 도입하였던 인돌 N-위치의 보호기(PT1)를 제거하는 단계로 이해할 수 있다.In this case, step 6 may be understood as removing the protecting group PT 1 of the indole N-position introduced in step 1.
이때, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 프로판올, 이소프로판올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 이소프로판올을 사용할 수 있다.In this case, as the solvent usable in the step, dimethylformamide (DMF), H 2 O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably Preferably isopropanol.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 50 내지 90℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 일례로, 화학식 12로 표시되는 화합물, K3PO4를 이소프로판올에서 반응시켜 수행될 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 50 to 90 ℃, the 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.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 7은 상기 단계 6에서 제조한 화학식 13으로 표시되는 화합물을 화학식 3으로 표시되는 화합물과 반응시켜 화학식 14로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, 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.
이때, 상기 단계 7은 -R3 치환기를 도입하는 단계로 이해할 수 있고, 상기 반응식 1의 단계 1에서 수행한 것과 같은 방법으로 수행되는 것으로 이해할 수 있다.In this case, 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.
한편, 상기 단계에서 사용 가능한 용매로는 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 프로판올, 이소프로판올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있고, 바람직하게는 DMF를 사용할 수 있다.Meanwhile, as the solvent usable in the above step, dimethylformamide (DMF), H 2 O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, and the like may be used. For example, DMF can be used.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 동안 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 일례로, 화학식 13으로 표시되는 화합물, 화학식 3으로 표시되는 화합물, Cs2CO3를 DMF에서 반응시켜 수행될 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the 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.
본 발명에 따른 반응식 2의 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 8은 상기 단계 7에서 제조한 화학식 14로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계이다.In the method for preparing a compound represented by Chemical Formula 1 of Scheme 2 according to the present invention, 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.
이때, 상기 단계 8은 사이클로프로필 부분의 보호기를 모두 제거하는 단계이고, 특히 TBS로 보호되어 있는 부분에 -OH 부분에 NH2SO2Cl을 도입하여 -O-SO2-NH2의 치환기를 도입하는 단계를 포함한다.In this case, 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.
한편, 상기 단계에서 사용 가능한 용매로는 특별한 제한은 없으나, 바람직하게 DMF가 있고, 디메틸포름아미드(DMF), H2O, 메탄올, 에탄올, 프로판올, 이소프로판올, 테트라하이드로퓨란(THF), 메틸렌클로라이드, 톨루엔, 아세토니트릴 등을 사용할 수 있다.On the other hand, 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.
또한, 상기 단계에서 반응온도는 특별한 제약은 없으나, 바람직하게 0 내지 30℃에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 0.5-20시간 또는 1일 내지 3일에 걸쳐 반응하는 것이 바람직하고, 본 발명의 제조방법에 있어 이에 제한되지 않으나, 일례로, 상기 단계 8을 3단계로 진행할 수 있는데, 먼저 화학식 14로 표시되는 화합물, TASF를 DMF에서 반응시키고, 다음 단계로, NH2SO2Cl을 DMF에서 반응시키되, 밤새도록 또는 하루에 걸쳐 수행하고, 마지막으로 TfOH:H2O(9:1)과 메탄올에서 밤새도록 반응시켜 수행될 수 있다.In addition, the reaction temperature in the step is not particularly limited, but preferably carried out at 0 to 30 ℃, the reaction time is not particularly limited, it is preferable to react over 0.5-20 hours or 1 to 3 days. In addition, 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.
나아가, 상술된 본 발명의 제조방법은 상기 반응식 1 및 반응식 2에서도 확인할 수 있듯이, 목적하는 화합물, 달성 수율 등을 고려하여 각 단계를 도치하는 것과 같이, 변경 또는 수정하여 진행이 가능하고, 이에 본 발명의 제조방법에서 변경 또는 수정 가능한 것이라면 본 발명에 포함됨을 용이하게 이해할 수 있을 것이다.Furthermore, 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.
따라서, 본 명세서에 기술된 제조방법은 바람직한 일 구체예로 이해되어야 하고, 이의 바람직한 구체예로 하기 실시예와 같이 수행하여 본 발명의 화합물을 제조할 수 있음을 당 분야의 통상의 기술자라면 용이하게 이해할 수 있을 것이다.Therefore, the preparation method described herein should be understood as one preferred embodiment, and those skilled in the art can easily prepare a compound of the present invention by performing as described in the following examples in the preferred embodiment thereof I can understand.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, 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.
여기서, 상기 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환은 상술된 본 발명의 배경기술에서와 같이, 현재까지 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme)와 상관 관계를 갖는 것으로 규명된 모든 질환을 말하며, 예를 들어, NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환은 암(cancer), 염증(inflammatory), 심혈관계 질환(cardiovascular disease), 신경퇴행성 질환(neurodegenerative diseases), 등을 포함할 수 있다.Here, 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.
상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B세포림프종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.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, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, nerve Glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, Unknown cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, Metastatic brain cancer, Mediastinal cancer, Rectal cancer, Rectal carcinoma, Vaginal cancer, Spinal cord cancer, Auditor neuroma, Pancreatic cancer, Salivary gland cancer, Kaposi's sarcoma, Paget's disease, Tonsil cancer, Squamous cell carcinoma, Lung adenocarcinoma, Lung cancer, Lung squamous cell carcinoma, It may be at least one selected from the group consisting of skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic cancer.
또한, 바람직하게 상기 암은 유방암, 대장암, 결장암, 폐암, 전립선암, 식도암, 방광암, 및 두경부암으로부터 선택되는 1종 이상일 수 있다.In addition, 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.
나아가, 바람직하게 상기 암은 급성 골수 백혈병(AML); 만성적 골수성 백혈병(CML); 급성 림프아구성 백혈병(ALL); 만성적 림프구성 백혈병(CLL); 호지킨 질환(HD); 비-호지킨 림프종(NHL); B-세포 림프종; T-세포 림프종; 다발성 골수종(MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군(MDS); 작은 림프구 림프종(SLL); 변연부 림프종; 무증상 다발성 골수종; 및 골수증식성 증후군으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.Furthermore, preferably 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.
이때, NAE 관련 질환은 이에 제한되지 않으나, NAE의 이상, 변형, 과발현 등과 같은 정상적인 활성이 아닌 현상으로부터 발현될 수 있는 모든 질병을 말한다. 특히, NAE 관련 질환의 일 예로 암을 들 수 있는데, 암세포의 세포증식과 관련되어 NAE의 이상 활성으로부터 기인한 경우, 본 발명의 화합물, 이의 입체 이성질체 및 이로부터 허용 가능한 염은 NAE의 활성을 나노몰의 단위로 효과적으로 억제할 수 있어, 상기 NAE 관련 질환으로 언급된 질병의 개선, 예방 또는 치료에 유용하게 사용될 수 있다.In this case, the 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. In particular, 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.
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.Furthermore, 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.
여기서, 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme)를 억제하여 암을 예방 또는 치료하는 것을 특징으로 할 수 있고, 상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B세포림프종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.Here, 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. 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, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma, batter's swollen cancer, bladder cancer , Peritoneal cancer, Parathyroid cancer, Adrenal cancer, Non-sinus cancer, Non-small cell lung cancer, Non-Hodgkin's lymphoma, Sulfur cancer, Astrocytoma, Small cell lung cancer, Pediatric brain cancer, Pediatric lymphoma, Pediatric bag Disease, 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, Malignant mesothelioma, Malignant melanoma, Eye cancer, Vulvar cancer, Ureter Cancer, Urethral Cancer, Primary Cancer, Gastric Lymphoma, Gastric Cancer, Gastric Carcinoma, Gastrointestinal Interstitial Cancer, Wilms Cancer, Breast Cancer, Sarcoma, Penile Cancer, Pharyngeal Cancer, Pregnancy Induced Disease, Cervical Cancer, Endometrial Cancer, Uterine Sarcoma, Prostate Cancer, Metastatic Bone Cancer, Metastatic Brain Cancer, Mediastinal Cancer, Rectal Cancer, Rectal Carcinoma, Vaginal Cancer, Spinal Cord Cancer, Auditory Carcinoma, Pancreatic Cancer, Salivary Gland Cancer, Kaposi's Sarcoma, Paget's Disease, Tonsil Cancer, Squamous Cell Carcinoma, Lung Adenocarcinoma, Lung Cancer, Lung And at least one member selected from the group consisting of squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic cancer.
또한, 바람직하게 상기 암은 유방암, 대장암, 결장암, 폐암, 전립선암, 식도암, 방광암, 및 두경부암으로부터 선택되는 1종 이상일 수 있다.In addition, 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.
나아가, 바람직하게 상기 암은 급성 골수 백혈병(AML); 만성적 골수성 백혈병(CML); 급성 림프아구성 백혈병(ALL); 만성적 림프구성 백혈병(CLL); 호지킨 질환(HD); 비-호지킨 림프종(NHL); B-세포 림프종; T-세포 림프종; 다발성 골수종(MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군(MDS); 작은 림프구 림프종(SLL); 변연부 림프종; 무증상 다발성 골수종; 및 골수증식성 증후군으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.Furthermore, preferably 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.
본 명세서에서 사용된 바와 같이, 용어 "암"은 조절되지 않는 또는 이상조절된 세포 증식, 감소된 세포성 분화, 주위의 조직에 침입하는 부절적한 능력, 및/또는 이소성 부위에서 신규 성장을 확립하는 능력을 특징으로 하는 세포성 장애를 의미한다. 용어 "암"은 비제한적으로, 고형 종양 및 혈액매개 종양 (혈액성 악성종양)을 포함한다. 용어 "암"은 피부, 조직, 기관, 골, 연골, 혈액, 및 혈관의 질환을 포함한다. 용어 "암"은 추가로, 1차 및 전이암을 포함한다.As used herein, the term "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). The term "cancer" includes diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further includes primary and metastatic cancers.
상기 고형 종양은 췌장암; 침습성 방광암 포함하는 방광암; 결장직장암; 갑상선암, 위암, 전이성 유방암을 포함하는 유방암; 안드로겐-의존적 및 안드로겐-독립적인 전립선암을 포함하는 전립선암; 예를 들면, 전이성 신장 세포 암종을 포함하는 신장암; 예를 들면 간세포 암 및 간내 담관을 포함하는 간암; 비-소세포 폐암 (NSCLC), 편평상피 폐암, 세기관지폐포 암종 (BAC), 폐의 선암종, 및 소세포 폐암 (SCLC)을 포함하는 폐 및 기관지 암; 예를 들면, 진행성 상피성 또는 1차 복막 암을 포함하는 난소암; 자궁경부암; 예를 들면 자궁 체부 및 자궁 경부를 포함하는 자궁암; 자궁내막 암; 위암; 식도암; 예를 들면, 두경부의 편평상피 세포 암종, 비인두 암, 구강 및 인두를 포함하는 두경부 암; 흑색종; 전이성 신경내분비 종양을 포함하는 신경내분비 암; 예를 들면, 신경아교종/교모세포종, 역형성 희소돌기아교세포종, 성인 교모세포종 다형성, 및 성인 역형성 별아교세포종을 포함하는 뇌암; 전이성 신경내분비 종양; 골 암이고; 그리고 연조직 육종을 포함하는 신경내분비를 포함한다.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 and neck, nasopharyngeal cancer, oral cavity and pharynx; Melanoma; Neuroendocrine cancer, including metastatic neuroendocrine tumors; Brain cancers including, for example, glioma / glioblastoma, anaplastic oligodendrocyte glioma, adult glioblastoma polymorphism, and adult anaplastic astrocytoma; Metastatic neuroendocrine tumors; Bone cancer; And neuroendocrine, including soft tissue sarcoma.
상기 혈액성 악성종양은 급성 골수 백혈병 (AML); 만성적 골수성 백혈병 (CML) (가속화된 CML 및 CML 아세포기 (CML-BP) 포함); 급성 림프아구성 백혈병 (ALL); 만성적 림프구성 백혈병 (CLL); 호지킨 질환 (HD); 비-호지킨 림프종 (NHL) (여포성 림프종 및 외투 세포 림프종 포함); B-세포 림프종 (미만성 큰 B-세포 림프종 (DLBCL) 포함); T-세포 림프종; 다발성 골수종 (MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군 (MDS) (난치의 빈혈 (RA), 관상 철아구 (RARS)를 갖는 난치의 빈혈 (과다 모세포 (RAEB), 및 형질전환 동반 RAEB (RAEB-T)를 갖는 난치의 빈혈) 포함); 작은 림프구 림프종 (SLL); 변연부 림프종; 무증상 다발성 골수종; 및 골수증식성 증후군을 포함한다.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 lymphocyte lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, 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.
여기서, 상기 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환은 암(cancer), 염증(inflammatory), 심혈관계 질환(cardiovascular disease), 신경퇴행성 질환(neurodegenerative diseases), 등을 포함할 수 있고, 바람직하게 암이다.Here, 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.
한편, 상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B세포림프종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.Meanwhile, 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. Cancer, 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, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethra Cancer, Primary unknown cancer, Gastric lymphoma, Gastric cancer, Gastric carcinoma, Gastrointestinal stromal cancer, Wilms cancer, Breast cancer, Sarcoma, Penile cancer, Pharyngeal cancer, Pregnancy in chorionic disease, Cervical cancer, Endometrial cancer, Uterine sarcoma, Prostate cancer, Metastatic Bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, colorectal carcinoma, vaginal cancer, spinal cord cancer, auditory schwanoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell And at least one member selected from the group consisting of cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic cancer.
또한, 바람직하게 상기 암은 유방암, 대장암, 결장암, 폐암, 전립선암, 식도암, 방광암, 및 두경부암으로부터 선택되는 1종 이상일 수 있다.In addition, 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.
나아가, 바람직하게 상기 암은 급성 골수 백혈병(AML); 만성적 골수성 백혈병(CML); 급성 림프아구성 백혈병(ALL); 만성적 림프구성 백혈병(CLL); 호지킨 질환(HD); 비-호지킨 림프종(NHL); B-세포 림프종; T-세포 림프종; 다발성 골수종(MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군(MDS); 작은 림프구 림프종(SLL); 변연부 림프종; 무증상 다발성 골수종; 및 골수증식성 증후군으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.Furthermore, preferably 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.
본 발명에 따른 약학적 조성물에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충전제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다.In the pharmaceutical composition according to the present invention, 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. Can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. which are commonly used.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.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.
상기 화학식 1로 표시되는 화합물을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의하였다. Pharmaceutical 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.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.In this case, 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.
제제화의 예로는 하기와 같다.Examples of formulations are as follows.
<제제예 1> 산제의 제조Preparation Example 1 Preparation of Powder
화학식 1로 표시되는 유도체: 2gDerivative represented by formula (1): 2 g
유당: 1gLactose: 1 g
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in airtight cloth to prepare a powder.
<제제예 2> 정제의 제조Preparation Example 2 Preparation of Tablet
화학식 1로 표시되는 유도체: 100 ㎎Derivative represented by Formula 1: 100 mg
옥수수전분: 100 ㎎Corn starch: 100 mg
유당: 100 ㎎Lactose: 100 mg
스테아린산 마그네슘: 2 ㎎Magnesium Stearate: 2 mg
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
<제제예 3> 캡슐제의 제조Preparation Example 3 Preparation of Capsule
화학식 1로 표시되는 유도체: 100 ㎎Derivative represented by Formula 1: 100 mg
옥수수전분: 100 ㎎Corn starch: 100 mg
유당: 100 ㎎Lactose: 100 mg
스테아린산 마그네슘: 2 ㎎Magnesium Stearate: 2 mg
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
<제제예 4> 주사제의 제조Preparation Example 4 Preparation of Injection
화학식 1로 표시되는 유도체: 100 ㎎Derivative represented by Formula 1: 100 mg
만니톨: 180 ㎎Mannitol: 180 mg
Na2HPO4ㆍ2H2O: 26 ㎎Na 2 HPO 4 2H 2 O: 26 mg
증류수: 2974 ㎎Distilled water: 2974 mg
통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.
상기 제제화의 예시는 통상적인 제제예에 관한 것일 뿐, 본 발명의 제제화가 이에 제한되지는 않음을 통상의 기술지식을 가진 자라면 용이하게 이해할 수 있다.Examples of the formulation is related to the conventional formulation, it will be readily understood by those skilled in the art that the formulation of the present invention is not limited thereto.
나아가, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 인체에 대한 투여량은 대상의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70Kg인 성인 대상를 기준으로 할 때, 일반적으로 0.1-1000 mg/일이며, 바람직하게는 1-500 mg/일이며, 또한 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.Furthermore, 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.
또한, 본 발명의 약학적 조성물은 유로텐신-Ⅱ 수용체 과활성에 의한 질환의 예방 또는 치료를 위하여 단독으로, 또는 수술, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.In addition, the pharmaceutical 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.
나아가, 본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 치료 방법을 제공한다.Furthermore, 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.
이때, 상기 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환은 본 명세서에서 설명된 바와 같이, NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 활성을 저해하는 것으로부터 예방 또는 치료할 수 있는 질환을 말하고, 바람직하게 암이다. 또한, 상기 암은 상술된 바와 같은 암을 모두 포함한다.At this time, the NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related disease is prevented or prevented from inhibiting NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) activity as described herein. Refers to a disease that can be treated, preferably cancer. The cancer also includes all of the cancers described above.
상기 치료학적 유효량은 투여 방법에 따라, 체내로 투여시 대상(subject)의 증상 또는 상태를 개선시킬 수 있을 정도의 양을 말한다. 또한 상기 양은 투여하는 대상의 체중, 나이, 성별, 상태, 가족력에 따라 상이할 수 있고, 본 발명에서 상기 치료 방법은 이처럼 대상별로 상이한 조건에 따라 다른 양의 투여량을 정할 수 있다.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. In addition, 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.
상기 "유효한 양"은 증식성, 염증성, 감염성, 신경적 또는 심혈관 장애를 치료하는데 유용한 양, 또는 암을 치료하는데 유효한 양이다. 다른 구체예에서, 화합물의 "유효한 양"은 NAE 또는 SAE의 결합을 억제하는 양이다.The "effective amount" is an amount useful for treating proliferative, inflammatory, infectious, neurological or cardiovascular disorders, or an amount effective for treating cancer. In another embodiment, an "effective amount" of a compound is an amount that inhibits binding of NAE or SAE.
본 발명의 방법에 따른 화합물 및 조성물은 질환을 치료하는데 유효한 임의의 양 및 임의의 투여 경로를 사용하여 투여될 수 있다. 필요한 정확한 양은 대상체의 종, 연령, 및 일반적인 병태, 감염의 중증도, 특정한 제제, 그것의 투여 방식, 등에 따라 대상별로 변할 것이다. 본 발명의 화합물은 복용량의 투여 용이성 및 균일성에 대해 투약량 단위 형태로 빈번하게 제형화된다. 표현 "투약량 단위 형태"는, 본 명세서에서 사용된 바와 같이 치료될 대상에 적절한 제제의 물리적으로 별개의 단위를 의미한다. 그러나, 본 발명의 화합물 및 조성물의 총 일일 사용량이 건전한 의료 판단의 범위 내에 주치의에 의해 결정될 것으로 이해될 것이다. 임의의 특정한 대상 또는 유기체에 대한 특정 유효한 투여 수준은 하기를 포함하는 다양한 인자에 의존할 것이다.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. The expression “dose unit form” as used herein 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.
치료될 질환 및 질환의 중증도; 이용된 특정 화합물의 활성; 특정 조성물 이용된; 연령, 체중, 일반적인 건강, 대상의 성별 및 다이어트; 투여 시간, 투여 경로, 및 이용된 특정 화합물의 배출 속도; 치료의 지속시간; 이용된 특정 화합물와 함께 또는동시에 사용된 약물, 및 예컨대 의료 기술에서 잘 알려진 인자.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.
용어 "대상"은, 본 명세서에서 사용된 바와 같이, 동물, 예를 들면 포유동물, 예컨대 인간을 의미한다.The term "subject" as used herein refers to an animal, eg a mammal, such as a human.
본 발명의 약학적 조성물은 치료될 감염의 중증도에 따라 인간 및 다른 동물에게 경구로, 직장으로, 비경구로, 낭내로, 질내로, 복강내로, 국소로 (분말, 연고, 로션, 고약, 또는 드롭스에 의해서), 구강으로, 경구 또는 비강 스프레이로서, 등으로 투여될 수 있다. 특정 구체예에서, 본 발명의 화합물은 원하는 치료 효과를 얻기 위해 약 0.01 mg/kg 내지 약 50 mg/kg, 예를 들면 약 1 mg/kg 내지 약 25 mg/대상체 체중 kg / 1일, 1회 이상 /1일의 복용량 수준으로 경구로 또는 비경구로 투여될 수 있다.The pharmaceutical 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. In certain embodiments, 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.
경구 투여용 액체 투약 형태는, 비제한적으로, 약제학적으로 허용 가능한 에멀젼, 마이크로에멀젼, 용액, 현탁액, 시럽 및 엘릭시르를 포함한다. 활성 화합물에 추가하여, 액체 투약 형태는 당해기술에서 통상적으로 사용된 하기 예의 불활성 희석제를 함유할 수 있다: 물 또는 다른 용매, 가용화제, 및 유화제 예컨대 에틸 알코올, 이소프로필 알코올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸렌 글리콜, 디메틸포름아미드, 오일 (예를 들면, 목화씨, 땅콩, 옥수수, 세균, 올리브, 캐스터, 및 참께 오일), 글리세롤, 테트라하이드로푸르푸릴 알코올, 폴리에틸렌 글리콜 및 소르비탄의 지방산 에스테르, 및 이들의 혼합물. 불활성 희석제 외에, 경구 조성물은 아쥬반트 예컨대 습윤제, 유화 및 현탁화 제제, 감미제, 풍미제, 및 방향제를 또한 포함할 수 있다.Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. In addition to inert diluents, oral compositions may also include adjuvant such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and fragrances.
주사가능 제제, 예를 들면, 멸균된 주사가능 수성 또는 지질생산성 현탁액은 적합한 분산제 또는 습윤제 및 현탁화제를 사용하여 공지된 기술에 따라 제형화될 수 있다. 멸균된 주사가능 제제는 또한 비독성 비경구로 허용 가능한 희석제 또는 용매 중 멸균된 주사가능 용액, 현탁액 또는 에멀젼일 수 있고, 예를 들면 1,3-부탄디올 중 용액이다. 이용될 수 있는 허용 가능한 비히클 및 용매 중에서, 물, 링거액, U.S.P. 및 등장의 염화나트륨 용액이 있다. 또한, 멸균된, 고정유는 용매 또는 분산매로서 종래에 이용된다. 이러한 목적을 위해 임의의 블랜드 고정유가 이용될 수 있고, 합성 모노- 또는 디글리세라이드를 포함한다. 또한, 지방산 예컨대 올레산은 주사제의 제조에 사용된다. 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.
주사가능 제형은, 예를 들면, 박테리아-고정 필터를 통한 여과, 또는 사용 전에 멸균수 또는 다른 멸균된 주사가능 매질에서 용해 또는 분산될 있는 멸균된 고형 조성물의 현태로 산귤제를 편입시켜 멸균될 수 있다.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.
본 발명의 화합물의 효과를 지속하기 위해서, 피하 또는 근육내 주사로부터 화합물의 느린 흡수가 종종 요망된다. 이것은 좋지 못한 수용해도를 갖는 결정성 또는 비정질 물질의 액체 현탁액의 사용에 의해 달성될 수 있다. 화합물의 흡수율은 결정 크기 및 결정 형태에 의존할 수 있는 그것의 용해 속도에 따라 달라질 수 있다 의존한다. 대안적으로, 비경구로 투여된 화합물 형태의 지연된 흡수는 화합물을 오일 비히클에서 용해 또는 현탁시켜 달성된다. 주사가능 데포 형태는 생분해성 폴리머 예컨대 폴리락타이드-폴리글라이콜라이드에서 화합물의 마이크로엔캡슐 매트릭스를 형성하여 만들어진다. 화합물 대 폴리머의 비 및 이용된 특정 폴리머의 본성에 따라, 화합물 방출 속도는 제어될 수 있다. 다른 생분해성 폴리머의 예는 폴리(오르토에스테르) 및 폴리(무수물)를 포함한다. 데포 주사가능 제형은 신체 조직과 양립가능한 리포좀 또는 마이크로에멀젼에서 화합물을 포획하여 또한 제조된다.In order to sustain the effects of the compounds of the invention, slow absorption of the compounds from subcutaneous or intramuscular injection is often desired. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a compound depends on its dissolution rate, which may depend on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. 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.
직장 또는 질 투여용 조성물은, 예를 들면, 본 발명의 화합물을 적합한 무-자극 부형제 또는 담체 예컨대 코코아 버터, 폴리에틸렌 글리콜 또는 좌약 왁스와 혼합하여 제조될 수 있는 있는 좌약이고, 이 좌약은 고체 주위 온도에서 고체이지만 체온에서 액체이고 따라서 직장 또는 질강에서 용융되어 활성 화합물을 방출한다.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.
경구 투여용 고체 투약 형태는 캡슐, 정제, 알약, 분말, 및 과립을 포함한다. 그와 같은 고체 투약 형태에서, 활성 화합물은 하기와 혼합된다: 적어도 1종의 불활성, 약제학적으로 허용 가능한 부형제 또는 담체 예컨대 나트륨 시트레이트 또는 디칼슘 포스페이트 및/또는 a) 충전제 또는 증량제 예컨대 전분, 락토오스, 수크로오스, 글루코오스, 만니톨, 및 규산, b) 결합제 예컨대, 예를 들면, 카복시메틸셀룰로오스, 알기네이트, 젤라틴, 폴리비닐피롤리디논, 수크로오스, 및 아카시아, c) 휴멕턴트 예컨대 글리세롤, d) 붕해제 예컨대 한천--한천, 탈산칼슘, 감자 또는 타피오카 전분, 알긴산, 어떤 실리케이트, 및 탄산나트륨, e) 용액 지연제 예컨대 파라핀, f) 흡수 가속제 예컨대 4차 암모늄 화합물, g) 습윤제 예컨대, 예를 들면, 세틸 알코올 및 글리세롤 모노스테아레이트, h) 흡수제 예컨대 카올린 및 벤토나이트 점토, 및 i) 윤활제 예컨대 탈크, 칼슘 스테아레이트, 마그네슘 스테아레이트, 고체 폴리에틸렌 글리콜, 나트륨 라우릴 설페이트, 및 이들의 혼합물. 캡슐, 정제 및 알약의 경우에, 복용 형태는 완충제를 또한 포함할 수 있다.Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants examples For talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.
유사한 유형의 고형 조성물은 락토오스 또는 유당뿐만 아니라 고분자량 폴리에틸렌 글리콜 등과 같은 부형제를 사용하여 연질 및 경질-충전된 젤라틴 캡슐 내의 충전제로서 또한 이용될 있다. 고체 투약 형태의 정제, 당의정, 캡슐, 알약, 및 과립은 코팅물 및 쉘 예컨대 장용 코팅물 및 약제학적 제형 기술에서 잘 알려진 다른 코팅물과 제조될 수 있다. 불투명화제를 임의로 함유할 수 있고, 또한 활성 성분(들)만을, 예를 들면, 장관의 특정 일부에서, 임의로, 지연 방식으로 방출하는 조성물일 수 있다. 사용될 수 있는 포매 조성물의 예는 폴리머성 서브스턴스 및 왁스를 포함한다. 유사한 유형의 고형 조성물은 락토오스 또는 유당 뿐만 아니라 고분자량 폴리에틸렌 글리콜 등과 같은 부형제를 사용하여 연질 및 경질-충전된 젤라틴 캡슐 내의 충전제로서 또한 이용될 수 있다.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. Examples of 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.
활성 화합물은 또한 1종 이상의 부형제 전술한 바와 같은 1종 이상의 부형제와의 마이크로-캡슐화된 형태일 수 있다. 고체 투약 형태의 정제, 당의정, 캡슐, 알약, 및 과립은 코팅물 및 쉘 예컨대 장용 코팅물, 방출 조절 코팅물 및 약제학적 제형 기술에서 잘 알려진 다른 코팅물로 제조될 수 있다. 그와 같은 고체 투약 형태에서 활성 화합물은 적어도 1종의 불활성 희석제 예컨대 수크로오스, 락토오스 또는 전분과 혼합될 수 있다. 그와 같은 복용 형태는, 정상 실시에서와 같이, 불활성 희석제 이외의 추가 물질, 예를 들면, 정제화 윤활제 및 다른 정제화 조제 예컨대 마그네슘 스테아레이트 및 미세결정성 셀룰로오스를 또한 포함할 수 있다. 캡슐, 정제 및 알약의 경우에, 복용 형태는 완충제를 또한 포함할 수 있다. 불투명화제를 임의로 함유할 수 있고 또한 활성 성분(들)만을, 예를 들면, 장관의 특정 일부에서, 임의로, 지연 방식으로 방출하는 조성물일 수 있다. 사용될 수 있는 포매 조성물의 예는 폴리머성 서브스턴스 및 왁스를 포함한다.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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions that can be used include polymeric substances and waxes.
본 발명의 화합물의 국소 또는 경피 투여용 복용 형태는 연고, 페이스트, 크림, 로션, 겔, 분말, 용액, 스프레이, 흡입제 또는 패치를 포함한다. 활성 성분은 요구되는 대로, 멸균 조건 하에서 약제학적으로 허용 가능한 담체 및 임의의 필요한 보존제 또는 버퍼와 혼합된다. 안과 제형, 귀물약, 및 안약은 본 발명의 범위 내에 있는 것으로 또한 고려된다. 추가로, 본 발명은 화합물의 신체에의 제어된 절단을 제공하는 부가된 이점을 갖는 경피 패치의 사용을 고려한다. 그와 같은 복용 형태는 화합물을 적절한 매질에서 용해 또는 분산시켜 만들어질 수 있다. 흡수 촉진제는 피부를 가로질로 화합물의 유동을 증가시키기 위해 또한 사용될 수 있다. 속도는 속도 조절 막을 제공하거나 또는 폴리머 매트릭스 또는 겔에서 화합물을 분산시켜 제어될 수 있다.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. In addition, 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.
일부 구체예에서, 본 발명의 화합물 또는 그것의 약제학적 조성물은 항암제와 함께 투여된다. 본 명세서에서 사용된 바와 같이, 용어 "항암제"는 암을 치료하기 위해 암이 있는 대상체에게 투여된 임의의 제제를 의미한다. 병용 요법은 동반하여 또는 순차적으로 치료제를 투여하는 것을 포함한다. 대안적으로, 치료제는 대상에게 투여되는 1종의 조성물에 조합될 수 있다. In some embodiments, a compound of the invention or a pharmaceutical composition thereof is administered with an anticancer agent. As used herein, the term “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. Alternatively, the therapeutic agent may be combined in one composition administered to the subject.
일 구체예에서, 본 발명의 화합물은 다른 치료제와 함께 사용된다. 일부 구체예에서, 추가의 치료제는 다른 SAE의 저해제 로부터 선택된다. 다른 구체예에서, 본 발명의 화합물은 세포독성 약물, 방사선요법, 및 면역요법으로 구성된 군으로부터 선택된 치료제와 함께 투여된다. 일부 구체예에서, 본 발명의 화합물은 DLBCL 및 CLL을 포함하는 재발한/난치의 비-호지킨 림프종의 치료를 위해 화학치료 레지멘과 함께 사용될 수 있다. 화학치료 레지멘은, 비제한적으로 하기를 포함한다: R-ICE (리툭시맙, 이포스파마이드, 카보플라틴 및 에토포시드), R-DHAP (리툭시맙, 덱사메타손, 높은-용량 사이타라빈 및 시스플라틴), 및 R-GDP (리툭시맙, 젬시타빈, 시스플라틴 및 덱사메타손). 본 발명의 범위 내에서 다른 조합이 착수될 수 있음이 이해된다. In one embodiment, the compounds of the present invention are used in combination with other therapeutic agents. In some embodiments, the additional therapeutic agent is selected from inhibitors of other SAEs. In another embodiment, the compound of the present invention is administered with a therapeutic agent selected from the group consisting of cytotoxic drugs, radiotherapy, and immunotherapy. In some embodiments, 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.
추가 제제들은 다중 투약량 요법의 일부로서 제공된 병용 요법으로부터 별도로 투여될 수 있다. 대안적으로, 제제들은 본 발명의 화합물와 함께 혼합된 단일 복용 형태의 일부이리 수 있다. 병용 요법의 일부로서 투여된다면, 2종의 치료제는 동시에, 순차적으로, 또는 간헐적으로 제공될 수 있다. 병용 요법은 본 명세서에서 기재된 치료적 징후 중 임의의 것을 위해 사용될 수 있다. 일부 구체예에서, 병용 요법은 대상에서 증식성 장애 (예를 들면, 암)를 치료하기 위한 것이다. 일부 구체예에서, 증식성 장애는 유방암, 폐암, 난소암, 다발성 골수종, 급성 골수 백혈병 또는 급성 림프아구성 백혈병이다.Additional agents may be administered separately from the combination therapy provided as part of a multiple dosage regimen. Alternatively, 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. In some embodiments, the combination therapy is for treating a proliferative disorder (eg, cancer) in a subject. In some embodiments, the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myeloid leukemia or acute lymphoblastic leukemia.
본 발명의 또 다른 측면은 생물학적 샘플 또는 대상에서 SAE 활성을 억제하는 것에 관한 것이고, 상기 방법은 화학식 1로 표시되는 화합물, 또는 상기 화합물을 포함하는 조성물을 투여하거나, 이것에 상기 생물학적 샘플을 접촉시키는 것을 포함한다. 용어 "생물학적 샘플"은, 본 명세서에서 사용된 바와 같이, 일반적으로 생체내, 시험관내, 및 생체외 물질을 포함하고, 또한, 비제한적으로, 세포 배양물 또는 그것의 추출물; 포유동물로부터 수득된 생체검사된 물질 또는 그것의 추출물; 그리고 혈액, 타액, 소변, 대변, 정액, 눈물, 또는 다른 체액 또는 그것의 추출물을 포함한다.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. The term “biological sample”, as used herein, 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.
본 발명의 또 다른 측면은 단일 패키지로 별개의 용기를 포함하는 키트를 제공하는 것이고, 여기서 본 명세서에서 개시된 화합물 또는 약제학적 조성물 및/또는 그것의 염은 SAE가 역할을 하는 1종 이상의 장애, 증상 및 질환을 치료하는데 사용하기 위한1종 이상의 약제학적으로 허용 가능한 담체와 함께 제공된다. Another aspect of the invention is to provide a kit 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.
본 발명에 따른 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염은, NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme)의 활성을 억제하여 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 개선, 예방 또는 치료에 유용한 효과가 있음을 실험을 통해 확인하였다.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.
먼저, 본 발명에 따른 헤테로고리 화합물의 암세포 성장 저해 평가를 하기 위해, ATCC에서 구입한 인간 유래 유방암세포(HCT-116, THP-1)에 대하여 실험을 수행한 결과, 본 발명에 따른 실시예 1-45 화합물은 인간 유래 유방암세포(HCT-116, THP-1)에 대하여 마이크로몰 또는 나노몰의 단위 농도로 우수하게 암세포 성장을 저해하는 것으로 확인되어, 본 발명에 따른 헤테로고리 화합물은 암의 예방 또는 치료용 약학적 조성물의 유효성분으로 유용하게 사용될 수 있음을 확인 하였다(실험예 1 참조).First, in order to evaluate cancer cell growth inhibition of the heterocyclic compound according to the present invention, the experiment was performed on human-derived breast cancer cells (HCT-116, THP-1) purchased from ATCC, Example 1 according to the present invention 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).
또한, 본 발명에 따른 헤테로고리 화합물의 SAE 및 NAE에 대한 억제 활성을 평가하기 위한 실험을 수행한 결과, 본 발명에 따른 실시예 1-45 화합물은 마이크로몰 또는 나노몰 단위의 농도로 우수하게 SAE 및 NAE의 활성을 저해할 수 있는 것으로 확인되어, 이를 함유하는 암의 예방 및 치료용 약학적 조성물로 유용하게 사용될 수 있음을 확인 하였다(실험예 2 및 실험예 3 참조).In addition, as a result of the experiment to evaluate the inhibitory activity against SAE and NAE of the heterocyclic compound according to the present invention, 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).
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명하였다.Hereinafter, the present invention has been described in detail by Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.
<< 실시예Example 1> (( 1> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3-) -4-((5- (1- (3- 브로모벤질Bromobenzyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드로옥시사이클로펜틸)메틸 설파메이트의 제조Preparation of Pyrimidin-4-yl) amino) -2,3-dihydrooxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000048
Figure PCTKR2017004246-appb-I000048
단계 1: 1-(2-브로모벤질)-1H-인돌-3-카브알데하이드의 합성Step 1: Synthesis of 1- (2-bromobenzyl) -1H-indole-3-carbaldehyde
1H-인돌-3-카브알데하이드(500 mg, 3.4 mmol)을 무수 DMF(2ml)에 녹인 후, 질소기체 하에서 얼음물을 이용하여 용액을 5℃로 냉각한 상태에서, Cs2CO3(1.1 g, 3.4 mmol)를 첨가하였다. 같은 온도에서 3-브로모벤질브로마이드(2.1 g, 8.6 mmol)을 천천히 적가한 후, 상온에서 2시간 동안 교반하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조 시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마트그래피(EA:n-hexane = 1:5)로 정제하여 흰색 고체의 화합물(1.0 g, 94 %)을 수득하였다.1H-indole-3-carbaldehyde (500 mg, 3.4 mmol) was dissolved in anhydrous DMF (2 ml), and the solution was cooled to 5 ° C. using ice water under nitrogen gas. Cs 2 CO 3 (1.1 g, 3.4 mmol) was added. 3-bromobenzylbromide (2.1 g, 8.6 mmol) was slowly added dropwise at the same temperature, followed by stirring at room temperature for 2 hours. After completion of the reaction by TLC, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: n-hexane = 1: 5) to give a white solid compound (1.0 g, 94%).
1H NMR (300 MHz, CDCl3) δ 9.89 (s, 1H), 8.26-8.29 (m, 1H), 7.66 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.22-7.28 (m, 3H), 7.07-7.17 (m, 1H), 6.99 (d, J = 7.4 Hz, 1H), 5.20 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.89 (s, 1H), 8.26-8.29 (m, 1H), 7.66 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.22-7.28 ( m, 3H), 7.07-7.17 (m, 1 H), 6.99 (d, J = 7.4 Hz, 1 H), 5.20 (s, 2H).
단계 2: (1-(3-브로모벤질)-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄올의 제조Step 2: Preparation of (1- (3-bromobenzyl) -1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanol
50ml 2구 둥근 바닥플라스크에 4-클로로-5-아이오도피리미딘(1.27 mmol, 306 mg)을 첨가하고 THF(2.0ml)에 녹여 -78℃에서 교반하였다. 여기에 n-BuLi(1.6 mmol, 0.64ml)를 한 방울씩 첨가하고 30분 동안 반응시킨다. THF(3.0ml)에 녹인 1-(2-브로모벤질)-1H-인돌-3-카브알데하이드(0.8 mmol, 250 mg)을 천천히 첨가한 뒤, 0℃에서 2시간 동안 반응시킨다. 반응 종료 후, 포화 NH4Cl을 사용하여 퀀칭하고, EA/H2O를 사용하여 추출한 뒤, MgSO4를 사용하여 건조하였다. 실리카겔 컬럼 크로마토그래피를 통해 30% EA/Hex 조건으로 분리, 정제하여 노란색 고체의 생성물(204.4 mg, 60%)을 수득하였다.4-chloro-5-iodopyrimidine (1.27 mmol, 306 mg) was added to a 50 ml two-necked round bottom flask, dissolved in THF (2.0 ml) and stirred at -78 ° C. N-BuLi (1.6 mmol, 0.64 ml) was added dropwise thereto and reacted for 30 minutes. 1- (2-bromobenzyl) -1H-indole-3-carbaldehyde (0.8 mmol, 250 mg) dissolved in THF (3.0 ml) was added slowly, followed by reaction at 0 ° C. for 2 hours. After completion of the reaction, it was quenched with saturated NH 4 Cl, extracted with EA / H 2 O, and dried using MgSO 4 . Silica gel column chromatography separated and purified under 30% EA / Hex conditions to give the product as a yellow solid (204.4 mg, 60%).
1H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 8.92 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.24-7.10 (m, 3H), 6.95 (d, J = 6.1 Hz, 2H), 6.40 (s, 1H), 5.24 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.15 (s, 1H), 8.92 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.24 -7.10 (m, 3H), 6.95 (d, J = 6.1 Hz, 2H), 6.40 (s, 1H), 5.24 (s, 2H).
단계 3: (1-(3-브로모벤질)-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온의 제조Step 3: Preparation of (1- (3-bromobenzyl) -1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone
20ml 바이알에 (1-(3-브로모벤질)-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄올(0.47 mmol, 200 mg), MnO2(4.7 mmol, 404.7 mg) 및 CH2Cl2(5.0ml)를 첨가하고 상온에서 12시간 동안 반응시킨다. 반응 종료 후, 셀라이트로 여과하여 MC로 여러 번 씻어준 후, 농축하였다. 실리카겔 컬럼 크로마토그래피를 통해 30% EA/Hex 조건으로 분리, 정제하여 노란색 고체의 생성물(124.1 mg, 62%)을 수득하였다.In a 20 ml vial (1- (3-bromobenzyl) -1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanol (0.47 mmol, 200 mg), MnO 2 (4.7 mmol, 404.7 mg ) And CH 2 Cl 2 (5.0 ml) are added and reacted at room temperature for 12 hours. After the reaction was completed, the mixture was filtered through Celite, washed with MC several times, and concentrated. Silica gel column chromatography separated and purified under 30% EA / Hex conditions to give the product as a yellow solid (124.1 mg, 62%).
1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.78 (s, 1H), 8.40 (d, 1H, J = 7.0 Hz), 7.48-7.29 (m, 6H), 7.20 (t, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 7.7 Hz), 5.32 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.10 (s, 1H), 8.78 (s, 1H), 8.40 (d, 1H, J = 7.0 Hz), 7.48-7.29 (m, 6H), 7.20 (t, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 7.7 Hz), 5.32 (s, 2H).
단계 4: (1-(3-브로모벤질)-1H-인돌-3-일)(4-(((3aR,4R,6R,6aS)-6-(하이드록시메틸-2,2-디메틸테트라하이드로-4H-사이클로펜타[d][1,3]디옥솔-4-일)아미노)피리미딘-5-일)메탄온의 제조Step 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
(1-(3-브로모벤질)-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온(44 mg, 0.1 mmol)과 ((3aS,4R,6R,6aR)-6-아미노-2,2-디메틸테트라하이드로-4H-사이클로펜타[d][1,3]디옥솔-4-일)메탄올(23 mg, 0.12 mmol)을 무수 n-BuOH(0.5ml)에 녹이고, DIPEA(0.04ml, 0.2 mmol)을 적가 하였다. 반응 혼합물은 105℃에서 2.5 시간 동안 교반하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 Na2SO4로 건조 시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬 컬럼 크로마토그래피(EA:n-hexane = 1:1)로 정제하여 흰색 고체의 화합물(41 mg, 70 %)을 수득하였다.(1- (3-bromobenzyl) -1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone (44 mg, 0.1 mmol) and ((3aS, 4R, 6R, 6aR) -6-amino-2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methanol (23 mg, 0.12 mmol) in anhydrous n-BuOH (0.5 ml) It dissolved and DIPEA (0.04 ml, 0.2 mmol) was added dropwise. The reaction mixture was stirred at 105 ° C. for 2.5 hours. After completion of the reaction by TLC, the 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. The reaction mixture was purified by flash column chromatography (EA: n-hexane = 1: 1) to give a white solid compound (41 mg, 70%).
1H NMR (300 MHz, CDCl3) δ 8.96 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 2.9 Hz, 2H), 8.23-8.27 (m, 1H), 7.61 (s, 1H), 7.41-7.44 (m, 1H), 7.29-7.33 (m, 4H), 7.18 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.32 (s, 2H), 4.72-4.80 (m, 1H), 4.61 (dd, J = 6.2, 2.5 Hz, 1H), 4.55 (dd, J = 6.2, 2.3 Hz, 1H), 3.82 (dd, J = 10.2, 4.9 Hz, 1H), 3.74 (dd, J = 10.2, 5.5 Hz, 1H), 2.54-2.64 (m, 1H), 2.40-2.44 (m, 1H), 1.61-1.69 (m, 1H), 1.53 (s, 3H), 1.30 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.96 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 2.9 Hz, 2H), 8.23-8.27 (m, 1H), 7.61 (s, 1H) , 7.41-7.44 (m, 1H), 7.29-7.33 (m, 4H), 7.18 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.32 (s, 2H), 4.72-4.80 (m, 1H), 4.61 (dd, J = 6.2, 2.5 Hz, 1H), 4.55 (dd, J = 6.2, 2.3 Hz, 1H), 3.82 (dd, J = 10.2, 4.9 Hz, 1H) , 3.74 (dd, J = 10.2, 5.5 Hz, 1H), 2.54-2.64 (m, 1H), 2.40-2.44 (m, 1H), 1.61-1.69 (m, 1H), 1.53 (s, 3H), 1.30 (s, 3 H).
단계 5: ((3aS,4R,6R,6aR)-6-((5-(1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,2-디메틸테트로하이드로-4H-사이클로펜타[d][1,3]디옥솔-4-일)메틸 설파메이트의 제조Step 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
(1-(3-브로모벤질)-1H-인돌-3-일)(4-(((3aR,4R,6R,6aS)-6-(하이드로메틸)-2,2-디메틸테트라하이드로-4H-사이클로펜타[d][1,3]디옥솔-4-일)아미노)피리미딘-5-일)메탄온(40 mg, 0.07 mmol)과 설파모일 클로라이드(60 mg, 0.5 mmol)을 무수 DMF(0.5ml)에 녹이고, 상온에서 20시간 동안 반응시킨다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 Na2SO4로 건조 시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼 크로마토그래피(CH2Cl2:MeOH = 10:1)로 정제하여 흰색 고체의 화합물(31 mg, 68 %)을 수득하였다.(1- (3-bromobenzyl) -1H-indol-3-yl) (4-(((3aR, 4R, 6R, 6aS) -6- (hydromethyl) -2,2-dimethyltetrahydro-4H Cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrimidin-5-yl) methanone (40 mg, 0.07 mmol) and sulfamoyl chloride (60 mg, 0.5 mmol) (0.5ml) and reacted at room temperature for 20 hours. After completion of the reaction by TLC, the 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. The reaction mixture was flash column chromatography (CH 2 Cl 2: MeOH = 10: 1) to give the compound as a white solid (31 mg, 68%).
1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.70 (s, 1H), 8.59-8.66 (m, 1H), 8.19-8.23 (m, 1H), 7.66 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.31-7.36 (m, 4H), 7.19 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.04 (br, 2H), 5.35 (s, 2H), 4.56-4.68 (m, 3H), 4.29 (d, J = 5.1 Hz, 2H), 2.63-2.72 (m, 2H), 1.70-1.79 (m, 1H), 1.52 (s, 3H), 1.30 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.73 (s, 1H), 8.70 (s, 1H), 8.59-8.66 (m, 1H), 8.19-8.23 (m, 1H), 7.66 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.31-7.36 (m, 4H), 7.19 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.04 (br, 2H ), 5.35 (s, 2H), 4.56-4.68 (m, 3H), 4.29 (d, J = 5.1 Hz, 2H), 2.63-2.72 (m, 2H), 1.70-1.79 (m, 1H), 1.52 ( s, 3H), 1.30 (s, 3H).
단계 6: ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드로옥시사이클로펜틸)메틸 설파메이트의 제조Step 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
((3aS,4R,6R,6aR)-6-((5-(1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,2-디메틸테트라하이드로-4H-사이클로펜타[d][1,3]디옥솔-4-일)메틸 설파메이트(31 mg, 0.05 mmol)을 THF(0.5ml)에 녹이고, 0℃에서 진한 HCl(0.15ml, 1.4 mmol)을 천천히 적가 하였다. 반응 혼합물을 상온에서 2시간 동안 교반하였고, 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 Na2SO4로 건조 시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼 크로마토그래피(CH2Cl2:MeOH = 10:1)로 정제하여 흰색 고체의 화합물(5 mg, 18 %)을 수득하였다.((3aS, 4R, 6R, 6aR) -6-((5- (1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,2 -Dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate (31 mg, 0.05 mmol) was dissolved in THF (0.5 ml) and concentrated HCl (0. ml, 1.4 mmol) was slowly added dropwise. The 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 reaction mixture was purified by flash column chromatography (CH 2 Cl 2 : MeOH = 10: 1) to give a white solid compound (5 mg, 18%).
1H NMR (300 MHz, CD3OD) δ 8.69 (s, 1H), 8.59 (s, 1H), 8.24-8.28 (m, 1H), 8.09 (s, 1H), 7.44-7.47 (m, 4H), 7.30-7.33 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 5.53 (s, 2H), 4.54-4.59 (m, 1H), 4.22 (dd, J = 5.4, 1.7 Hz, 2H), 3.94-4.00 (m, 2H), 2.49-2.56 (m, 1H), 2.36-2.45 (m, 1H), 1.36-1.46 (m, 1H). 1 H NMR (300 MHz, CD 3 OD) δ 8.69 (s, 1H), 8.59 (s, 1H), 8.24-8.28 (m, 1H), 8.09 (s, 1H), 7.44-7.47 (m, 4H) , 7.30-7.33 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 5.53 (s, 2H), 4.54-4.59 (m, 1H), 4.22 (dd, J = 5.4, 1.7 Hz, 2H), 3.94-4.00 (m, 2H), 2.49-2.56 (m, 1H), 2.36-2.45 (m, 1H), 1.36-1.46 (m, 1H).
<실시예 2> ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-인다졸-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Example 2 ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-indazol-3-carbonyl) pyrimidin-4-yl) Preparation of Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000049
Figure PCTKR2017004246-appb-I000049
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 1H-인다졸-3-카브알데하이드를 사용하는 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 616.1).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).
1H NMR (300 MHz, DMSO) δ 9.49 (s, 1H), 9.07 (d, J = 7.5 Hz, 1H), 8.66 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.40 - 7.60 (m, 5H), 7.23 - 7.35 (m, 2H), 5.90 (s, 2H), 4.40 - 4.63 (m, 1H), 3.98 - 4.13 (m, 2H), 3.72 - 3.90 (m, 2H), 2.16 - 2.43 (m, 2H), 1.16 - 1.26 (m, 1H). 1 H NMR (300 MHz, DMSO) δ 9.49 (s, 1H), 9.07 (d, J = 7.5 Hz, 1H), 8.66 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.93 ( d, J = 8.5 Hz, 1H), 7.40-7.60 (m, 5H), 7.23-7.35 (m, 2H), 5.90 (s, 2H), 4.40-4.63 (m, 1H), 3.98-4.13 (m, 2H), 3.72-3.90 (m, 2H), 2.16-2.43 (m, 2H), 1.16-1.26 (m, 1H).
<실시예 3> ((1R,2R,3S,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Example 3 ((1R, 2R, 3S, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3- Preparation of Dihydroxycyclopentyl) methyl Sulfamate
Figure PCTKR2017004246-appb-I000050
Figure PCTKR2017004246-appb-I000050
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 538.2).Except for using benzyl bromide in place of 3-bromobenzyl bromide used in Step 1 of Example 1, the target compound was prepared in the same manner as in Example 1 (LC / MS M + H: 538.2).
1H NMR (300 MHz, MeOD) δ 8.63 (s, 1H), 8.57 (s, 1H), 8.23 (dd, J = 5.9, 3.1 Hz, 1H), 8.00 (s, 1H), 7.43 (dd, J = 6.1, 3.0 Hz, 1H), 7.37 - 7.13 (m, 8H), 5.47 (s, 2H), 4.55 (dd, J = 13.7, 7.9 Hz, 1H), 4.09 - 4.33 (m, 2H), 3.87 - 4.05 (m, 2H), 2.29 - 2.64 (m, 2H), 1.35 - 1.43 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.63 (s, 1H), 8.57 (s, 1H), 8.23 (dd, J = 5.9, 3.1 Hz, 1H), 8.00 (s, 1H), 7.43 (dd, J = 6.1, 3.0 Hz, 1H), 7.37-7.13 (m, 8H), 5.47 (s, 2H), 4.55 (dd, J = 13.7, 7.9 Hz, 1H), 4.09-4.33 (m, 2H), 3.87- 4.05 (m, 2H), 2.29-2.64 (m, 2H), 1.35-1.43 (m, 1H).
<실시예 4> ((1R,2R,3S,4R)-4-((5-(1-(3-클로로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Example 4 ((1R, 2R, 3S, 4R) -4-((5- (1- (3-chlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) Preparation of -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000051
Figure PCTKR2017004246-appb-I000051
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-클로로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 572.1).Except for using 3-chlorobenzyl bromide in place of 3-bromobenzyl bromide used in Step 1 of Example 1, the target compound was prepared in the same manner as in Example 1 (LC / MS M + H: 572.1).
1H NMR (300 MHz, DMSO) δ 8.73 (s, 1H), 8.64 (s, 1H), 8.39 - 8.48 (m, 2H), 8.20 - 8.27 (m, 1H), 7.53 - 7.63 (m, 1H), 7.46 (s, 1H), 7.34 - 7.37 (m, 2H), 7.26 - 7.32 (m, 3H), 5.58 (s, 2H), 4.91 (s, 1H), 4.76 (s, 1H), 4.37 - 4.55 (m, 1H), 3.92 - 4.18 (m, 2H), 3.69 - 3.85 (m, 2H), 2.15 - 2.39 (m, 2H), 1.05 - 1.29 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 8.73 (s, 1H), 8.64 (s, 1H), 8.39-8.48 (m, 2H), 8.20-8.27 (m, 1H), 7.53-7.63 (m, 1H) , 7.46 (s, 1H), 7.34-7.37 (m, 2H), 7.26-7.32 (m, 3H), 5.58 (s, 2H), 4.91 (s, 1H), 4.76 (s, 1H), 4.37-4.55 (m, 1H), 3.92-4.18 (m, 2H), 3.69-3.85 (m, 2H), 2.15-2.39 (m, 2H), 1.05-1.29 (m, 2H).
<실시예 5> ((1R,2R,3S,4R)-4-((5-(1-(3-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Example 5 ((1R, 2R, 3S, 4R) -4-((5- (1- (3-fluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino Preparation of) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000052
Figure PCTKR2017004246-appb-I000052
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-플루오로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 556.2).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).
1H NMR (300 MHz, DMSO) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.16 - 8.30 (m, 1H), 7.53 - 7.64 (m, 1H), 7.33 - 7.51 (m, 2H), 7.05 - 7.33 (m, 4H), 5.58 (s, 2H), 4.89 (d, J = 5.9 Hz, 1H), 4.73 (s, 1H), 4.40 - 4.50 (m, 2H), 3.92 - 4.04 (m, 1H), 3.67 - 3.88 (m, 2H), 2.19 - 2.36 (m, 2H), 1.07 - 1.30 (m, 1H). 1 H NMR (300 MHz, DMSO) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.16-8.30 (m, 1H), 7.53-7.64 (m, 1H), 7.33-7.51 (m, 2H), 7.05-7.33 (m, 4H), 5.58 (s, 2H), 4.89 (d, J = 5.9 Hz, 1H), 4.73 (s, 1H), 4.40-4.50 (m, 2H), 3.92-4.04 (m, 1H), 3.67-3.88 (m, 2H), 2.19-2.36 (m, 2H), 1.07-1.30 (m, 1H).
<< 실시예Example 6> (( 6> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((5-(1-(3-(-4-((5- (1- (3- ( 트리플루오로Trifluoro )) 벤질benzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000053
Figure PCTKR2017004246-appb-I000053
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-트리플루오로메틸벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 606.2).Except for using 3-trifluoromethylbenzyl bromide in place of the 3-bromobenzyl bromide used in step 1 of Example 1, the target compound was prepared in the same manner as in Example 1 (LC / MS M + H: 606.2).
1H NMR (300 MHz, DMSO) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.52 - 8.38 (m, 2H), 8.21 - 8.27 (m, 1H), 7.83 (s, 1H), 7.28 - 7.67 (m, 6H), 5.68 (s, 2H), 4.39 - 4.50 (m, 2H), 3.96 - 4.02 (m, 1H), 3.69 - 3.85 (m, 2H), 2.15 - 2.38 (m, 2H), 1.07 - 1.30 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.52-8.38 (m, 2H), 8.21-8.27 (m, 1H), 7.83 (s, 1H), 7.28 -7.67 (m, 6H), 5.68 (s, 2H), 4.39-4.50 (m, 2H), 3.96-4.02 (m, 1H), 3.69-3.85 (m, 2H), 2.15-2.38 (m, 2H) , 1.07-1.30 (s, 1 H).
<< 실시예Example 7> (( 7> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((5-(1-(3-메톡시벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 -4-((5- (1- (3-methoxybenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000054
Figure PCTKR2017004246-appb-I000054
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-메톡시벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 568.2).Except for using 3-methoxybenzyl bromide instead of 3-bromobenzyl bromide used in Step 1 of Example 1, the target compound was prepared in the same manner as in Example 1 (LC / MS M + H : 568.2).
<< 실시예Example 8> (( 8> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3-) -4-((5- (1- (3- 클로로Chloro -4--4- 플루오로벤질Fluorobenzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000055
Figure PCTKR2017004246-appb-I000055
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-클로로-4-플루오로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 590.1).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).
<< 실시예Example 9> (( 9> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(2,5-) -4-((5- (1- (2,5- 디클로로벤질Dichlorobenzyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000056
Figure PCTKR2017004246-appb-I000056
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 2,5-디클로로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 606.1).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).
<< 실시예Example 10> (( 10> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3,4-) -4-((5- (1- (3,4- 디플루오로벤질Difluorobenzyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000057
Figure PCTKR2017004246-appb-I000057
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 In place of 3-bromobenzyl bromide used in step 1 of Example 1
3,4-디플루오로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 574.2).Except for using 3,4-difluorobenzyl bromide was carried out in the same manner as in Example 1 to prepare the target compound (LC / MS M + H: 574.2).
1H NMR (300 MHz, DMSO) δ 8.75 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.14 - 8.28 (m, 1H), 7.12 - 7.64 (m, 7H), 5.55 (s, 2H), 4.88 (s, 1H), 4.73 (s, 1H), 4.41 - 4.50 (m, 2H), 4.09 (dd, J = 9.3, 6.0 Hz, 2H), 3.92 - 4.04 (m, 2H), 3.72 - 3.80(m, 2H), 2.10 - 2.42 (m, 2H), 1.14 - 1.24 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 8.75 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.14-8.28 (m, 1H), 7.12-7.64 (m, 7H), 5.55 (s, 2H), 4.88 (s, 1H), 4.73 (s, 1H), 4.41-4.50 (m, 2H), 4.09 (dd, J = 9.3, 6.0 Hz, 2H), 3.92-4.04 (m, 2H ), 3.72-3.80 (m, 2H), 2.10-2.42 (m, 2H), 1.14-1.24 (m, 2H).
<< 실시예Example 11> (( 11> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(2,4-) -4-((5- (1- (2,4- 디플루오로벤질Difluorobenzyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000058
Figure PCTKR2017004246-appb-I000058
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 In place of 3-bromobenzyl bromide used in step 1 of Example 1
2,4-디플루오로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 574.2).Except for using 2,4-difluorobenzyl bromide, the same procedure as in Example 1 was carried out to obtain the target compound (LC / MS M + H: 574.2).
<< 실시예Example 12> (( 12> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((5-(1-(3--4-((5- (1- (3- 아이오도벤질Iodobenzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000059
Figure PCTKR2017004246-appb-I000059
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-아이오도벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 664.1).Except for using 3-iodobenzyl bromide in place of 3-bromobenzyl bromide used in Step 1 of Example 1, the target compound was prepared in the same manner as in Example 1 (LC / MS M + H : 664.1).
1H NMR (300 MHz, MeOD) δ 8.67 (s, 1H), 8.58 (s, 1H), 8.22 - 8.27 (m, 1H), 8.07 (s, 1H), 7.62 - 7.64 (m, 2H), 7.42 - 7.44 (m, 1H), 7.27 - 7.33 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 5.49 (s, 2H), 4.52 - 4.61 (m, 1H), 4.18 - 4.22 (m, 2H), 3.92 - 3.96 (m, 2H), 2.46 - 2.56 (m, 1H), 2.34 - 2.42 (m, 1H), 1.34 - 1.44 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.67 (s, 1H), 8.58 (s, 1H), 8.22-8.27 (m, 1H), 8.07 (s, 1H), 7.62-7.64 (m, 2H), 7.42 7.44 (m, 1H), 7.27-7.33 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 5.49 (s, 2H), 4.52- 4.61 (m, 1H), 4.18-4.22 (m, 2H), 3.92-3.96 (m, 2H), 2.46-2.56 (m, 1H), 2.34-2.42 (m, 1H), 1.34-1.44 (m, 1H ).
<< 실시예Example 13> (( 13> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3-) -4-((5- (1- (3- 시아노벤질Cyanobenzyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000060
Figure PCTKR2017004246-appb-I000060
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 In place of 3-bromobenzyl bromide used in step 1 of Example 1
3-시아노벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 563.2).Except for using 3-cyanobenzyl bromide, the same procedure as in Example 1 was carried out to obtain the target compound (LC / MS M + H: 563.2).
1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.64 (s, 1H), 8.29 - 8.23 (m, 1H), 7.70 - 7.58 (m, 2H), 7.50 - 7.41 (m, 2H), 7.27 - 7.38 (m, 4H), 5.44 (s, 2H), 4.87 (s, 2H), 4.31 (s, 2H), 3.99 (t, J = 6.0 Hz, 1H), 2.53 (s, 1H), 2.17 (s, 1H), 1.68 (s, 1H), 1.41 (d, J = 2.9 Hz, 2H). 1 H NMR (300 MHz, CDCl 3) δ 8.78 (s, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.64 (s, 1H), 8.29-8.23 (m, 1H), 7.70-7.58 (m , 2H), 7.50-7.41 (m, 2H), 7.27-7.38 (m, 4H), 5.44 (s, 2H), 4.87 (s, 2H), 4.31 (s, 2H), 3.99 (t, J = 6.0 Hz, 1H), 2.53 (s, 1H), 2.17 (s, 1H), 1.68 (s, 1H), 1.41 (d, J = 2.9 Hz, 2H).
<< 실시예Example 14> (( 14> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(2-) -4-((5- (1- (2- 플루오로벤질Fluorobenzyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000061
Figure PCTKR2017004246-appb-I000061
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 2-플루오로벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 556.2).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).
1H NMR (300 MHz, MeOD) δ 8.62 (s, 1H), 8.56 (s, 1H), 8.21 - 8.24 (m, 1H), 8.01 (s, 1H), 7.46 - 7.52 (m, 1H), 7.25 - 7.37 (m, 3H), 7.07 - 7.22 (m, 4H), 5.56 (s, 2H), 4.51 - 4.61 (m, 1H), 3.88 - 3.97 (m, 2H), 3.61 (d, J = 5.5 Hz, 2H), 2.40 - 2.56 (m, 2H), 2.12 - 2.21 (m, 2H), 1.32 - 1.41 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.62 (s, 1H), 8.56 (s, 1H), 8.21-8.24 (m, 1H), 8.01 (s, 1H), 7.46-7.52 (m, 1H), 7.25 -7.37 (m, 3H), 7.07-7.22 (m, 4H), 5.56 (s, 2H), 4.51-4.61 (m, 1H), 3.88-3.97 (m, 2H), 3.61 (d, J = 5.5 Hz , 2H), 2.40-2.56 (m, 2H), 2.12-2.21 (m, 2H), 1.32-1.41 (m, 1H).
<< 실시예Example 15> (( 15> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3,5-) -4-((5- (1- (3,5- 비스(트리플루오로메틸)벤질Bis (trifluoromethyl) benzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Preparation of) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000062
Figure PCTKR2017004246-appb-I000062
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 In place of 3-bromobenzyl bromide used in step 1 of Example 1
4-트리플루오로메틸싸이오벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 674.1).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).
1H NMR (300 MHz, MeOD) δ 8.70 (s, 1H), 8.58 (s, 1H), 8.25 - 8.28 (m, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.80 (s, 2H), 7.42 - 7.45 (m, 1H), 7.30 - 7.35 (m, 2H), 5.73 (s, 2H), 4.53 - 4.62 (m, 1H), 4.19 - 4.21 (m, 2H), 3.93 - 3.98 (m, 2H), 2.47 - 2.59 (m, 1H), 2.38 - 2.42 (m, 1H), 1.35 - 1.45 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.70 (s, 1H), 8.58 (s, 1H), 8.25-8.28 (m, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.80 (s , 2H), 7.42-7.45 (m, 1H), 7.30-7.35 (m, 2H), 5.73 (s, 2H), 4.53-4.62 (m, 1H), 4.19-4.21 (m, 2H), 3.93-3.98 (m, 2H), 2.47-2.59 (m, 1H), 2.38-2.42 (m, 1H), 1.35-1.45 (m, 1H).
<< 실시예Example 16> (( 16> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-(-4-( (트리플루오로메틸)싸이오(Trifluoromethyl) thio )벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 ) Benzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000063
Figure PCTKR2017004246-appb-I000063
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3,5-디트리플루오로메틸벤질 브로마이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 638.1).Except for using 3,5-ditrifluoromethylbenzyl bromide in place of 3-bromobenzyl bromide used in Step 1 of Example 1, the target compound was prepared in the same manner as in Example 1 (LC / MS M + H: 638.1).
<< 실시예Example 17> (( 17> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-([1,1'-) -4-((5- (1-([1,1'- 바이페닐Biphenyl ]-4-]-4- 일메틸Methyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000064
Figure PCTKR2017004246-appb-I000064
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 In place of 3-bromobenzyl bromide used in step 1 of Example 1
4-(브로모메틸)-1,1'-바이페닐을 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 614.20).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).
<< 실시예Example 18> (( 18> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((5-(1-((6--4-((5- (1-((6- 메틸피리딘Methylpyridine -2-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 -2-yl) methyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000065
Figure PCTKR2017004246-appb-I000065
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 In place of 3-bromobenzyl bromide used in step 1 of Example 1
2-(브로모메틸)-6-메틸피리딘을 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 553.2).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).
<< 실시예Example 19> (( 19> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((5-(1-((5-(-4-((5- (1-((5- ( 트리플루오로메틸Trifluoromethyl )퓨란_2-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트의 제조Preparation of furan_2-yl) methyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000066
Figure PCTKR2017004246-appb-I000066
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 2-(브로모메틸)-5-(트리플루오로메틸)퓨란을 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 596.1).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).
1H NMR (300 MHz, MeOD) δ 8.64 (s, 1H), 8.60 (s, 1H), 8.25 (d, J = 6.7 Hz, 1H), 8.06 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.30 - 7.36 (m, 2H), 6.92 (s, 1H), 6.55 (d, J = 3.3 Hz, 1H), 5.60 (s, 2H), 4.60 (d, J = 2.8 Hz, 2H), 4.18 - 4.30 (m, 2H), 4.07 (d, J = 5.5 Hz, 1H), 2.40 - 2.52 (m, 2H), 1.38 - 1.43 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.64 (s, 1H), 8.60 (s, 1H), 8.25 (d, J = 6.7 Hz, 1H), 8.06 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.30-7.36 (m, 2H), 6.92 (s, 1H), 6.55 (d, J = 3.3 Hz, 1H), 5.60 (s, 2H), 4.60 (d, J = 2.8 Hz, 2H ), 4.18-4.30 (m, 2H), 4.07 (d, J = 5.5 Hz, 1H), 2.40-2.52 (m, 2H), 1.38-1.43 (m, 1H).
<< 실시예Example 20> (( 20> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((5-(1-((5--4-((5- (1-((5- 메틸이소옥사졸Methylisoxazole -3-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 -3-yl) methyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이Sulfamay 트의 제조Manufacturing
Figure PCTKR2017004246-appb-I000067
Figure PCTKR2017004246-appb-I000067
상기 실시예 1의 단계 1에서 사용한 3-브로모벤질 브로마이드를 대신하여 3-(브로모메틸)-5-메틸이소옥사졸을 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 543.2).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).
<< 실시예Example 21> (( 21> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3-) -4-((5- (1- (3- 브로모벤질Bromobenzyl )-5-) -5- 메틸methyl -1H-인돌-3--1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000068
Figure PCTKR2017004246-appb-I000068
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-메틸-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 630.1).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).
1H NMR (300 MHz, MeOD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.46 (s, 2H), 7.32 - 7.21 (m, 4H), 7.07 - 7.16 (m, 3H), 5.54 (s, 2H), 4.62 (s, 1H), 4.23 (s, 2H), 3.98 (s, 2H), 2.48 (s, 3H), 2.46 (s, 1H), 1.87 (s, 1H), 1.41 (s, 1H). 1 H NMR (300 MHz, MeOD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.46 (s, 2H), 7.32-7.21 (m, 4H), 7.07-7.16 (m, 3H), 5.54 (s, 2H), 4.62 (s, 1H), 4.23 (s, 2H), 3.98 (s, 2H), 2.48 (s, 3H), 2.46 (s, 1H), 1.87 ( s, 1 H), 1.41 (s, 1 H).
<< 실시예Example 22> (( 22> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(3-) -4-((5- (1- (3- 브로모벤질Bromobenzyl )-5-) -5- 플루오로Fluoro -1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000069
Figure PCTKR2017004246-appb-I000069
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 634.1).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).
1H NMR (300 MHz, MeOD) δ 8.57 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.82 (dd, J = 9.6, 2.5 Hz, 1H), 7.26 - 7.37 (m, 4H), 7.05 - 7.17 (m, 2H), 6.96 (td, J = 9.0, 2.6 Hz, 1H), 5.40 (s, 2H), 4.42 - 4.49 (m, 1H), 4.08 - 4.11 (m, 2H), 3.84 - 3.86 (m, 2H), 2.35 - 2.47 (m, 1H), 2.24 - 2.33 (m, 1H), 1.27 - 1.33 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.57 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.82 (dd, J = 9.6, 2.5 Hz, 1H), 7.26-7.37 (m , 4H), 7.05-7.17 (m, 2H), 6.96 (td, J = 9.0, 2.6 Hz, 1H), 5.40 (s, 2H), 4.42-4.49 (m, 1H), 4.08-4.11 (m, 2H ), 3.84-3.86 (m, 2H), 2.35-2.47 (m, 1H), 2.24-2.33 (m, 1H), 1.27-1.33 (m, 1H).
<< 실시예Example 23> (( 23> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(5-() -4-((5- (5- ( 벤질옥시Benzyloxy )-1-(3-) -1- (3- 브로모벤질Bromobenzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트Sulfamate 의 제조Manufacture
Figure PCTKR2017004246-appb-I000070
Figure PCTKR2017004246-appb-I000070
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-(벤질옥시)-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 722.1).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).
<실시예 24> ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-피롤로[2,3-b]피리딘-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Example 24 ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl Preparation of Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000071
Figure PCTKR2017004246-appb-I000071
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 1H-피롤로[2,3-b]피리딘-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 617.1).Except for using 1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde in place of the 1H-indole-3-carbaldehyde used in Step 1 of Example 1, the same procedure as in Example 1 The desired compound was prepared (LC / MS M + H: 617.1).
1H NMR (300 MHz, MeOD) δ 8.69 (s, 1H), 8.56 - 8.61 (m, 2H), 8.43 (dd, J = 4.8, 1.5 Hz, 1H), 8.25 (s, 1H), 7.51 (s, 1H), 7.41 - 7.45 (m, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.20 - 7.29 (m, 2H), 5.59 (s, 2H), 4.53 - 4.60 (m, 1H), 4.17 - 4.22 (m, 2H), 3.91 - 3.98 (m, 2H), 2.46 - 2.58 (m, 1H), 2.34 - 2.43 (m, 1H), 1.36 - 1.43 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.69 (s, 1H), 8.56-8.61 (m, 2H), 8.43 (dd, J = 4.8, 1.5 Hz, 1H), 8.25 (s, 1H), 7.51 (s , 1H), 7.41-7.45 (m, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.20-7.29 (m, 2H), 5.59 (s, 2H), 4.53-4.60 (m, 1H ), 4.17-4.22 (m, 2H), 3.91-3.98 (m, 2H), 2.46-2.58 (m, 1H), 2.34-2.43 (m, 1H), 1.36-1.43 (m, 1H).
<< 실시예Example 25>  25> 메틸methyl 3-((3-(4-((( 3-((3- (4-((( 1R,2S,3R,4R1R, 2S, 3R, 4R )-2,3-) -2,3- 디하이드록시Dihydroxy -4-((-4-(( 설파모일Sulfa Mole 록시)메틸)사이클로펜틸)아미노)피리미딘-5-카보닐)-5-플루오로-1H-인돌-1-일)메틸)벤조에이트의 제조Preparation of oxy) methyl) cyclopentyl) amino) pyrimidine-5-carbonyl) -5-fluoro-1H-indol-1-yl) methyl) benzoate
Figure PCTKR2017004246-appb-I000072
Figure PCTKR2017004246-appb-I000072
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(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. Prepared (LC / MS M + H: 614.2).
1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.60 - 8.67 (m, 2H), 7.97 (d, J = 7.2 Hz, 2H), 7.85 - 7.92 (m, 1H), 7.71 (s, 1H), 7.14 - 7.20 (m, 3H), 6.96 - 7.04 (m, 1H), 5.41 (s, 2H), 4.20 - 4.38 (m, 3H), 4.06 (s, 1H), 3.95 (s, 1H), 3.88 (s, 3H), 3.65 (s, 1H), 2.49 (s, 2H), 1.46 - 1.55 (m, 1H). 1 H NMR (300 MHz, CDCl 3) δ 8.73 (s, 1H), 8.60-8.67 (m, 2H), 7.97 (d, J = 7.2 Hz, 2H), 7.85-7.92 (m, 1H), 7.71 (s , 1H), 7.14-7.20 (m, 3H), 6.96-7.04 (m, 1H), 5.41 (s, 2H), 4.20-4.38 (m, 3H), 4.06 (s, 1H), 3.95 (s, 1H ), 3.88 (s, 3H), 3.65 (s, 1H), 2.49 (s, 2H), 1.46-1.55 (m, 1H).
<< 실시예Example 26> (( 26> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(5-) -4-((5- (5- 플루오로Fluoro -1-(나프탈렌-2--1- (naphthalene-2- 일메틸Methyl )-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyridin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이Sulfamay 트의 제조Manufacturing
Figure PCTKR2017004246-appb-I000073
Figure PCTKR2017004246-appb-I000073
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 606.2).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: 606.2).
1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.58 - 8.67 (m, 2H), 7.91 - 7.98 (m, 1H), 7.69 - 7.86 (m, 4H), 7.61 (s, 1H), 7.47 - 7.52 (m, 2H), 7.19 - 7.35 (m, 2H), 7.02 - 7.09 (m, 1H), 5.53 (s, 2H), 5.18 - 5.23 (m, 2H), 4.29 (s, 2H), 4.07 (s, 1H), 3.96 (s, 1H), 3.65 (s, 1H), 2.51 (s, 2H), 1.25 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.58-8.67 (m, 2H), 7.91-7.98 (m, 1H), 7.69-7.86 (m, 4H), 7.61 (s, 1H ), 7.47-7.52 (m, 2H), 7.19-7.35 (m, 2H), 7.02-7.09 (m, 1H), 5.53 (s, 2H), 5.18-5.23 (m, 2H), 4.29 (s, 2H) ), 4.07 (s, 1H), 3.96 (s, 1H), 3.65 (s, 1H), 2.51 (s, 2H), 1.25 (s, 2H).
<< 실시예Example 27> (( 27> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(5-) -4-((5- (5- 플루오로Fluoro -1-(3--1- (3- 메틸벤질Methylbenzyl )-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyridin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000074
Figure PCTKR2017004246-appb-I000074
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 570.2).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: 570.2).
1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.65 (d, J = 4.2 Hz, 1H), 8.61 (s, 1H), 7.91 (dd, J = 9.8, 1.8 Hz, 1H), 7.67 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 - 7.04 (m, 1H), 6.90 - 6.98 (m, 2H), 5.31 (s, 2H), 4.28 (s, 2H), 4.06 (s, 1H), 3.96 (s, 1H), 3.64 (s, 1H), 2.49 (s, 2H), 2.30 (s, 3H), 1.34 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.72 (s, 1H), 8.65 (d, J = 4.2 Hz, 1H), 8.61 (s, 1H), 7.91 (dd, J = 9.8, 1.8 Hz, 1H) , 7.67 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00-7.04 (m, 1H), 6.90-6.98 (m, 2H), 5.31 (s, 2H), 4.28 (s, 2H), 4.06 (s, 1H), 3.96 (s, 1H), 3.64 (s, 1H), 2.49 (s, 2H), 2.30 (s, 3H), 1.34 (s, 1 H).
<< 실시예Example 28> (( 28> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(5-) -4-((5- (5- 플루오로Fluoro -1-(4--1- (4- 플루오로Fluoro -3--3- 메틸벤질Methylbenzyl )-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyridin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메Sulfame 이트의 제조Manufacture of wight
Figure PCTKR2017004246-appb-I000075
Figure PCTKR2017004246-appb-I000075
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 588.2).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: 588.2).
1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.68 (s, 1H), 7.18 (dd, J = 9.0, 4.0 Hz, 1H), 6.88 - 7.02 (m, 4H), 5.80 (s, 2H), 5.25 (s, 2H), 4.25 (s, 3H), 4.05 (s, 1H), 3.94 (s, 1H), 2.46 (s, 2H), 2.18 (s, 3H), 1.74 (s, 1H), 1.47 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.68 (s, 1H) , 7.18 (dd, J = 9.0, 4.0 Hz, 1H), 6.88-7.02 (m, 4H), 5.80 (s, 2H), 5.25 (s, 2H), 4.25 (s, 3H), 4.05 (s, 1H ), 3.94 (s, 1H), 2.46 (s, 2H), 2.18 (s, 3H), 1.74 (s, 1H), 1.47 (s, 1H).
<< 실시예Example 29> (( 29> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(5-) -4-((5- (5- 플루오로Fluoro -1-(4--1- (4- 플루오로Fluoro -3-메톡시벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Preparation of 3-methoxybenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000076
Figure PCTKR2017004246-appb-I000076
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(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: 604.2).
1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.63 (s, 1H), 7.92 (dd, J = 9.3, 2.5 Hz, 1H), 7.66 (s, 1H), 7.22 - 7.29 (m, 1H), 7.00 - 7.11 (m, 2H), 6.76 (dd, J = 7.6, 1.8 Hz, 1H), 6.63 - 6.70 (m, 1H), 5.32 (s, 2H), 4.30 (s, 2H), 4.06 (s, 1H), 3.93 - 4.00 (m, 1H), 3.82 (s, 3H), 2.51 (s, 2H), 1.45 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.63 (s, 1H), 7.92 (dd, J = 9.3, 2.5 Hz, 1H) , 7.66 (s, 1H), 7.22-7.29 (m, 1H), 7.00-7.11 (m, 2H), 6.76 (dd, J = 7.6, 1.8 Hz, 1H), 6.63-6.70 (m, 1H), 5.32 (s, 2H), 4.30 (s, 2H), 4.06 (s, 1H), 3.93-4.00 (m, 1H), 3.82 (s, 3H), 2.51 (s, 2H), 1.45 (s, 1H).
<< 실시예Example 30> ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(펜타플루오로-l6-설파닐)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조 30> ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (pentafluoro-16-sulfanyl) benzyl) -1H-indole-3-carbo Preparation of Nyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000077
Figure PCTKR2017004246-appb-I000077
상기 실시예 1의 단계 1에서 사용한 1H-인돌-3-카브알데하이드를 대신하여 5-플루오로-1H-인돌-3-카브알데하이드를 사용한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 682.1).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: 682.1).
1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.69 (d, J = 4.1 Hz, 1H), 8.63 (s, 1H), 7.92 (dd, J = 9.2, 2.7 Hz, 1H), 7.74 (s, 1H), 7.71 (s, 2H), 7.15 - 7.23 (m, 3H), 7.10 - 7.03 (m, 1H), 5.44 (s, 2H), 4.30 (s, 2H), 4.07 (s, 1H), 3.96 (s, 1H), 3.65 (s, 1H), 2.50 (s, 2H), 1.47 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.69 (d, J = 4.1 Hz, 1H), 8.63 (s, 1H), 7.92 (dd, J = 9.2, 2.7 Hz, 1H) , 7.74 (s, 1H), 7.71 (s, 2H), 7.15-7.23 (m, 3H), 7.10-7.03 (m, 1H), 5.44 (s, 2H), 4.30 (s, 2H), 4.07 (s , 1H), 3.96 (s, 1H), 3.65 (s, 1H), 2.50 (s, 2H), 1.47 (s, 1H).
<< 실시예Example 31> (( 31> (( 1R,2S,4R1R, 2S, 4R )-4-((5-(1-) -4-((5- (1- 벤질benzyl -1H-인돌-3--1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2-하이드로시싸이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2-hydrocyclocyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000078
Figure PCTKR2017004246-appb-I000078
단계 1: (1-벤질-1H-인돌-3-일)(4-(((1R,3R,4S)-3-(하이드로시메틸)-4-((트라이아이소프로실필릴)옥시)싸이클로펜틸)아미노)피리미딘-5-일)메탄온의 합성Step 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
25mL 둥근 바닥플라스크에 (1-벤질-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온 (70 mg, 0.22 mmol) 을 무수 n-BuOH에 녹인 후, DIPEA (64 mg, 0.49 mmol)와 2,2,2-트라이플루오로아세틸알데하이드 ((1R,2S,4R)-4-아미노-2-((트라이아이소프로필실릴)옥시)싸이클로펜틸)메탄올 (100 mg, 0.24 mmol) 을 적가하였다. 반응 혼합물을 105℃ 에서 3.5 시간 교반 하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피 (EA:HEX = 1:1)로 정제하여 흰색 고체의 화합물을 (20 mg, 18 %) 수득하였다.(1-benzyl-1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone (70 mg, 0.22 mmol) was dissolved in anhydrous n-BuOH in a 25 mL round bottom flask, followed by DIPEA (64 mg, 0.49 mmol) and 2,2,2-trifluoroacetylaldehyde ((1R, 2S, 4R) -4-amino-2-((triisopropylsilyl) oxy) cyclopentyl) methanol (100 mg, 0.24 mmol) was added dropwise. The reaction mixture was stirred at 105 ° C. for 3.5 hours. After completion of the reaction, the 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. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid compound (20 mg, 18%).
1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.63 (s, 1H), 7.60 (s, 1H), 7.38 - 7.26 (m, 7H), 7.16 - 7.13(m, 2H), 5.34 (s, 2H), 4.80 (s, 1H), 4.30(q, J = 6.2 Hz, 1H), 3.69(d, J = 5.9 Hz, 1H), 2.52 - 2.48(m, 1H), 2.25 - 2.16(m, 2H), 1.92 - 1.83 (m, 2H), 1.37 - 1.23(m, 2H), 1.05 (s, 20H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.67 (s, 1H), 8.63 (s, 1H), 7.60 (s, 1H), 7.38-7.26 (m, 7H), 7.16-7.13 (m, 2H), 5.34 (s, 2H), 4.80 (s, 1H), 4.30 (q, J = 6.2 Hz, 1H), 3.69 (d, J = 5.9 Hz, 1H), 2.52-2.48 (m, 1H), 2.25-2.16 (m, 2H), 1.92-1.83 (m, 2H), 1.37-1.23 (m, 2H), 1.05 (s, 20H).
단계 2: ((1R,2S,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2-하이드로시싸이클로펜틸)메틸설파메이트의 제조Step 2: ((1R, 2S, 4R) -4-((5- (1-benzyl-1H-indol-3-carbonyl) pyrimidin-4-yl) amino) -2-hydrocyclopentyl) methyl Preparation of Sulfamate
25mL 둥근 바닥플라스크에 (1-벤질-1H-인돌-3-일)(4-(((1R,3R,4S)-3-(하이드로시메틸)-4-((트라이아이소프로실필릴)옥시)싸이클로펜틸)아미노)피리미딘-5-일)메탄온 (20 mg, 0.03 mmol) 과 설파모일 클로라이드 (19 mg, 0.16 mmol) 을 무수 DMF에 녹이고, 상온에서 20시간 동안 반응 시킨다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피 (CH2Cl2:MeOH = 10:1)로 정제하여 옅은 노란색 고체의 화합물을 (13 mg, 75 %) 수득하였다.(1-benzyl-1H-indol-3-yl) (4-(((1R, 3R, 4S) -3- (hydroxymethyl) -4-((triisoprosilyl)) oxy in a 25 mL round bottom flask ) Cyclopentyl) amino) pyrimidin-5-yl) methanone (20 mg, 0.03 mmol) and sulfamoyl chloride (19 mg, 0.16 mmol) are dissolved in anhydrous DMF and reacted at room temperature for 20 hours. After completion of the reaction by TLC, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (CH 2 Cl 2: MeOH = 10: 1) to give a pale yellow solid compound (13 mg, 75%).
1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.66 (s, 1H), 8.60 (d, J = 6.91 Hz, 1H), 8.23 (d, J = 7.54, 1H), 7.64 (s, 1H), 7.40 - 7.29 (m, 5H), 7.20 - 7.18 (m, 2H), 5.50 (s, 2H), 5.41 (s, 2H), 4.79 (q, J = 6.91 Hz, 1H), 4.44 - 4.38 (m, 2H), 4.30 (dd, J = 10.06, 5.66 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.35 (m, 1H), 2.15 - 2.07 (m, 2H), 1.54 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.66 (s, 1H), 8.60 (d, J = 6.91 Hz, 1H), 8.23 (d, J = 7.54, 1H), 7.64 ( s, 1H), 7.40-7.29 (m, 5H), 7.20-7.18 (m, 2H), 5.50 (s, 2H), 5.41 (s, 2H), 4.79 (q, J = 6.91 Hz, 1H), 4.44 -4.38 (m, 2H), 4.30 (dd, J = 10.06, 5.66 Hz, 1H), 2.62-2.54 (m, 1H), 2.35 (m, 1H), 2.15-2.07 (m, 2H), 1.54 (s , 2H).
<< 실시예Example 32> (( 32> (( 1R,2R,3R,4R1R, 2R, 3R, 4R )-4-((5-(1-) -4-((5- (1- 벤질benzyl -1H-인돌-3--1H-indole-3- 카보닐Carbonyl )피리미딘-4-yl)아미노)-3-플루오로-2-하이드로시싸이클로펜틸)메틸 ) Pyrimidine-4-yl) amino) -3-fluoro-2-hydrocyclocyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000079
Figure PCTKR2017004246-appb-I000079
단계 1: (1-벤질-1H-인돌-3-일)(4-(((1R,2R,3R,4R)-2-플루오로-3-하이드록시-4-(하이드로시메틸)싸이클로펜틸)아미노)피리미딘-5-일)메탄온의 제조Step 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
상기 실시예 31의 단계 1에서 사용한 (1-벤질-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온을 대신하여 (1R,2R,3R,5R)-3-아미노-2-플루오로-5-(하이드록시메틸)싸이클로펜턴-1-올 하이드로클로라이드를 사용하는 것을 제외하고 실시예 31의 단계 1과 동일하게 수행하였다.(1R, 2R, 3R, 5R) -3- in place of (1-benzyl-1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone used in step 1 of Example 31 above The same procedure was followed as in Step 1 of Example 31, except that amino-2-fluoro-5- (hydroxymethyl) cyclopenten-1-ol hydrochloride was used.
1H NMR (300 MHz, CDCl3) δ 8.79 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 25.2 Hz, 2H), 8.33 - 8.23 (m, 1H), 7.61 (s, 1H), 7.29 - 7.01 (m, 10H), 5.38 - 5.19 (m, 2H), 4.30 - 4.10 (m, 1H), 3.78 (dd, J = 10.5, 5.4 Hz, 1H), 3.47 (s, 2H), 2.38 - 2.28 (m, 1H), 2.21 - 2.01 (m, 1H), 1.50 (q, J = 10.9 Hz, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.79 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 25.2 Hz, 2H), 8.33-8.23 (m, 1H), 7.61 (s, 1H) , 7.29-7.01 (m, 10H), 5.38-5.19 (m, 2H), 4.30-4.10 (m, 1H), 3.78 (dd, J = 10.5, 5.4 Hz, 1H), 3.47 (s, 2H), 2.38 2.28 (m, 1 H), 2.21-2.01 (m, 1 H), 1.50 (q, J = 10.9 Hz, 1 H).
단계 2: (1-벤질l-1H-인돌-3-일)(4-(((1R,2R,3R,4R)-3-((털트-뷰틸다이메틸실릴)옥시)-4-(털트-뷰틸다이메틸실릴)옥시)메틸)2-플루오로싸이클로펜틸)아미노)피리미딘-5-일)메탄온의 제조Step 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
(1-벤질-1H-인돌-3-일)(4-(((1R,2R,3R,4R)-2-플루오로-3-하이드록시-4-(하이드로시메틸)싸이클로펜틸)아미노)피리미딘-5-일)메탄온 (20 mg, 0.04 mmol) 과 이미다졸 (14 mg, 0.21 mmol) 을 무수 DMF에 녹인 후 TBSCl (19 mg, 0.13 mmol) 을 넣고 20 시간 동안 교반 하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피 (EA:HEX=1:1)로 정제하여 흰색 고체의 화합물을 (20 mg, 75 %) 수득하였다.(1-benzyl-1H-indol-3-yl) (4-(((1R, 2R, 3R, 4R) -2-fluoro-3-hydroxy-4- (hydroxymethyl) cyclopentyl) amino) Pyrimidin-5-yl) methanone (20 mg, 0.04 mmol) and imidazole (14 mg, 0.21 mmol) were dissolved in anhydrous DMF, and TBSCl (19 mg, 0.13 mmol) was added thereto and stirred for 20 hours. After completion of the reaction, the 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. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid compound (20 mg, 75%).
1H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 8.06 Hz, 1H), 8.67(2, 1H), 8.59 (s, 1H), 8.33 - 8.20 (m, 1H), 7.55 (s, 1H), 7.35 - 7.18 (m, 6H), 7.14 - 7.03 (m, 2H), 5.31 (s, 2H), 4.88 - 4.68 (m, 2H), 4.09 (ddd, J = 21.7, 5.1, 1.5 Hz, 1H), 3.67 - 3.49 (m, 2H), 2.33 - 2.24 (m 1H), 2.09 - 1.95 (m, 1H), 1.55 - 1.37 (m, 1H), 0.85 (d, J = 2.2 Hz, 18H), 0.06 (d, J = 1.4 Hz, 12H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.73 (d, J = 8.06 Hz, 1H), 8.67 (2, 1H), 8.59 (s, 1H), 8.33-8.20 (m, 1H), 7.55 (s, 1H), 7.35-7.18 (m, 6H), 7.14-7.03 (m, 2H), 5.31 (s, 2H), 4.88-4.68 (m, 2H), 4.09 (ddd, J = 21.7, 5.1, 1.5 Hz, 1H), 3.67-3.49 (m, 2H), 2.33-2.24 (m 1H), 2.09-1.95 (m, 1H), 1.55-1.37 (m, 1H), 0.85 (d, J = 2.2 Hz, 18H), 0.06 (d, J = 1.4 Hz, 12H).
단계 3: (1-벤질-1H-인돌-3-일)(4-(((1R,2R,3R,4R)-3-((털트-뷰틸다이메틸실릴)옥시)-2-플루오로-4-(하이드로시메틸)싸이클로펜틸)아미노)피리미딘-5-일)메탄온의 제조Step 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
(1-벤질l-1H-인돌-3-일)(4-(((1R,2R,3R,4R)-3-((털트-뷰틸다이메틸실릴)옥시)-4-(털트-뷰틸다이메틸실릴)옥시)메틸)2-플루오로싸이클로펜틸)아미노)피리미딘-5-일)메탄온 (10 mg, 0.01 mmol) 을 에탄올에 녹인 후 반응용기를 0℃로 냉각한 상태에서 1 % HCl을 적가한 후 상온에서 17 시간을 교반하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피 (CH2Cl2:MeOH=10:1)로 정제하여 흰색 고체의 화합물을 (10 mg, 60 %) 수득하였다.(1-benzyll-1H-indol-3-yl) (4-(((1R, 2R, 3R, 4R) -3-((tert-butyldimethylsilyl) oxy) -4- (talt-butyldi Methylsilyl) oxy) methyl) 2-fluorocyclopentyl) amino) pyrimidin-5-yl) methanone (10 mg, 0.01 mmol) was dissolved in ethanol and the reaction vessel was cooled to 0 ° C. in 1% HCl. Was added dropwise and stirred for 17 hours at room temperature. After completion of the reaction, the 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. The reaction mixture was purified by flash column chromatography (CH 2 Cl 2: MeOH = 10: 1) to give a white solid compound (10 mg, 60%).
1H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 7.7 Hz, 1H), 8.61 (s, 1H), 8.53 (s, 1H), 8.24 - 8.14 (m, 1H), 7.48 (s, 1H), 7.27 - 7.10 (m, 5H), 7.03 (d, J = 7.2Hz, 2H), 5.25 (s, 2H), 4.87 - 4.79 (m, 1H), 4.09 - 3.93 (m, 1H), 3.67 - 3.50 (m, 2H), 2.34 - 2.24 (m, 1H), 2.07 - 1.96 1.97 (m, 1H), 1.49 - 1.26 (m, 1H), 0.79 (s, 9H), - 0.12 (s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.73 (d, J = 7.7 Hz, 1H), 8.61 (s, 1H), 8.53 (s, 1H), 8.24-8.14 (m, 1H), 7.48 (s, 1H), 7.27-7.10 (m, 5H), 7.03 (d, J = 7.2 Hz, 2H), 5.25 (s, 2H), 4.87-4.79 (m, 1H), 4.09-3.93 (m, 1H), 3.67 -3.50 (m, 2H), 2.34-2.24 (m, 1H), 2.07-1.96 1.97 (m, 1H), 1.49-1.26 (m, 1H), 0.79 (s, 9H),-0.12 (s, 6H) .
단계 4: ((1R,2R,3R,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-3-플루오로-2-하이드로시싸이클로펜틸)메틸 설파메트의 제조Step 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
상기 실시예 31의 단계 2에서 사용한 (1-벤질-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온을 대신하여 (1-벤질-1H-인돌-3-일)(4-(((1R,2R,3R,4R)-3-((털트-뷰틸다이메틸실릴)옥시)-2-플루오로-4-(하이드로시메틸)싸이클로펜틸)아미노)피리미딘-5-일)메탄온를 사용하는 것을 제외하고 실시예 31의 단계 2와 동일하게 수행하였다.(1-benzyl-1H-indol-3-yl instead of (1-benzyl-1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone used in step 2 of Example 31 above ) (4-(((1R, 2R, 3R, 4R) -3-((Tlt-butyldimethylsilyl) oxy) -2-fluoro-4- (hydromethylmethyl) cyclopentyl) amino) pyrimidine- Same as step 2 of Example 31 except that 5-yl) methanone was used.
1H NMR (300 MHz, MeOD) δ 8.74 (d, J = 5.31, 1H), 8.64 (d, J = 6.87, 1H), 8.26 (q, J = 3.12, 1H), 8.07 (d, J = 2.50, 1H), 7.48 (m, 1H), 7.38 - 7.26 (6H, m), 5.54 (s, 2H), 4.33 - 4.10 (m, 4H), 2.56-2.48 (m, 2H), 1.86-1.57 (m, 1H), 1.00 (4H, m), 0.97 - 0.90 (m, 2H). 1 H NMR (300 MHz, MeOD) δ 8.74 (d, J = 5.31, 1H), 8.64 (d, J = 6.87, 1H), 8.26 (q, J = 3.12, 1H), 8.07 (d, J = 2.50 , 1H), 7.48 (m, 1H), 7.38-7.26 (6H, m), 5.54 (s, 2H), 4.33-4.10 (m, 4H), 2.56-2.48 (m, 2H), 1.86-1.57 (m , 1H), 1.00 (4H, m), 0.97-0.90 (m, 2H).
<< 실시예Example 33> (( 33> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-(2-) -4-((5- (1- (2- 뷰틴Butin -1-일)-1H-인돌-3--1-yl) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-다이하이드로시싸이클로펜틸) ) Pyrimidin-4-yl) amino) -2,3-dihydrocyclocyclopentyl) 메틸methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000080
Figure PCTKR2017004246-appb-I000080
단계 1: (1-(2-뷰틴-1-일)-5-플루오로-1H-인돌-3-일)(3-(((3aS,4R,6R,6aR)-6-(((털트-뷰틸다이메틸실릴)옥시)메틸)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)아미노)피라진-2-일)메탄온의 제조Step 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
(3-(((3aS,4R,6R,6aR)-6-(((털트-뷰틸다이메틸실릴)옥시)메틸)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타-4H-[d][1,3]다이옥솔-4-일)아미노)피라진-2-일)(5-플루오로-1H-인돌-3-일)메탄온 (20 mg, 0.04 mmol) 을 무수 DMF 용매에 녹인 후, Cs2CO3 (23 mg, 0.07 mmol)을 넣었다. 1-브로모-2-뷰틴(7.6 mg, 0.05 mmol)을 천천히 적가 한 후 4 시간 교반하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피(EA:HEX = 1:1)로 정제하여 흰색 고체의 화합물을 (26 mg, 92 %) 수득하였다.(3-(((3aS, 4R, 6R, 6aR) -6-(((talt-butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-4H-cyclopenta-4H- [d ] [1,3] dioxol-4-yl) amino) pyrazin-2-yl) (5-fluoro-1H-indol-3-yl) methanone (20 mg, 0.04 mmol) was dissolved in anhydrous DMF solvent. Then Cs 2 CO 3 (23 mg, 0.07 mmol) was added. 1-bromo-2-butyne (7.6 mg, 0.05 mmol) was slowly added dropwise and stirred for 4 hours. After completion of the reaction by TLC, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid compound (26 mg, 92%).
1H NMR (300 MHz, CDCl3) δ 8.72 (t, J = 10.4 Hz, 3H), 8.07 - 7.94 (m, 1H), 7.77 (s, 1H), 7.41 (dd, J = 8.9, 4.2 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 4.89 (q, J = 2.5 Hz, 2H), 4.73 - 4.59 (m, 1H), 4.60 - 4.48 (m, 2H), 3.73 (q, J = 10.2 Hz, 2H), 2.97 (s, 1H), 2.90 (s, 1H), 2.55 - 2.32 (m, 2H), 1.88 (t, J = 2.4 Hz, 3H), 1.71 (d, J = 12.8 Hz, 1H), 1.33 (s, 3H), 1.27 (t, J = 7.1 Hz, 0H), 0.92 (s, 9H), 0.09 (d, J = 1.5 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.72 (t, J = 10.4 Hz, 3H), 8.07-7.94 (m, 1H), 7.77 (s, 1H), 7.41 (dd, J = 8.9, 4.2 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 4.89 (q, J = 2.5 Hz, 2H), 4.73-4.59 (m, 1H), 4.60-4.48 (m, 2H), 3.73 (q, J = 10.2 Hz, 2H), 2.97 (s, 1H), 2.90 (s, 1H), 2.55-2.32 (m, 2H), 1.88 (t, J = 2.4 Hz, 3H), 1.71 (d, J = 12.8 Hz , 1H), 1.33 (s, 3H), 1.27 (t, J = 7.1 Hz, 0H), 0.92 (s, 9H), 0.09 (d, J = 1.5 Hz, 6H).
단계 2: (1-(2-뷰틴-1-일)-5-플루오로-1H-인돌-3-일)(3-(((3aS,4R,6R,6aR)-6-하이드로시메틸-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)아미노)피라진-2-일)메탄온의 제조Step 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
(1-(2-뷰틴-1-일)-5-플루오로-1H-인돌-3-일)(3-(((3aS,4R,6R,6aR)-6-(((털트-뷰틸다이메틸실릴)옥시)메틸)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)아미노)피라진-2-일)메탄온 (26 mg, 0.04 mmol) 을 무수 DMF에 녹인 후, 얼음물을 이용하여 반응 용기를 0℃로 만든다. TBAF (57 mg, 0.21 mmol) 를 천천히 적가 한후 0℃에서 1시간 동안 교반 하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압하에서 용매를 제거하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피 (EA:HEX = 1:1)로 정제하여 흰색 고체의 화합물을 (20 mg, 97 %) 수득하였다.(1- (2-Butyn-1-yl) -5-fluoro-1H-indol-3-yl) (3-(((3aS, 4R, 6R, 6aR) -6-(((Tlt-Butyldi Methylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrazin-2-yl) methanone (26 mg, 0.04 mmol) is dissolved in anhydrous DMF, and then the reaction vessel is brought to 0 DEG C using ice water. TBAF (57 mg, 0.21 mmol) was slowly added dropwise and stirred at 0 ° C. for 1 hour. After completion of the reaction, the 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. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid compound (20 mg, 97%).
1H NMR (300 MHz, CDCl3) δ 8.89 (d, J = 7.9 Hz, 1H), 8.71 (d, J = 3.7 Hz, 2H), 8.07 - 7.91 (m, 2H), 7.75 (s, 1H), 7.41 (dd, J = 8.9, 4.2 Hz, 1H), 7.13 (t, J = 9.0 Hz, 1H), 4.88 (q, J = 2.5 Hz, 2H), 4.84 - 4.71 (m, 1H), 4.69 - 4.52 (m, 2H), 3.86 (dd, J = 10.2, 4.9 Hz, 1H), 3.78 (dd, J = 10.2, 5.4 Hz, 1H), 2.97 (s, 2H), 2.90 (s, 2H), 2.70 - 2.54 (m, 1H), 2.45 (t, J = 5.4 Hz, 1H), 2.28 (s, 1H), 1.87 (t, J = 2.4 Hz, 3H), 1.76 (s, 1H), 1.68 (d, J = 13.7 Hz, 1H), 1.33 (s, 3H), 1.31 - 1.24 (m, 1H).1 H NMR (300 MHz, CDCl 3) δ 8.89 (d, J = 7.9 Hz, 1H), 8.71 (d, J = 3.7 Hz, 2H), 8.07-7.91 (m, 2H), 7.75 (s, 1H), 7.41 (dd, J = 8.9, 4.2 Hz, 1H), 7.13 (t, J = 9.0 Hz, 1H), 4.88 (q, J = 2.5 Hz, 2H), 4.84-4.71 (m, 1H), 4.69-4.52 ( m, 2H), 3.86 (dd, J = 10.2, 4.9 Hz, 1H), 3.78 (dd, J = 10.2, 5.4 Hz, 1H), 2.97 (s, 2H), 2.90 (s, 2H), 2.70-2.54 (m, 1H), 2.45 (t, J = 5.4 Hz, 1H), 2.28 (s, 1H), 1.87 (t, J = 2.4 Hz, 3H), 1.76 (s, 1H), 1.68 (d, J = 13.7 Hz, 1H), 1.33 (s, 3H), 1.31-1.24 (m, 1H).
단계 3: ((3aR,4R,6R,6aS)-6-((3-(1-(2-뷰틴-1일)5-플루오로-1H-인돌-3-카보닐)피라진-2-일)아미노)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)메틸 설파메이트의 제조Step 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
상기 실시예 1의 단계 2에서 사용한 (1-벤질-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온을 대신하여 (1-(2-뷰틴-1-일)-5-플루오로-1H-인돌-3-일)(3-(((3aS,4R,6R,6aR)-6-하이드로시메틸-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)아미노)피라진-2-일)메탄온을 사용하는 것을 제외하고 실시예 1의 단계 2와 동일하게 수행하였다.(1- (2-butyn-1-yl) in place of (1-benzyl-1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone used in step 2 of Example 1 above -5-Fluoro-1H-indol-3-yl) (3-(((3aS, 4R, 6R, 6aR) -6-hydromethylmethyl-2,2-dimethyltetrahydro-4H-cyclopenta [d ] [1,3] dioxol-4-yl) amino) pyrazin-2-yl) methanone was carried out in the same manner as in step 2 of Example 1, except that.
1H NMR (300 MHz, CDCl3) δ 8.72 (d, J = 5.1 Hz, 4H), 8.60 (d, J = 7.1 Hz, 2H), 8.01 (s, 4H), 7.93 - 7.76 (m, 4H), 7.41 (dd, J = 9.0, 4.2 Hz, 2H), 7.11 (t, J = 9.0 Hz, 2H), 5.91 (s, 1H), 4.88 (q, J = 2.4 Hz, 4H), 4.63 (d, J = 21.4 Hz, 6H), 4.34 - 4.25 (m, 4H), 2.96 (s, 14H), 2.88 (s, 14H), 2.66 (d, J = 11.2 Hz, 4H), 2.05 (d, J = 7.6 Hz, 2H), 1.86 (t, J = 2.4 Hz, 6H), 1.82 - 1.66 (m, 3H), 1.28 (d, J = 15.9 Hz, 8H), 0.88 (t, J = 6.4 Hz, 1H). 1 H NMR (300 MHz, CDCl 3) δ 8.72 (d, J = 5.1 Hz, 4H), 8.60 (d, J = 7.1 Hz, 2H), 8.01 (s, 4H), 7.93 - 7.76 (m, 4H) , 7.41 (dd, J = 9.0, 4.2 Hz, 2H), 7.11 (t, J = 9.0 Hz, 2H), 5.91 (s, 1H), 4.88 (q, J = 2.4 Hz, 4H), 4.63 (d, J = 21.4 Hz, 6H), 4.34-4.25 (m, 4H), 2.96 (s, 14H), 2.88 (s, 14H), 2.66 (d, J = 11.2 Hz, 4H), 2.05 (d, J = 7.6 Hz, 2H), 1.86 (t, J = 2.4 Hz, 6H), 1.82-1.66 (m, 3H), 1.28 (d, J = 15.9 Hz, 8H), 0.88 (t, J = 6.4 Hz, 1H).
단계 4: ((1R,2R,3S,4R)-4-((3-(1-(2-뷰틴-1일)5-플루오로-1H-인돌-3-카보닐)피라진-2-일)아미노)-2,3-다이하이드록시싸이클로펜틸)메틸 설파메이트의 제조Step 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
((3aR,4R,6R,6aS)-6-((3-(1-(2-뷰틴-1일)5-플루오로-1H-인돌-3-카보닐)피라진-2-일)아미노)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)메틸 설파메이트 (19 mg, 0.03 mmol) 를 MeOH에 녹인 후 얼음물을 이용하여 반응 용기를 0℃로 냉각하였다. TfOH:H2O = 1:9를 1ml를 적가하고 0℃ 에서 30분 교반 한 후 상온에서 18 시간 교반 하였다. NaHCO3을 사용하여 반응을 종결 시킨후 에틸아세테이트를 사용하여 추출한 뒤, MgSO4를 사용하여 건조하였다. 반응 혼합물을 플레쉬컬럼크로마토그래피 통해 (CH2Cl2:MeOH = 10:1) 로 정제하여 노란색 고체의 화합물을 (13 mg, 73 %) 수득하였다.((3aR, 4R, 6R, 6aS) -6-((3- (1- (2-butyn-1yl) 5-fluoro-1H-indol-3-carbonyl) pyrazin-2-yl) amino) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate (19 mg, 0.03 mmol) was dissolved in MeOH, and then the reaction vessel was prepared using ice water. Was cooled to 0 ° C. 1 ml of TfOH: H 2 O = 1: 9 was added dropwise and stirred at 0 ° C. for 30 minutes, followed by stirring at room temperature for 18 hours. The reaction was terminated with NaHCO3, extracted with ethyl acetate, and dried over MgSO4. The reaction mixture was purified by flash column chromatography (CH 2 Cl 2 : MeOH = 10: 1) to give a yellow solid compound (13 mg, 73%).
1H NMR (300 MHz, MeOD) δ 8.67 (s, 1H), 8.61 (s, 1H), 8.04 (s, 1H), 7.97 (d, J = 9.95 Hz, 1H), 7.62 (q, J = 8.93 Hz, 1H), 7.15 (t, J = 8.93 Hz, 1H), 5.06 (s, 2H), 4.58 (q, J = 7.65 Hz, 1H), 4.24 (d, J = 5.36 Hz, 2H), 4.02-3.97 (m, 2H), 2.59 - 2.42 (m, 2H), 1.83 (s, 3H), 1.48 - 1.38 (m, 1H), 1.29 (s, 1H). 1 H NMR (300 MHz, MeOD) δ 8.67 (s, 1H), 8.61 (s, 1H), 8.04 (s, 1H), 7.97 (d, J = 9.95 Hz, 1H), 7.62 (q, J = 8.93 Hz, 1H), 7.15 (t, J = 8.93 Hz, 1H), 5.06 (s, 2H), 4.58 (q, J = 7.65 Hz, 1H), 4.24 (d, J = 5.36 Hz, 2H), 4.02- 3.97 (m, 2H), 2.59-2.42 (m, 2H), 1.83 (s, 3H), 1.48-1.38 (m, 1H), 1.29 (s, 1H).
<< 실시예Example 34> (( 34> (( 1R,2R,3S,4S1R, 2R, 3S, 4S )-4-((5-(1-((E)-2-) -4-((5- (1-((E) -2- 뷰텐Buten -1-일)-1H-인돌-3--1-yl) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-다이하이드로시싸이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydrocyclocyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000081
Figure PCTKR2017004246-appb-I000081
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 (E)-1-2-브로모뷰텐을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다.Preparation of the target compound in the same manner as in Example 33, except for using (E) -1-2-bromobutene in place of 1-bromo-2-butyne used in Step 1 of Example 33 It was.
(LC/MS M+H: 502.2);(LC / MS M + H: 502.2);
1H NMR (300 MHz, MeOD) δ 8.65 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 9.64 Hz, 1H), 7.56 - 7.48(m, 1H), 7.15 - 7.09 (m, 1H), 5.84 - 5.66 (m, 2H), 4.84 (d, J = 5.78 Hz, 2H), 4.58 (q, J = 8.26 Hz, 1H), 4.22 (d, J = 4.96, 2H), 3.96 (q, J = 4.96 Hz, 2H), 2.59 - 2.37 (m, 2H), 1.88 (d, J = 7.45 Hz, 1H), 1.73 (d, J = 5.98 Hz, 2H), 1.45 - 1.35 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.65 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 9.64 Hz, 1H), 7.56-7.48 (m, 1H ), 7.15-7.09 (m, 1H), 5.84-5.66 (m, 2H), 4.84 (d, J = 5.78 Hz, 2H), 4.58 (q, J = 8.26 Hz, 1H), 4.22 (d, J = 4.96, 2H), 3.96 (q, J = 4.96 Hz, 2H), 2.59-2.37 (m, 2H), 1.88 (d, J = 7.45 Hz, 1H), 1.73 (d, J = 5.98 Hz, 2H), 1.45-1.35 (m, 1 H).
<< 실시예Example 35> (( 35> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 다이하이드록시Dihydroxy -4-((5-(1-(2--4-((5- (1- (2- 메톡시에틸Methoxyethyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000082
Figure PCTKR2017004246-appb-I000082
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴을 대신하여 (1-브로모-2-메톡시에테인을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다.Preparation of the target compound in the same manner as in Example 33, except that (1-bromo-2-methoxyethane was used instead of 1-bromo-2-butyne used in Step 1 of Example 33 It was.
(LC/MS M+H: 506.2);(LC / MS M + H: 506.2);
1H NMR (300 MHz, MeOD) δ 8.54 (d, J = 6.3 Hz, 1H), 7.92 (s, 1H), 7.83 (dd, J = 9.7, 2.6 Hz, 1H), 7.49 (dd, J = 9.0, 4.3 Hz, 1H), 7.09 - 6.96 (m, 1H), 4.52 (d, J = 6.2 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.15 - 3.93 (m, 2H), 3.86 (d, J = 4.8 Hz, 2H), 3.65 (t, J = 5.0 Hz, 2H), 2.41 (m, 2H), 2.06 (s, 3H), 1.39 - 1.21 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.54 (d, J = 6.3 Hz, 1H), 7.92 (s, 1H), 7.83 (dd, J = 9.7, 2.6 Hz, 1H), 7.49 (dd, J = 9.0 , 4.3 Hz, 1H), 7.09-6.96 (m, 1H), 4.52 (d, J = 6.2 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.15-3.93 (m, 2H), 3.86 (d, J = 4.8 Hz, 2H), 3.65 (t, J = 5.0 Hz, 2H), 2.41 (m, 2H), 2.06 (s, 3H), 1.39-1.21 (m, 1H).
<< 실시예Example 36> (( 36> (( 1R,2R,3S,4S1R, 2R, 3S, 4S )-2,3-) -2,3- 다이하이드록시Dihydroxy -4-((5-(1--4-((5- (1- 아이소뷰틸Isobutyl -1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000083
Figure PCTKR2017004246-appb-I000083
단계 1: 1-(2-뷰틴-1-일)-1H-인돌-3-카발데하이드의 제조Step 1: Preparation of 1- (2-butyn-1-yl) -1H-indole-3-carbaldehyde
1H-인돌-3-카발데하이드(500 mg, 3.1 mmol)를 무수 DMF 용매에 녹인 후, Cs2CO3 (1.1 g, 3.41 mmol) 을 넣었다. 1-브로모-2-메틸프로페인 (1.06 g, 6.2 mmol)을 천천히 적가 한 후 4 시간 교반 하였다. 반응이 종결된 것을 TLC로 확인한 후, 에틸아세테이트로 추출하고, 유기층을 무수 MgSO4로 건조시키고 감압 하에서 용매를 제거하였다. 반응 혼합물을 플레쉬 컬럼크로마토그래피 (EA:HEX = 1:1)로 정제하여 흰색 고체의 화합물을 (380 mg, 57 %) 수득하였다.1H-indole-3-carbaldehyde (500 mg, 3.1 mmol) was dissolved in anhydrous DMF solvent, and then Cs 2 CO 3 (1.1 g, 3.41 mmol) was added thereto. 1-bromo-2-methylpropane (1.06 g, 6.2 mmol) was slowly added dropwise and stirred for 4 hours. After completion of the reaction by TLC, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid compound (380 mg, 57%).
1H NMR (300 MHz, MeOD) δ 10.02 (s, 1H), 8.33 (dd, J = 7.0, 3.8 Hz, 1H), 7.69 (s, 1H), 7.45 - 7.25 (m, 3H), 3.98 (d, J = 7.3 Hz, 2H), 2.33 - 2.24 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H). 1 H NMR (300 MHz, MeOD) δ 10.02 (s, 1H), 8.33 (dd, J = 7.0, 3.8 Hz, 1H), 7.69 (s, 1H), 7.45-7.25 (m, 3H), 3.98 (d , J = 7.3 Hz, 2H), 2.33-2.24 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H).
단계 2: ((4-클로로피리미딘-5-일)(1-아이소뷰틸-1H-인돌-3-일)메탄올의 제조Step 2: Preparation of ((4-chloropyrimidin-5-yl) (1-isobutyl-1H-indol-3-yl) methanol
50ml 2구 둥근 바닥플라스크에 4-클로로-5-아이오도피리미딘 (350 mg, 1.49 mmol) 을 첨가하고 THF (3.0ml) 에 녹여 -78℃에서 교반하였다. 여기에 n-BuLi (95 mg, 1.49 mmol) 를 천천히 적가하고 30분 동안 반응시킨다. THF (3.0ml) 에 녹인 1-(2-뷰틴-1-일)-1H-인돌-3-카발데하이드(150 mg, 0.74 mmol) 을 천천히 첨가한 뒤, 0℃ 에서 2시간 동안 반응시킨다. 반응 종료 후, 포화 NH4Cl을 사용하여 반응을 종료하고, EA 를 사용하여 추출한 뒤, MgSO4를 사용하여 건조하였다. 반응 혼합물을 플레쉬 컬럼크로마토그래피 통해 (EA:HEX = 1:1) 분리, 정제하여 노란색 고체의 생성물 (80 mg, 34 %) 을 수득하였다.4-chloro-5-iodopyrimidine (350 mg, 1.49 mmol) was added to a 50 ml two-necked round bottom flask, dissolved in THF (3.0 ml) and stirred at -78 ° C. N-BuLi (95 mg, 1.49 mmol) was slowly added dropwise thereto and reacted for 30 minutes. 1- (2-butyn-1-yl) -1H-indole-3-carbaldehyde (150 mg, 0.74 mmol) dissolved in THF (3.0 ml) was slowly added, followed by reaction at 0 ° C. for 2 hours. After completion of the reaction, the reaction was terminated using saturated NH 4 Cl, extracted using EA, and dried using MgSO 4 . The reaction mixture was separated and purified through flash column chromatography (EA: HEX = 1: 1) to give the product as a yellow solid (80 mg, 34%).
1H NMR (300 MHz, MeOD) δ 9.14 (s, 1H), 8.87 (s, 1H), 7.69 (dd, J = 8.0, 1.0 Hz, 1H), 7.40 - 7.08 (m, 4H), 6.89 (s, 1H), 6.37 (d, J = 3.1 Hz, 1H), 3.87 (d, J = 7.3 Hz, 2H), 2.99 (d, J = 3.4 Hz, 1H), 2.25 - 2.02 (m, 1H), 0.91 (d, J = 6.7, Hz, 6H). 1 H NMR (300 MHz, MeOD ) δ 9.14 (s, 1H), 8.87 (s, 1H), 7.69 (dd, J = 8.0, 1.0 Hz, 1H), 7.40 - 7.08 (m, 4H), 6.89 (s , 1H), 6.37 (d, J = 3.1 Hz, 1H), 3.87 (d, J = 7.3 Hz, 2H), 2.99 (d, J = 3.4 Hz, 1H), 2.25-2.02 (m, 1H), 0.91 (d, J = 6.7, Hz, 6H).
단계 3: (4-클로로피리미딘-5-일)(1-아이소뷰틸-1H-인돌-3-일)메탄온의 제조Step 3: Preparation of (4-Chloropyrimidin-5-yl) (1-isobutyl-1H-indol-3-yl) methanone
20ml 바이알에 ((4-클로로피리미딘-5-일)(1-아이소뷰틸-1H-인돌-3-일)메탄올 (80 mg, 0.24 mmol), MnO2 (215 mg, 2.47 mmol) 및 CH2Cl2 (5.0ml)를 첨가하고 상온에서 12시간 동안 반응시킨다. 반응 종료 후, 셀라이트로 여과하여 MC로 여러 번 씻어준 후, 농축하였다. 실리카겔 컬럼 크로마토그래피 (EA:Hex = 1:1) 조건으로 분리, 정제하여 노란색 고체의 생성물(75 mg, 92 %)을 수득하였다.In a 20 ml vial ((4-chloropyrimidin-5-yl) (1-isobutyl-1H-indol-3-yl) methanol (80 mg, 0.24 mmol), MnO 2 (215 mg, 2.47 mmol) and CH 2 Cl 2 (5.0 ml) was added and reacted at room temperature for 12 hours After completion of the reaction, the mixture was filtered through Celite, washed several times with MC, and then concentrated, silica gel column chromatography (EA: Hex = 1: 1) Isolation and purification under conditions gave the product as a yellow solid (75 mg, 92%).
1H NMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 8.78 (s, 1H), 8.46 - 8.34 (m, 1H), 7.49 - 7.07 (m, 4H), 3.96 (d, J = 7.4 Hz, 2H), 2.35 - 2.08 (m, 1H), 0.93 (d, J = 6.7 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.11 (s, 1H), 8.78 (s, 1H), 8.46-8.34 (m, 1H), 7.49-7.07 (m, 4H), 3.96 (d, J = 7.4 Hz, 2H), 2.35-2.08 (m, 1H), 0.93 (d, J = 6.7 Hz, 6H).
단계 4: (4-(((3aS,4S,6R,6aR)-6-(하이드록시메틸)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)아미노)피리미딘-5-일)(1-아이소뷰틸-1H-인돌-3-일)메탄온의 제조Step 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
상기 실시예 1의 단계 1에서 사용한 (1-벤질-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온을 대신하여 ((3aR,4R,6R,6aS)-6-아미노-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]dioxol-4-yl)메탄올을 사용하는 것을 제외하고 실시예 1의 단계 1과 동일하게 수행하였다. ((3aR, 4R, 6R, 6aS) -6 instead of (1-benzyl-1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone used in Step 1 of Example 1 above -Amino-2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methanol was carried out in the same manner as in Step 1 of Example 1.
1H NMR (300 MHz, CDCl3) δ 8.88 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 7.2 Hz, 2H), 8.35 - 8.21 (m, 1H), 7.46 - 7.25 (m, 3H), 4.75 (dd, J = 7.8, 5.3 Hz, 1H), 4.63 - 4.54 (m, 2H), 3.96 (d, J = 7.3 Hz, 2H), 3.85 - 3.71 (m, 2H), 2.64 - 2.54 (m, 1H), 2.45 - 2.39 (m, 2H) 2.34 - 2.13 (m, 2H), 1.71 - 1.63 (m, 1H), 1.53 (s, 3H), 1.31 (s, 3H), 0.95 (d, J = 6.6 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.88 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 7.2 Hz, 2H), 8.35-8.21 (m, 1H), 7.46-7.25 (m, 3H), 4.75 (dd, J = 7.8, 5.3 Hz, 1H), 4.63-4.54 (m, 2H), 3.96 (d, J = 7.3 Hz, 2H), 3.85-3.71 (m, 2H), 2.64-2.54 (m, 1H), 2.45-2.39 (m, 2H) 2.34-2.13 (m, 2H), 1.71-1.63 (m, 1H), 1.53 (s, 3H), 1.31 (s, 3H), 0.95 (d, J = 6.6 Hz, 6H).
단계 5 : ((3aR,4R,6S,6aS)-6-((5-(1-(2-뷰틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)메틸 설파메이트의 제조 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
상기 실시예 1의 단계 2에서 사용한 (1-벤질-1H-인돌-3-일)(4-클로로피리미딘-5-일)메탄온을 대신하여 (4-(((3aS,4S,6R,6aR)-6-(하이드록시메틸)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)아미노)피리미딘-5-일)(1-아이소뷰틸-1H-인돌-3-일)메탄온을 사용하는 것을 제외하고 실시예 1의 단계 2와 동일하게 수행하였다.In place of (1-benzyl-1H-indol-3-yl) (4-chloropyrimidin-5-yl) methanone used in step 2 of Example 1, (4-(((3aS, 4S, 6R, 6aR) -6- (hydroxymethyl) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrimidin-5-yl) (1 -Isobutyl-1H-indol-3-yl) methanone was carried out in the same manner as in Example 1 except that step 2 was used.
1H NMR (300 MHz, CDCl3) δ 8.67 (d, J = 6.21 Hz, 1H), 8.21 (d, J = 10. 5 Hz, 1H), 7.6 (s, 1H), 7.47 - 7.27 (m, 3H), 6.30 (s, 2H), 4.74 - 4.54 (m, 3H), 4.29 (d, J = 5.4 Hz, 2H), 4.00 (d, J = 7.4 Hz, 2H), 2.72 - 2.59 (m, 2H), 1.53 (s, 3H), 1.31 (s, 3H), 0.97 (d, J = 6.6, Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.67 (d, J = 6.21 Hz, 1H), 8.21 (d, J = 10 Hz, 1H), 7.6 (s, 1H), 7.47-7.27 (m, 3H), 6.30 (s, 2H), 4.74-4.54 (m, 3H), 4.29 (d, J = 5.4 Hz, 2H), 4.00 (d, J = 7.4 Hz, 2H), 2.72-2.59 (m, 2H ), 1.53 (s, 3H), 1.31 (s, 3H), 0.97 (d, J = 6.6, Hz, 6H).
단계 6: ((1R,2R,3S,4S)-2,3-다이하이드록시-4-((5-(1-아이소뷰틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트의 제조Step 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
((3aR,4R,6S,6aS)-6-((5-(1-(2-뷰틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,2-다이메틸테트라하이드로-4H-싸이클로펜타[d][1,3]다이옥솔-4-일)메틸 설파메이트 (22 mg, 0.04 mmol)을 MeOH에 녹인 후 얼음물을 이용하여 반응 용기를 0℃로 냉각하였다. TfOH:H2O=1:9를 1ml를 적가하고 0℃에서 30분 교반한 후 상온에서 18 시간 교반하였다. NaHCO3을 사용하여 반응을 종결시킨 후 에틸아세테이트를 사용하여 추출한 뒤, MgSO4를 사용하여 건조하였다. 실리카겔 컬럼 크로마토그래피를 통해 (CH2Cl2:MeOH=10:1)로 정제하여 노란색 고체의 화합물을 (18 mg, 82 %) 수득하였다.((3aR, 4R, 6S, 6aS) -6-((5- (1- (2-butyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,2-dimethyl Tetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate (22 mg, 0.04 mmol) was dissolved in MeOH and the reaction vessel was cooled to 0 ° C. using ice water. 1 ml of TfOH: H 2 O = 1: 9 was added dropwise, stirred for 30 minutes at 0 ° C., and stirred for 18 hours at room temperature.The reaction was terminated with NaHCO 3 , extracted with ethyl acetate, and then extracted with MgSO 4 . Purification by silica gel column chromatography (CH 2 Cl 2 : MeOH = 10: 1) afforded a compound as a yellow solid (18 mg, 82%).
(LC/MS M+H: 504.2);(LC / MS M + H: 504.2);
1H NMR (300 MHz, MeOD) δ 8.61 (d, J = 10.8 Hz, 2H), 8.30 -8.18 (m, 1H), 7.92 (s, 1H), 7.60 -7.50 (m, 1H), 7.38 - 7.26 (m, 2H), 4.57 (td, J = 8.1, 5.7 Hz, 1H), 4.29 - 4.15 (m, 2H), 4.20 - 4.04 (m, 2H), 4.03 - 3.90 (m, 2H), 2.58 - 2.48 (m, 1H), 2.46 - 2.34 (m, 1H), 2.40 - 2.16 (m, 1H), 2.03 (s, 1H), 1.48 - 1.19 (m, 1H), 0.95 (d, J = 6.7 Hz, 6H). 1 H NMR (300 MHz, MeOD) δ 8.61 (d, J = 10.8 Hz, 2H), 8.30 -8.18 (m, 1H), 7.92 (s, 1H), 7.60 -7.50 (m, 1H), 7.38-7.26 (m, 2H), 4.57 (td, J = 8.1, 5.7 Hz, 1H), 4.29-4.15 (m, 2H), 4.20-4.04 (m, 2H), 4.03-3.90 (m, 2H), 2.58-2.48 (m, 1H), 2.46-2.34 (m, 1H), 2.40-2.16 (m, 1H), 2.03 (s, 1H), 1.48-1.19 (m, 1H), 0.95 (d, J = 6.7 Hz, 6H ).
<< 실시예Example 37> (( 37> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(1-() -4-((5- (1- ( 싸이클로헥실메틸Cyclohexylmethyl )-1H-인돌-3-) -1H-indole-3- 카보닐Carbonyl )피리미딘-4-일)아미노)-2,3-다이하이드록시싸이클로펜틸)메틸 ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000084
Figure PCTKR2017004246-appb-I000084
상기 실시예 36의 단계 1에서 사용한 1-브로모-2-메틸프로페인(mg, mmol)를 대신하여 브로모메틸)싸이클로헥세인을 사용하는 것을 제외하고, 실시예 36과 동일하게 수행하여 목적 화합물을 제조하였다.Except for using the bromomethyl) cyclohexane instead of 1-bromo-2-methylpropane (mg, mmol) used in step 1 of Example 36, the purpose of The compound was prepared.
(LC/MS M+H: 544.2);(LC / MS M + H: 544.2);
1H NMR (300 MHz, MeOD) δ 8.46 (t, J = 6.9 Hz, 2H), 8.08 (d, J = 7.5 Hz, 1H), 7.80 - 7.68 (m, 1H), 7.39 (t, J = 7.0 Hz, 1H), 7.16 (dt, J = 17.9, 7.4 Hz, 2H), 4.48 - 4.35 (m, 1H), 4.16 - 3.99 (m, 2H), 4.02 - 3.93 (m, 3H), 3.84 (td, J = 4.6, 3.9, 2.0 Hz, 2H), 2.38 - 2.20 (m, 2H), 1.90 (s, 2H), 1.84 - 1.69 )m ,1H), 1.55 - 1.16 (m, 6H), 1.21 - 0.91 (m, 8H). 1 H NMR (300 MHz, MeOD) δ 8.46 (t, J = 6.9 Hz, 2H), 8.08 (d, J = 7.5 Hz, 1H), 7.80-7.68 (m, 1H), 7.39 (t, J = 7.0 Hz, 1H), 7.16 (dt, J = 17.9, 7.4 Hz, 2H), 4.48-4.35 (m, 1H), 4.16-3.99 (m, 2H), 4.02-3.93 (m, 3H), 3.84 (td, J = 4.6, 3.9, 2.0 Hz, 2H), 2.38-2.20 (m, 2H), 1.90 (s, 2H), 1.84-1.69) m, 1H), 1.55-1.16 (m, 6H), 1.21-0.91 ( m, 8H).
<< 실시예Example 38> (( 38> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 다이하이드록시Dihydroxy -4-((5-(1-(-4-((5- (1- ( 몰포리노에틸Morpholinoethyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000085
Figure PCTKR2017004246-appb-I000085
상기 실시예 36의 단계 1에서 사용한 1-브로모-2-메틸프로페인를 대신하여 4-(2-클로로에틸)몰포린을 사용하는 것을 제외하고, 실시예 36과 동일하게 수행하여 목적 화합물을 제조하였다.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.
(LC/MS M+H: 561.2);(LC / MS M + H: 561.2);
1H NMR (300 MHz, MeOD) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.28 - 8.19 (m, 1H), 8.00 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.39 - 7.27 (m, 2H), 4.63 - 4.49 (m, 1H), 4.41 (t, J = 6.2 Hz, 2H), 4.29 - 4.05 (m, 2H), 4.03 - 3.90 (m, 2H), 3.67 (t, J = 4.7 Hz, 4H), 2.83 (t, J = 6.2 Hz, 2H), 2.54 (q, J = 4.4 Hz, 4H), 2.52 - 2.32 (m, 1H), 1.45 - 1.35 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.28-8.19 (m, 1H), 8.00 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H ), 7.39-7.27 (m, 2H), 4.63-4.49 (m, 1H), 4.41 (t, J = 6.2 Hz, 2H), 4.29-4.05 (m, 2H), 4.03-3.90 (m, 2H), 3.67 (t, J = 4.7 Hz, 4H), 2.83 (t, J = 6.2 Hz, 2H), 2.54 (q, J = 4.4 Hz, 4H), 2.52-2.32 (m, 1H), 1.45-1.35 (m , 1H).
<< 실시예Example 39> (( 39> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-2,3-) -2,3- 다이하이드록시Dihydroxy -4-((5-(1-(3--4-((5- (1- (3- 몰포리노벤질Morpholinobenzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl 설파메이트의Sulfamate 제조 Produce
Figure PCTKR2017004246-appb-I000086
Figure PCTKR2017004246-appb-I000086
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 4-(3-(클로로메틸)페닐)몰포린을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다.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.
(LC/MS M+H: 623.2)(LC / MS M + H: 623.2)
1H NMR (300 MHz, MeOD) δ 8.66 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.92 (dd, J = 9.7, 2.6 Hz, 1H), 7.47 (dd, J = 9.0, 4.3 Hz, 1H), 7.22 (dd, J = 9.0, 7.5 Hz, 1H), 7.06 (td, J = 9.1, 2.6 Hz, 1H), 6.90 (d, J = 6.1 Hz, 2H), 6.73 (d, J = 7.5 Hz, 1H), 5.45 (s, 2H), 4.57 (q, J = 8.0 Hz, 1H), 4.29 - 4.12 (m, 2H), 4.03 - 3.86 (m, 2H), 3.85 - 3.75 (m, 4H), 3.23 - 2.98 (m, 4H), 2.61 - 2.32 (m, 2H), 1.45 - 1.37 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.66 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.92 (dd, J = 9.7, 2.6 Hz, 1H), 7.47 (dd, J = 9.0, 4.3 Hz, 1H), 7.22 (dd, J = 9.0, 7.5 Hz, 1H), 7.06 (td, J = 9.1, 2.6 Hz, 1H), 6.90 (d, J = 6.1 Hz, 2H), 6.73 (d, J = 7.5 Hz, 1H), 5.45 (s, 2H), 4.57 (q, J = 8.0 Hz, 1H), 4.29-4.12 (m, 2H), 4.03-3.86 (m, 2H), 3.85- 3.75 (m, 4H), 3.23-2.98 (m, 4H), 2.61-2.32 (m, 2H), 1.45-1.37 (m, 1H).
<< 실시예Example 40> ((1R,2R,3S,4R)-4-((5-(1-((6-(1H-피라졸-1-일)피리딘-3-일)메틸)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조 40> ((1R, 2R, 3S, 4R) -4-((5- (1-((6- (1H-pyrazol-1-yl) pyridin-3-yl) methyl) -5-fluoro- Preparation of 1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000087
Figure PCTKR2017004246-appb-I000087
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 5-(클로로메틸)-2-(1H-피라졸-1-일)피리딘을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다.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.
(LC/MS M+H: 623.2);(LC / MS M + H: 623.2);
1H NMR (300 MHz, CDCl3 + MeOD) δ 8.56 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.70 - 7.26 (m, 4H), 7.20 - 7.17 (m, 1H), 6.86 - 6.80 (m, 1H), 6.22 (m, 1H), 5.31 (br s, 2H), 4.50 - 4.38 (m, 3H), 3.98 (m, 2H), 2.96 - 2.88 (m, 2H), 2.33 (m, 1H), 1.56 - 1.20 (m, 2H), 1.19 - 1.06 (m, 3H), 1.00 (s, 1H).1 H NMR (300 MHz, CDCl3 + MeOD) δ 8.56 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.70-7.26 ( m, 4H), 7.20-7.17 (m, 1H), 6.86-6.80 (m, 1H), 6.22 (m, 1H), 5.31 (br s, 2H), 4.50-4.38 (m, 3H), 3.98 (m , 2H), 2.96-2.88 (m, 2H), 2.33 (m, 1H), 1.56-1.20 (m, 2H), 1.19-1.06 (m, 3H), 1.00 (s, 1H).
<< 실시예Example 41> ((1R,2R,3S,4R)-4-((5-(1-((6-브로모벤조퓨란-3-일)메틸)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조 41> ((1R, 2R, 3S, 4R) -4-((5- (1-((6-bromobenzofuran-3-yl) methyl) -5-fluoro-1H-indole-3-carbo Preparation of Nyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000088
Figure PCTKR2017004246-appb-I000088
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 6-브로모-3-(클로로메틸)벤조퓨란을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다.Except for using 6-bromo-3- (chloromethyl) benzofuran in place of 1-bromo-2-butyne used in step 1 of Example 33, the target compound was carried out in the same manner as in Example 33 Was prepared.
(LC/MS M+H: 674.1);(LC / MS M + H: 674.1);
1H NMR (300 MHz, CDCl3 + MeOD) δ 8.80 (br s, 1H), 8.67 (br s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.87 - 7.84 (d, J = 9.7 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.21 - 7.01 (m, 4H), 5.66 (br s, 2H), 4.65 - 4.58 (m, 3H), 4.25 (br s, 2H), 2.56-2.48 (m, 2H), 1.86-1.57 (m, 1H), 1.27 - 1.22 (4H, m), 0.97 - 0.90 (m, 2H). 1 H NMR (300 MHz, CDCl 3 + MeOD) δ 8.80 (br s, 1H), 8.67 (br s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.87-7.84 (d, J = 9.7 Hz, 1H), 7.62-7.56 (m, 2H), 7.21-7.01 (m, 4H), 5.66 (br s, 2H), 4.65-4.58 (m, 3H), 4.25 (br s, 2H), 2.56-2.48 (m, 2H), 1.86-1.57 (m, 1H), 1.27-1.22 (4H, m), 0.97-0.90 (m, 2H).
<< 실시예Example 42> ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(메틸설포닐)-3-니트로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조 42> ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (methylsulfonyl) -3-nitrobenzyl) -1H-indole-3-carbonyl Preparation of Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000089
Figure PCTKR2017004246-appb-I000089
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 4-(클로로메틸)-1-(메틸설포닐)-2-니트로벤젠을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 679.1).Except for using 4- (chloromethyl) -1- (methylsulfonyl) -2-nitrobenzene in place of the 1-bromo-2-butyne used in Step 1 of Example 33, The same procedure was followed to prepare the target compound (LC / MS M + H: 679.1).
<< 실시예Example 43> (( 43> (( 1R,2R,3S,4R1R, 2R, 3S, 4R )-4-((5-(5-) -4-((5- (5- 플루오로Fluoro -1-(3-(-1- (3- ( 메틸설폰아미도Methylsulfonamido )) 벤질benzyl )-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Preparation of) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000090
Figure PCTKR2017004246-appb-I000090
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 N-(3-(클로로메틸)페닐)메탄설폰아미드를 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 649.1).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).
<실시예 44> ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(N-메틸설파모일)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트의 제조Example 44 ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (N-methylsulfamoyl) benzyl) -1H-indole-3-carbo Preparation of Nyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000091
Figure PCTKR2017004246-appb-I000091
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 4-(클로로메틸)-N-메틸벤젠설폰아미드를 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다(LC/MS M+H: 649.1).Except for using 4- (chloromethyl) -N-methylbenzenesulfonamide in place of 1-bromo-2-butyne used in Step 1 of Example 33, and was carried out in the same manner as in Example 33, to obtain the target compound. Was prepared (LC / MS M + H: 649.1).
<< 실시예Example 45> ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(2-메틸-3-(트리플루오로메틸)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3,-다이하이드로시싸이클로펜틸)메틸 설파메이트 45> ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (2-methyl-3- (trifluoromethyl) benzyl) -1H-indole-3-carbo Yl) pyrimidin-4-yl) amino) -2,3, -dihydrocyclocyclopentyl) methyl sulfamate
Figure PCTKR2017004246-appb-I000092
Figure PCTKR2017004246-appb-I000092
상기 실시예 33의 단계 1에서 사용한 1-브로모-2-뷰틴를 대신하여 1-(클로로메틸)-2-메틸-3-(트리플루오로메틸)벤젠을 사용하는 것을 제외하고, 실시예 33과 동일하게 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, MeOD) δ 8.78 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.04 (dd, J = 9.5, 2.6 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = 9.0, 4.2 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.12 (td, J = 9.1, 2.7 Hz, 1H), 6.87 (d, J = 7.8 Hz, 2H), 5.68 (s, 2H), 4.27 - 4.15 (m, 2H), 4.15 - 3.96 (m, 2H), 3.69 - 3.55 (m, 2H), 2.48 (m, 4H), 1.59 - 1.44 (m, 1H). 1 H NMR (300 MHz, MeOD) δ 8.78 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.04 (dd, J = 9.5, 2.6 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = 9.0, 4.2 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.12 (td, J = 9.1, 2.7 Hz, 1H), 6.87 (d , J = 7.8 Hz, 2H), 5.68 (s, 2H), 4.27-4.15 (m, 2H), 4.15-3.96 (m, 2H), 3.69-3.55 (m, 2H), 2.48 (m, 4H), 1.59-1.44 (m, 1 H).
하기 표 1에 실시예 1-45에서 제조한 화합물의 화학구조식을 정리하여 나타내었다.Table 1 below shows the chemical structural formulas of the compounds prepared in Examples 1-45.
실시예Example 구조식constitutional formula 실시예Example 구조식constitutional formula
1One
Figure PCTKR2017004246-appb-I000093
Figure PCTKR2017004246-appb-I000093
 		2424
Figure PCTKR2017004246-appb-I000094
Figure PCTKR2017004246-appb-I000094
22
Figure PCTKR2017004246-appb-I000095
Figure PCTKR2017004246-appb-I000095
 		2525
Figure PCTKR2017004246-appb-I000096
Figure PCTKR2017004246-appb-I000096
33
Figure PCTKR2017004246-appb-I000097
Figure PCTKR2017004246-appb-I000097
 		2626
Figure PCTKR2017004246-appb-I000098
Figure PCTKR2017004246-appb-I000098
44
Figure PCTKR2017004246-appb-I000099
Figure PCTKR2017004246-appb-I000099
 		2727
Figure PCTKR2017004246-appb-I000100
Figure PCTKR2017004246-appb-I000100
55
Figure PCTKR2017004246-appb-I000101
Figure PCTKR2017004246-appb-I000101
 		2828
Figure PCTKR2017004246-appb-I000102
Figure PCTKR2017004246-appb-I000102
66
Figure PCTKR2017004246-appb-I000103
Figure PCTKR2017004246-appb-I000103
 		2929
Figure PCTKR2017004246-appb-I000104
Figure PCTKR2017004246-appb-I000104
77
Figure PCTKR2017004246-appb-I000105
Figure PCTKR2017004246-appb-I000105
 		3030
Figure PCTKR2017004246-appb-I000106
Figure PCTKR2017004246-appb-I000106
88
Figure PCTKR2017004246-appb-I000107
Figure PCTKR2017004246-appb-I000107
 		3131
Figure PCTKR2017004246-appb-I000108
Figure PCTKR2017004246-appb-I000108
99
Figure PCTKR2017004246-appb-I000109
Figure PCTKR2017004246-appb-I000109
 		3232
Figure PCTKR2017004246-appb-I000110
Figure PCTKR2017004246-appb-I000110
1010
Figure PCTKR2017004246-appb-I000111
Figure PCTKR2017004246-appb-I000111
 		3333
Figure PCTKR2017004246-appb-I000112
Figure PCTKR2017004246-appb-I000112
1111
Figure PCTKR2017004246-appb-I000113
Figure PCTKR2017004246-appb-I000113
 		3434
Figure PCTKR2017004246-appb-I000114
Figure PCTKR2017004246-appb-I000114
1212
Figure PCTKR2017004246-appb-I000115
Figure PCTKR2017004246-appb-I000115
 		3535
Figure PCTKR2017004246-appb-I000116
Figure PCTKR2017004246-appb-I000116
1313
Figure PCTKR2017004246-appb-I000117
Figure PCTKR2017004246-appb-I000117
 		3636
Figure PCTKR2017004246-appb-I000118
Figure PCTKR2017004246-appb-I000118
1414
Figure PCTKR2017004246-appb-I000119
Figure PCTKR2017004246-appb-I000119
 		3737
Figure PCTKR2017004246-appb-I000120
Figure PCTKR2017004246-appb-I000120
1515
Figure PCTKR2017004246-appb-I000121
Figure PCTKR2017004246-appb-I000121
 		3838
Figure PCTKR2017004246-appb-I000122
Figure PCTKR2017004246-appb-I000122
1616
Figure PCTKR2017004246-appb-I000123
Figure PCTKR2017004246-appb-I000123
 		3939
Figure PCTKR2017004246-appb-I000124
Figure PCTKR2017004246-appb-I000124
1717
Figure PCTKR2017004246-appb-I000125
Figure PCTKR2017004246-appb-I000125
 		4040
Figure PCTKR2017004246-appb-I000126
Figure PCTKR2017004246-appb-I000126
1818
Figure PCTKR2017004246-appb-I000127
Figure PCTKR2017004246-appb-I000127
 		4141
Figure PCTKR2017004246-appb-I000128
Figure PCTKR2017004246-appb-I000128
1919
Figure PCTKR2017004246-appb-I000129
Figure PCTKR2017004246-appb-I000129
 		4242
Figure PCTKR2017004246-appb-I000130
Figure PCTKR2017004246-appb-I000130
2020
Figure PCTKR2017004246-appb-I000131
Figure PCTKR2017004246-appb-I000131
 		4343
Figure PCTKR2017004246-appb-I000132
Figure PCTKR2017004246-appb-I000132
2121
Figure PCTKR2017004246-appb-I000133
Figure PCTKR2017004246-appb-I000133
 		4444
Figure PCTKR2017004246-appb-I000134
Figure PCTKR2017004246-appb-I000134
2222
Figure PCTKR2017004246-appb-I000135
Figure PCTKR2017004246-appb-I000135
 		4545
Figure PCTKR2017004246-appb-I000136
Figure PCTKR2017004246-appb-I000136
2323
Figure PCTKR2017004246-appb-I000137
Figure PCTKR2017004246-appb-I000137
<실험예 1> 세포성장저해 실험Experimental Example 1 Cell Growth Inhibition Experiment
본 발명에 따른 헤테로고리 화합물의 암세포 성장 저해 평가를 하기 위해, 하기와 같이 실험하였다.In order to evaluate the inhibition of cancer cell growth of the heterocyclic compound according to the present invention, the following experiments were carried out.
구체적으로, ATCC에서 구입한 인간 유래 유방암세포(HCT-116, THP-1)를 10%의 소태아혈청이 들어있는 RPMI배지에서 배양하였다. 배양된 유방암세포를 2% 트립신으로 세포를 용기에서 분리하여 개별 세포로 만든 후, 세포 개수 측정기로 1ml당 세포 개수를 측정하였다. 투명 96웰에 세포를 3,000 세포/웰/100 ul양으로 주입하고 18시간 동안 배양하여 안정화시킨다. 여기에 DMSO에 녹인 본 발명의 실시예 화합물을 20 uM, 10 uM, 5 uM, 2.5 uM, 1.25 uM, 0.625 uM, 0.3125 uM로 처리하였다. 이때 DMSO의 농도는 세포 배지의 0.1%를 넘지 않게 하였다. 같은 비율로 DMSO만을 처리한 샘플을 대조군으로 하였다. 상기 실시예 화합물을 세포에 48시간 동안 처리하고, 48시간 후, 기존 배양액을 없애주고 20 mM, 10 mM, 5 mM, 2.5 mM, 1.25 mM, 0.625 mM, 0.3125 mM의 농도로 DMSO에 녹인 실시예 화합물을 배양배지에 1000배 희석하여 웰에 200 ul씩 주입하였다. 24시간 동안 추가로 배양하고, 세포성장을 측정하였다. 세포성장은 세포 개수 측정 키트-8(Dojindo, CK04-13)를 사용하여 측정하였다. 상기 세포에 CCK-8용액을 10 ul 추가하여 37℃에서 2시간 동안 반응시킨 뒤, 흡광 측정장비를 이용하여 450nm에서 흡광도를 측정하였다. 이때, 세포성장 저해도 계산식은 다음과 같다. Specifically, human-derived breast cancer cells (HCT-116, THP-1) 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. At this time, 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.
(%)저해= 100 - (실시예 화합물 처리군의 흡광도/대조군의 흡광도) X 100(%) Inhibition = 100-(absorbance of the example compound treatment group / absorbance of the control group) X 100
상기 실험을 통해 얻어진 실험값을 하기 표 2에 나타내었다.The experimental values obtained through the above experiments are shown in Table 2 below.
실시예Example LD50(μM)LD 50 (μM)
HCT116HCT116 THP1THP1
1One 0.9340.934 0.2230.223
33 0.22770.2277 ＜0.03<0.03
44 0.78970.7897 0.60020.6002
55 0.45570.4557 ＜0.03<0.03
66 1.2371.237 1.2841.284
77 0.43060.4306 ＜0.03<0.03
88 1.8011.801 1.4261.426
99 0.64290.6429 0.66190.6619
1010 2.2762.276 1.8081.808
1111 1.4811.481 1.5571.557
1212 0.5870.587 0.1630.163
1313 15.13115.131 13.17113.171
1414 3.1213.121 1.0021.002
1515 4.1214.121 2.7812.781
1818 0.41340.4134 0.05530.0553
1919 2.0142.014 0.8130.813
2222 1.0091.009 0.8960.896
2424 2.0142.014 0.8130.813
표 2의 결과 및 본 실험예를 수행하여 나타난 바로는, 본 발명에 따른 실시예 1-45 화합물은 모두 인간 유래 유방암세포(HCT-116, THP-1)에 대하여 마이크로몰 또는 나노몰의 단위 농도로 우수하게 암세포 성장을 저해하는 것으로 확인된다.As shown in the results of Table 2 and the present experimental example, 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.
따라서, 본 발명에 따른 헤테로고리 화합물은 암세포의 성장을 저해할 수 있는 것으로 확인되는 바, 암의 개선, 예방 또는 치료용 약학적 조성물, 또는 건강기능식품 조성물로 유용하게 사용될 수 있다.Therefore, 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.
<실험예 2> SAE(Sumo Activating Enzyme) 억제 활성 평가Experimental Example 2 Evaluation of Inhibitory Activity of Sum Activating Enzyme (SAE)
본 발명에 따른 헤테로고리 화합물의 SAE 억제 활성을 평가하기 위해, 하기와 같이 실험하였다.In order to evaluate the SAE inhibitory activity of the heterocyclic compounds according to the present invention, the following experiments were carried out.
생체 내 수모화 분석 키트(in vitro sumoylation assay kit, SA-001)와 sumo-1 His-tag(Enzo, BML-UW9195)를 사용하였다. 음성 대조군은 Reagent A 2 ul, sumo-1 His-tag 1 ug 및 Reagent C 1 ul을 DW로 총 20 ul가 되도록 맞추어 주었다. 양성 대조군 및 샘플은 Reagent A 2 ul, sumo-1 His-tag 1 ug, Reagent C 1 ul 및 Reagent D 1 ul을 DW로 총 19 ul가 되도록 맞추어 주었다. 양성 대조군은 DW로 1 ul, 처리군에는 20 X 샘플(DW에 희석) 1 ul를 주입하여 37℃에서 2시간 동안 반응시킨다. 반응이 종결된 후, HTRF방법으로 검출하기 위해 항 6HIS-Eu 크립테이트(cisbio, 61HI2KLA) 및 항 GST-d2(cisbio, 61GSTDLA)을 사용하였다. PBS에 0.1% BSA 및 0.5% 트윈20을 주입하여 만든 용액을 웰에 주입하고, 항 6HIS-Eu 0.2 ul 및 항 GST-d2 0.2 ul를 흰색 384 웰에 주입하여 준비하였다. 37℃에서 1시간 동안 반응시키고, .반응이 끝난 반응 용액을 1ul씩 3웰 반복하여 주입한 후, HRTRF 측정 장비인 I3 (분자 소자)를 사용하여 HTRF를 측정하였으며, 상기 실험 결과값을 하기 표 3에 나타내었다.In vivo sumoylation assay kit (SA-001) and sumo-1 His-tag (Enzo, BML-UW9195) were used. As a negative control, 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. After the reaction was terminated, anti 6HIS-Eu cryptate (cisbio, 61HI2KLA) and anti GST-d2 (cisbio, 61GSTDLA) were used for detection by the HTRF method. 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.
실시예Example SAE[IC50(μM)]SAE [IC 50 (μM)]
1One 0.100.10
22 1.701.70
33 0.120.12
44 0.460.46
55 1.651.65
66 3.183.18
77 0.040.04
88 1.601.60
1010 3.483.48
1111 0.030.03
1212 0.470.47
1414 2.882.88
1818 2.212.21
1919 1.291.29
2222 0.530.53
2424 0.6610.661
2727 0.680.68
2828 1.721.72
3131 0.560.56
3232 1.841.84
3434 1.861.86
3737 1.651.65
3939 >10> 10
4545 0.990.99
표 3의 결과 및 본 실험예를 수행하여 나타난 바로는, 본 발명에 따른 실시예 1-45 화합물은 모두 마이크로몰 또는 나노몰 단위의 농도로 우수하게 SAE 활성을 저해할 수 있는 것으로 확인된다.As shown in the results of Table 3 and the present experimental example, it is confirmed that the compounds of Examples 1-45 according to the present invention can inhibit SAE activity with excellent concentrations in micromolar or nanomolar units.
따라서, 본 발명에 따른 헤테로고리 화합물은 SAE 활성을 마이크로몰 또는 나노몰 단위의 농도로 우수하게 저해할 수 있는 바, 본 발명의 화합물은 암의 개선, 예방 또는 치료용 약학적 조성물, 또는 건강기능식품 조성물로 유용하게 사용될 수 있다.Therefore, 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.
<실험예 3> NAE(NEDD8-Activating Enzyme) 억제 활성 평가Experimental Example 3 Evaluation of Inhibitory Activity of NEDD8-Activating Enzyme (NAE)
본 발명에 따른 헤테로고리 화합물의 NAE 억제 활성을 평가하기 위해, 하기와 같이 실험하였다.In order to evaluate the NAE inhibitory activity of the heterocyclic compounds according to the present invention, the following experiments were carried out.
NAE 효소 활성은 시간분해 형광에너지 전달 방법 (time-resolved fluorescence energy transfer assay)을 이용하여 측정한다. 우선 50 μl 효소반응액 (50 mM HEPES (시그마), pH7.5, 0.05% BSA (시그마), 5 mM MgCl2 (시그마), 20 uM ATP (시그마), 250 uM glutathione (시그마))에 10 nM Ubc12-GST (Ubiquigent사), 75 nM NEDD8-Flag (Bostonbiochem사), 0.3 nM NAE 효소 (Enzo사)를 넣고 384 well plate에 실온에서 90분간 반응시킨 다음 25 ul 반응중지용액 (0.1 M HEPES (시그마), pH 7.5, 0.05% tween20 (시그마), 20 mM EDTA (시그마), 410 mM KF (시그마), 0.53 nM antiGST-d2 항체 (Cisbio사), 0.53 nM antiFLAG-cryptate 항체 (Cisbio사))를 넣고 실온에서 2시간 반응시킨 다음 형광측정기로 측정한다. NAE enzyme activity is measured using a time-resolved fluorescence energy transfer assay. 10 nM Ubc12 in 50 μl 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)). pH 7.5, 0.05% tween20 (Sigma), 20 mM EDTA (Sigma), 410 mM KF (Sigma), 0.53 nM antiGST-d2 Antibody (Cisbio), 0.53 nM antiFLAG-cryptate Antibody (Cisbio) After reacting for 2 hours at fluorescence measurement.
실시예Example NAE[IC50(μM)]NAE [IC 50 (μM)]
33 0.0050.005
44 0.0190.019
55 0.0910.091
66 0.0120.012
77 0.0220.022
99 0.0370.037
1010 0.020.02
1111 0.0080.008
2222 0.00090.0009
2626 0.1410.141
2828 0.0150.015
3030 0.0100.010
3131 0.00060.0006
3939 0.0130.013
4545 0.1120.112
표 4의 결과 및 본 실험예를 수행하여 나타난 바로는, 본 발명에 따른 실시예 1-45 화합물은 모두 마이크로몰 또는 나노몰 단위의 농도로 우수하게 NAE 활성을 저해할 수 있는 것으로 확인된다.As shown in the results of Table 4 and the present experimental example, it was confirmed that the compounds of Examples 1-45 according to the present invention can inhibit NAE activity excellently in the concentration of micromolar or nanomolar units.
따라서, 본 발명에 따른 헤테로고리 화합물은 NAE 활성을 마이크로몰 또는 나노몰 단위의 농도로 우수하게 저해할 수 있는 바, 본 발명의 화합물은 암의 개선, 예방 또는 치료용 약학적 조성물, 또는 건강기능식품 조성물로 유용하게 사용될 수 있다.Therefore, 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.
본 발명에 따른 헤테로고리 화합물은 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme)를 나노몰 단위의 농도로 우수하게 저해할 수 있어, NAE 또는 SAE 관련 질환 예를 들어 암의 개선, 예방 또는 치료를 위한 약학적 조성물 또는 건강기능식품 조성물로 사용할 수 있고, 또한 이를 유효한 양으로 상기 질환의 치료가 필요한 대상에 투여하는 단계를 포함하는 치료 방법을 제공하는 것과 같은 유용한 효과가 있다.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.

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염:A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2017004246-appb-I000138
    Figure PCTKR2017004246-appb-I000138
    (상기 화학식 1에서,(In Formula 1,
    R1 및 R2는 독립적으로 -H, -OH, 할로겐, 아민, 나이트로, 시아노, C1-10의 직쇄 또는 측쇄의 알킬, 또는 C1-10의 직쇄 또는 측쇄의 알콕시이고;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;
    R3은 -H, -OH, 할로겐, 아민, 나이트로, 시아노, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알킬, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 치환된 C3-10의 사이클로알킬, 비치환 또는 치환된 C3-10사이클로알킬-C1-10알킬, 비치환 또는 치환된 3 내지 10각 환의 헤테로사이클로알킬, 비치환 또는 치환된 3-10각 환의 헤테로사이클로알킬-C1-10알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴-C1-10알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴-C1-10알킬이고,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 S, or 5 to 5 or more comprising one or more heteroatoms selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl-C 1-10 alkyl in ten rings,
    여기서, 상기 치환된 알킬 및 치환된 알콕시의 C-C 단일결합은 각각 독립적으로 하나 이상의 이중결합(C=C) 또는 삼중결합(C≡C)으로 치환될 수 있고,Here, the C-C single bond of the substituted alkyl and substituted alkoxy may be independently substituted with one or more double bonds (C = C) or triple bonds (C≡C),
    상기 치환된 알킬, 치환된 알콕시, 치환된 사이클로알킬, 치환된 사이클로알킬-알킬, 치환된 헤테로사이클로알킬, 치환된 헤테로사이클로알킬-알킬, 치환된 아릴, 치환된 아릴-알킬, 치환된 헤테로아릴 및 치환된 헤테로아릴-알킬은 각각 독립적으로 -OH, -SCF3, -SF5, -SO2-C1-10알킬, -NH-SO2-C1-10알킬, -SO2-NH-C1-10알킬, -(C=O)-O-C1-10알킬, 할로겐, 아민, 나이트로, 시아노, 옥소(oxo), 비치환 또는 하나 이상의 할로겐 또는 하나 이상의 -OH가 치환된 C1-10의 직쇄 또는 측쇄의 알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 하나 이상의 할로겐이 치환된 C2-10의 직쇄 또는 측쇄의 알키닐(alkynyl), C1-10의 직쇄 또는 측쇄의 트리알킬실릴(trialkylsilyl), C3-10의 사이클로 알킬, C6-10의 아릴, N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 헤테로아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3 내지 8각 환의 비치환 또는 치환된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환되거나; 비치환 또는 하나 이상의 할로겐이 치환된 페닐, 또는 하나 이상의 N을 포함하는 비치환된 5 내지 6각 환의 헤테로아릴이 융합(fused)될 수 있고,Substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted cycloalkyl-alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl and Substituted heteroaryl-alkyl are each independently -OH, -SCF 3 , -SF 5 , -SO 2 -C 1-10 alkyl, -NH-SO 2 -C 1-10 alkyl, -SO 2 -NH-C 1-10 alkyl,-(C = O) -OC 1-10 alkyl, halogen, amine, nitro, cyano, oxo, unsubstituted or one or more halogen or one or more -OH substituted C 1- 10 linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C 1-10 is substituted C 2-10 carbonyl (alkynyl ), made of a tree of a straight or branched C 1-10 alkylsilyl (trialkylsilyl) aryl-cycloalkyl, C 6-10 of 3-10 C, N, O and S Unsubstituted or substituted heterocyclo of a 5 to 10-membered ring containing at least one hetero atom selected from 3 to 8-membered ring containing at least one hetero atom selected from the group consisting of N, O and S At least one substituent selected from the group consisting of alkyl is substituted; Unsubstituted or substituted at least one halogen may be fused, or unsubstituted 5- to 6-membered heteroaryl containing at least one N,
    다시 여기서, 상기 치환된 헤테로사이클로알킬에는 하나 이상의 -OH가 치환될 수 있고;Here again, the substituted heterocycloalkyl may be substituted with one or more -OH;
    Figure PCTKR2017004246-appb-I000139
    은 비치환 또는 치환된 페닐, N을 1-2개 포함하는 6각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로원자를 포함하는 5각 환의 비치환 또는 치환된 헤테로아릴이고,
    Figure PCTKR2017004246-appb-I000139
    Is an unsubstituted or substituted phenyl, a hexagonal ring containing 1 to 2 N, or an unsubstituted or substituted heteroaryl, or a pentagonal ring containing one or more heteroatoms selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl,
    여기서, 상기 치환된 페닐 및 치환된 헤테로아릴은 독립적으로 -H, -OH, 할로겐, -BnO, 아민, 나이트로, 시아노, C1-10의 직쇄 또는 측쇄의 알킬, 및 C1-10의 직쇄 또는 측쇄의 알콕시로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환될 수 있고; 및Wherein the 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 One or more substituents selected from the group consisting of straight or branched alkoxy may be substituted; And
    X는 CH 또는 N이다).X is CH or N).
  2. 제1항에 있어서,The method of claim 1,
    R3은 -H, -OH, 할로겐, 아민, 나이트로, 시아노, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알킬, 치환 또는 비치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 치환된 C3-10의 사이클로알킬, 비치환 또는 치환된 C3-10사이클로알킬-C1-2알킬, 비치환 또는 치환된 3 내지 10각 환의 헤테로사이클로알킬, 비치환 또는 치환된 3-10각 환의 헤테로사이클로알킬-C1-2알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴-C1-2알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 비치환 또는 치환된 헤테로아릴-C1-2알킬이고,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 1-2 alkyl, unsubstituted or substituted 3 to 10 heterocyclic alkyl, unsubstituted or substituted Heterocycloalkyl-C 1-2 alkyl of 3-10 each ring, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl-C 1-2 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 the group consisting of N, O and S Unsubstituted or substituted heteroaryl-C 1-2 alkyl of 10 rings,
    여기서, 상기 치환된 알킬 및 치환된 알콕시의 C-C 단일결합은 각각 독립적으로 하나 이상의 이중결합(C=C) 또는 삼중결합(C≡C)으로 치환될 수 있고,Here, the C-C single bond of the substituted alkyl and substituted alkoxy may be independently substituted with one or more double bonds (C = C) or triple bonds (C≡C),
    상기 치환된 알킬, 치환된 알콕시, 치환된 사이클로알킬, 치환된 사이클로알킬-알킬, 치환된 헤테로사이클로알킬, 치환된 헤테로사이클로알킬-알킬, 치환된 아릴, 치환된 아릴-알킬, 치환된 헤테로아릴 및 치환된 헤테로아릴-알킬은 각각 독립적으로 -OH, -SCF3, -SF5, -SO2-C1-2알킬, -NH-SO2-C1-2알킬, -SO2-NH-C1-2알킬, -(C=O)-O-C1-2알킬, 할로겐, 아민, 나이트로, 시아노, 옥소(oxo), 비치환 또는 하나 이상의 할로겐 또는 하나 이상의 -OH가 치환된 C1-10의 직쇄 또는 측쇄의 알킬, 비치환 또는 하나 이상의 할로겐이 치환된 C1-10의 직쇄 또는 측쇄의 알콕시, 비치환 또는 하나 이상의 할로겐이 치환된 C2-10의 직쇄 또는 측쇄의 알키닐(alkynyl), C1-10의 직쇄 또는 측쇄의 트리알킬실릴(trialkylsilyl), C3-10의 사이클로 알킬, C6-10의 아릴, N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5 내지 10각 환의 헤테로아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3 내지 8각 환의 비치환 또는 치환된 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환되거나; 비치환 또는 하나 이상의 할로겐이 치환된 페닐, 또는 하나 이상의 N을 포함하는 비치환된 5 내지 6각 환의 헤테로아릴이 융합(fused)될 수 있고,Substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted cycloalkyl-alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl and Substituted heteroaryl-alkyl are each independently -OH, -SCF 3 , -SF 5 , -SO 2 -C 1-2 alkyl, -NH-SO 2 -C 1-2 alkyl, -SO 2 -NH-C 1-2 alkyl,-(C = O) -OC 1-2 alkyl, halogen, amine, nitro, cyano, oxo, unsubstituted or at least one halogen or at least one -OH substituted C 1- 10 linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C 1-10 is substituted C 2-10 carbonyl (alkynyl ), C 1-10 straight or branched trialkylsilyl, C 3-10 cycloalkyl, C 6-10 aryl, N, O and S Unsubstituted or substituted heterocyclo of 5 to 10-membered rings containing at least one hetero atom selected from 3 to 8-membered rings containing at least one hetero atom selected from the group consisting of N, O and S At least one substituent selected from the group consisting of alkyl is substituted; Unsubstituted or substituted at least one halogen may be fused, or unsubstituted 5- to 6-membered heteroaryl containing at least one N,
    다시 여기서, 상기 치환된 헤테로사이클로알킬에는 하나 이상의 -OH가 치환될 수 있는 것을 특징으로 하는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.Here again, the substituted heterocycloalkyl may be substituted with one or more -OH, compounds, stereoisomers or pharmaceutically acceptable salts thereof.
  3. 제1항에 있어서,The method of claim 1,
    R1 및 R2는 각각 독립적으로 -H, -OH, 또는 할로겐인 것을 특징으로 하는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.R 1 and R 2 are each independently -H, -OH, or a halogen, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,The method of claim 1,
    R3은
    Figure PCTKR2017004246-appb-I000140
    ,
    Figure PCTKR2017004246-appb-I000141
    ,
    Figure PCTKR2017004246-appb-I000142
    ,
    Figure PCTKR2017004246-appb-I000143
    ,
    Figure PCTKR2017004246-appb-I000144
    ,
    Figure PCTKR2017004246-appb-I000145
    ,
    Figure PCTKR2017004246-appb-I000146
    ,
    Figure PCTKR2017004246-appb-I000147
    ,
    Figure PCTKR2017004246-appb-I000148
    ,
    Figure PCTKR2017004246-appb-I000149
    ,
    Figure PCTKR2017004246-appb-I000150
    ,
    Figure PCTKR2017004246-appb-I000151
    ,
    Figure PCTKR2017004246-appb-I000152
    ,
    Figure PCTKR2017004246-appb-I000153
    ,
    Figure PCTKR2017004246-appb-I000154
    ,
    Figure PCTKR2017004246-appb-I000155
    ,
    Figure PCTKR2017004246-appb-I000156
    ,
    Figure PCTKR2017004246-appb-I000157
    ,
    Figure PCTKR2017004246-appb-I000158
    ,
    Figure PCTKR2017004246-appb-I000159
    ,
    Figure PCTKR2017004246-appb-I000160
    ,
    Figure PCTKR2017004246-appb-I000161
    ,
    Figure PCTKR2017004246-appb-I000162
    ,
    Figure PCTKR2017004246-appb-I000163
    ,
    Figure PCTKR2017004246-appb-I000164
    ,
    Figure PCTKR2017004246-appb-I000165
    ,
    Figure PCTKR2017004246-appb-I000166
    ,
    Figure PCTKR2017004246-appb-I000167
    ,
    Figure PCTKR2017004246-appb-I000168
    ,
    Figure PCTKR2017004246-appb-I000169
    ,
    Figure PCTKR2017004246-appb-I000170
    ,
    Figure PCTKR2017004246-appb-I000171
    ,
    Figure PCTKR2017004246-appb-I000172
    ,
    Figure PCTKR2017004246-appb-I000173
    ,
    Figure PCTKR2017004246-appb-I000174
    ,
    Figure PCTKR2017004246-appb-I000175
    ,
    Figure PCTKR2017004246-appb-I000176
    , 또는
    Figure PCTKR2017004246-appb-I000177
    이고; 및    R 3 is
    Figure PCTKR2017004246-appb-I000140
    ,
    Figure PCTKR2017004246-appb-I000141
    ,
    Figure PCTKR2017004246-appb-I000142
    ,
    Figure PCTKR2017004246-appb-I000143
    ,
    Figure PCTKR2017004246-appb-I000144
    ,
    Figure PCTKR2017004246-appb-I000145
    ,
    Figure PCTKR2017004246-appb-I000146
    ,
    Figure PCTKR2017004246-appb-I000147
    ,
    Figure PCTKR2017004246-appb-I000148
    ,
    Figure PCTKR2017004246-appb-I000149
    ,
    Figure PCTKR2017004246-appb-I000150
    ,
    Figure PCTKR2017004246-appb-I000151
    ,
    Figure PCTKR2017004246-appb-I000152
    ,
    Figure PCTKR2017004246-appb-I000153
    ,
    Figure PCTKR2017004246-appb-I000154
    ,
    Figure PCTKR2017004246-appb-I000155
    ,
    Figure PCTKR2017004246-appb-I000156
    ,
    Figure PCTKR2017004246-appb-I000157
    ,
    Figure PCTKR2017004246-appb-I000158
    ,
    Figure PCTKR2017004246-appb-I000159
    ,
    Figure PCTKR2017004246-appb-I000160
    ,
    Figure PCTKR2017004246-appb-I000161
    ,
    Figure PCTKR2017004246-appb-I000162
    ,
    Figure PCTKR2017004246-appb-I000163
    ,
    Figure PCTKR2017004246-appb-I000164
    ,
    Figure PCTKR2017004246-appb-I000165
    ,
    Figure PCTKR2017004246-appb-I000166
    ,
    Figure PCTKR2017004246-appb-I000167
    ,
    Figure PCTKR2017004246-appb-I000168
    ,
    Figure PCTKR2017004246-appb-I000169
    ,
    Figure PCTKR2017004246-appb-I000170
    ,
    Figure PCTKR2017004246-appb-I000171
    ,
    Figure PCTKR2017004246-appb-I000172
    ,
    Figure PCTKR2017004246-appb-I000173
    ,
    Figure PCTKR2017004246-appb-I000174
    ,
    Figure PCTKR2017004246-appb-I000175
    ,
    Figure PCTKR2017004246-appb-I000176
    , or
    Figure PCTKR2017004246-appb-I000177
    ego; And
    Figure PCTKR2017004246-appb-I000178
    는 비치환된 페닐, 또는 -CH3, -F 또는 -BnOr로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환된 페닐 또는 하나의 N 원자를 포함하는 6각 환의 비치환된 헤테로아릴인 것을 특징으로 하는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.
    Figure PCTKR2017004246-appb-I000178
    Is an unsubstituted phenyl or phenyl substituted with one or more substituents selected from the group consisting of -CH 3 , -F or -BnOr or a hexagonal ring unsubstituted heteroaryl containing one N atom. Compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염:The compound represented by Formula 1 is any one selected from the following compound group, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
    (1) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드로옥시사이클로펜틸)메틸 설파메이트;(1) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydrooxycyclopentyl) methyl sulfamate;
    (2) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-인다졸-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(2) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-indazol-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (3) ((1R,2R,3S,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(3) ((1R, 2R, 3S, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydro Oxycyclopentyl) methyl sulfamate;
    (4) ((1R,2R,3S,4R)-4-((5-(1-(3-클로로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(4) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-chlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2 , 3-dihydroxycyclopentyl) methyl sulfamate;
    (5) ((1R,2R,3S,4R)-4-((5-(1-(3-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(5) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-fluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydroxycyclopentyl) methyl sulfamate;
    (6) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-(3-(트리플루오로)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(6) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3- (trifluoro) benzyl) -1H-indole-3-carbonyl ) Pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
    (7) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-(3-메톡시벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(7) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3-methoxybenzyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
    (8) ((1R,2R,3S,4R)-4-((5-(1-(3-클로로-4-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(8) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-chloro-4-fluorobenzyl) -1H-indol-3-carbonyl) pyrimidin-4-yl ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (9) ((1R,2R,3S,4R)-4-((5-(1-(2,5-디클로로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(9) ((1R, 2R, 3S, 4R) -4-((5- (1- (2,5-dichlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (10) ((1R,2R,3S,4R)-4-((5-(1-(3,4-디플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(10) ((1R, 2R, 3S, 4R) -4-((5- (1- (3,4-difluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (11) ((1R,2R,3S,4R)-4-((5-(1-(2,4-디플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(11) ((1R, 2R, 3S, 4R) -4-((5- (1- (2,4-difluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (12) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-(3-아이오도벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(12) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (3-iodobenzyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
    (13) ((1R,2R,3S,4R)-4-((5-(1-(3-시아노벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(13) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-cyanobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydroxycyclopentyl) methyl sulfamate;
    (14) ((1R,2R,3S,4R)-4-((5-(1-(2-플루오로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(14) ((1R, 2R, 3S, 4R) -4-((5- (1- (2-fluorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino)- 2,3-dihydroxycyclopentyl) methyl sulfamate;
    (15) ((1R,2R,3S,4R)-4-((5-(1-(3,5-비스(트리플루오로메틸)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(15) ((1R, 2R, 3S, 4R) -4-((5- (1- (3,5-bis (trifluoromethyl) benzyl) -1H-indole-3-carbonyl) pyrimidine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (16) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((트리플루오로메틸)싸이오)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(16) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((trifluoromethyl) thio) benzyl) -1H-indole-3-carbonyl) pyrimidine-4 -Yl) amino) cyclopentyl) methyl sulfamate;
    (17) ((1R,2R,3S,4R)-4-((5-(1-([1,1'-바이페닐]-4-일메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(17) ((1R, 2R, 3S, 4R) -4-((5- (1-([1,1'-biphenyl] -4-ylmethyl) -1H-indole-3-carbonyl) pyridine Midin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (18) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-((6-메틸피리딘-2-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(18) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1-((6-methylpyridin-2-yl) methyl) -1H-indole-3 -Carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
    (19) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-((5-(트리플루오로메틸)퓨란_2-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(19) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1-((5- (trifluoromethyl) furan_2-yl) methyl)- 1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
    (20) ((1R,2R,3S,4R)-2,3-디하이드록시-4-((5-(1-((5-메틸이소옥사졸-3-일)메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)사이클로펜틸)메틸 설파메이트;(20) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1-((5-methylisoxazol-3-yl) methyl) -1H-indole- 3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
    (21) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-5-메틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(21) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -5-methyl-1H-indol-3-carbonyl) pyrimidin-4-yl ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (22) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(22) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -5-fluoro-1H-indole-3-carbonyl) pyrimidine-4- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (23) ((1R,2R,3S,4R)-4-((5-(5-(벤질옥시)-1-(3-브로모벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(23) ((1R, 2R, 3S, 4R) -4-((5- (5- (benzyloxy) -1- (3-bromobenzyl) -1H-indole-3-carbonyl) pyrimidine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (24) ((1R,2R,3S,4R)-4-((5-(1-(3-브로모벤질)-1H-피롤로[2,3-b]피리딘-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(24) ((1R, 2R, 3S, 4R) -4-((5- (1- (3-bromobenzyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) pyrid Midin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (25) 메틸 3-((3-(4-(((1R,2S,3R,4R)-2,3-디하이드록시-4-((설파모일록시)메틸)사이클로펜틸)아미노)피리미딘-5-카보닐)-5-플루오로-1H-인돌-1-일)메틸)벤조에이트;(25) Methyl 3-((3- (4-(((1R, 2S, 3R, 4R) -2,3-dihydroxy-4-((sulfamoyloxy) methyl) cyclopentyl) amino) pyrimidine -5-carbonyl) -5-fluoro-1H-indol-1-yl) methyl) benzoate;
    (26) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(나프탈렌-2-일메틸)-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(26) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (naphthalen-2-ylmethyl) -1H-indole-3-carbonyl) pyridine-4- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (27) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(3-메틸벤질)-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(27) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (3-methylbenzyl) -1H-indol-3-carbonyl) pyridin-4-yl) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (28) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-플루오로-3-메틸벤질)-1H-인돌-3-카보닐)피리딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(28) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4-fluoro-3-methylbenzyl) -1H-indole-3-carbonyl) pyridine -4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (29) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-플루오로-3-메톡시벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(29) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4-fluoro-3-methoxybenzyl) -1H-indole-3-carbonyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (30) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(펜타플루오로-l6-설파닐)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(30) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (pentafluoro-16-sulfanyl) benzyl) -1H-indole-3- Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (31) ((1R,2S,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2-하이드로시싸이클로펜틸)메틸 설파메이트;(31) ((1R, 2S, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2-hydrocyclocyclopentyl) methyl Sulfamate;
    (32) ((1R,2R,3R,4R)-4-((5-(1-벤질-1H-인돌-3-카보닐)피리미딘-4-yl)아미노)-3-플루오로-2-하이드로시싸이클로펜틸)메틸 설파메이트;(32) ((1R, 2R, 3R, 4R) -4-((5- (1-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -3-fluoro-2 Hydrocyclocyclopentyl) methyl sulfamate;
    (33) ((1R,2R,3S,4R)-4-((5-(1-(2-뷰틴-1-일)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-다이하이드로시싸이클로펜틸) 메틸 설파메이트;(33) ((1R, 2R, 3S, 4R) -4-((5- (1- (2-butyn-1-yl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino ) -2,3-dihydrocyclocyclopentyl) methyl sulfamate;
    (34) ((1R,2R,3S,4S)-4-((5-(1-((E)-2-뷰텐-1-일)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-다이하이드로시싸이클로펜틸)메틸 설파메이트;(34) ((1R, 2R, 3S, 4S) -4-((5- (1-((E) -2-buten-1-yl) -1H-indole-3-carbonyl) pyrimidine-4 -Yl) amino) -2,3-dihydrocyclocyclopentyl) methyl sulfamate;
    (35) ((1R,2R,3S,4R)-2,3-다이하이드록시-4-((5-(1-(2-메톡시에틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(35) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (2-methoxyethyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
    (36) ((1R,2R,3S,4S)-2,3-다이하이드록시-4-((5-(1-아이소뷰틸-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(36) ((1R, 2R, 3S, 4S) -2,3-dihydroxy-4-((5- (1-isobutyl-1H-indole-3-carbonyl) pyrimidin-4-yl) Amino) cyclopentyl) methyl sulfamate;
    (37) ((1R,2R,3S,4R)-4-((5-(1-(싸이클로헥실메틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-다이하이드록시싸이클로펜틸)메틸 설파메이트;(37) ((1R, 2R, 3S, 4R) -4-((5- (1- (cyclohexylmethyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2, 3-dihydroxycyclopentyl) methyl sulfamate;
    (38) ((1R,2R,3S,4R)-2,3-다이하이드록시-4-((5-(1-(몰포리노에틸)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(38) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (morpholinoethyl) -1H-indole-3-carbonyl) pyrimidine-4 -Yl) amino) cyclopentyl) methyl sulfamate;
    (39) ((1R,2R,3S,4R)-2,3-다이하이드록시-4-((5-(1-(4-몰포리노벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)싸이클로펜틸)메틸 설파메이트;(39) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4-((5- (1- (4-morpholinobenzyl) -1H-indole-3-carbonyl) pyrimidine -4-yl) amino) cyclopentyl) methyl sulfamate;
    (40) ((1R,2R,3S,4R)-4-((5-(1-((6-(1H-피라졸-1-일)피리딘-3-일)메틸)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(40) ((1R, 2R, 3S, 4R) -4-((5- (1-((6- (1H-pyrazol-1-yl) pyridin-3-yl) methyl) -5-fluoro -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (41) ((1R,2R,3S,4R)-4-((5-(1-((6-브로모벤조퓨란-3-일)메틸)-5-플루오로-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(41) ((1R, 2R, 3S, 4R) -4-((5- (1-((6-bromobenzofuran-3-yl) methyl) -5-fluoro-1H-indole-3- Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (42) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(메틸설포닐)-3-니트로벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(42) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (methylsulfonyl) -3-nitrobenzyl) -1H-indole-3-carbo Yl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (43) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(3-(메틸설폰아미도)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트;(43) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (3- (methylsulfonamido) benzyl) -1H-indole-3-carbonyl) pyrid Midin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
    (44) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(4-(N-메틸설파모일)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3-디하이드록시사이클로펜틸)메틸 설파메이트; 및(44) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (4- (N-methylsulfamoyl) benzyl) -1H-indole-3-carbonyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate; And
    (45) ((1R,2R,3S,4R)-4-((5-(5-플루오로-1-(2-메틸-3-(트리플루오로메틸)벤질)-1H-인돌-3-카보닐)피리미딘-4-일)아미노)-2,3,-다이하이드로시싸이클로펜틸)메틸 설파메이트.(45) ((1R, 2R, 3S, 4R) -4-((5- (5-fluoro-1- (2-methyl-3- (trifluoromethyl) benzyl) -1H-indole-3- Carbonyl) pyrimidin-4-yl) amino) -2,3, -dihydrocyclocyclopentyl) methyl sulfamate.
  6. 제1항의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical for preventing or treating a disease related to NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Composition.
  7. 제1항의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound represented by the formula (1) of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  8. 제7항에 있어서,The method of claim 7, wherein
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 교모세포종, 구강암, 구순암, 균상식육종, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 담낭암, 담도암, 대장암, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 흉선암, 및 두경부암으로부터 선택되는 1종 이상의 고형 종양인 것을 특징으로 하는 약학적 조성물.The cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, glioblastoma, oral cancer, cleft lip cancer, mycosis sarcoma, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, Pituitary Adenoma, Gallbladder Cancer, Biliary Cancer, Colorectal Cancer, Retinoblastoma, Choroidal Melanoma, Batterous Enlarged Cancer, Bladder Cancer, Peritoneal Cancer, Parathyroid Cancer, Adrenal Cancer, Non-sinus Cancer, Non-Small Cell Lung Cancer, Sublingual Cancer, Astrocytoma, Small Cell Lung Cancer, Childhood Brain cancer, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethra Cancer, Primary unknown cancer, Gastric cancer, Gastric carcinoma, Gastrointestinal stromal cancer, Wilm's cancer, Breast cancer, Sarcoma, Penis cancer, Pharyngeal cancer, Pregnancy in chorionic disease, Cervical cancer, Endometrial cancer, Uterine sarcoma, Prostate cancer, Metastatic bone cancer, Metastatic Brain cancer, mediastinal cancer, rectal cancer, Rectal carcinoma, vaginal cancer, spinal cord cancer, neural carcinoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, A pharmaceutical composition, characterized in that it is at least one solid tumor selected from laryngeal cancer, pleural cancer, thymic cancer, and head and neck cancer.
  9. 제7항에 있어서,The method of claim 7, wherein
    상기 암은 급성 골수 백혈병(AML); 만성적 골수성 백혈병(CML); 급성 림프아구성 백혈병(ALL); 만성골수성백혈병; 만성적 림프구성 백혈병(CLL); 호지킨 질환(HD); 비-호지킨 림프종(NHL); B-세포 림프종; T-세포 림프종; 다발성 골수종(MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군(MDS); 작은 림프구 림프종(SLL); 변연부 림프종; 무증상 다발성 골수종; 소아림프종; 소아백혈병; 악성림프종; 위림프종 및 골수증식성 증후군으로 이루어진 군으로부터 선택되는 1종 이상의 혈액성 악성 종양인 것을 특징으로 하는 약학적 조성물.The cancer includes acute myeloid leukemia (AML); Chronic myeloid leukemia (CML); Acute lymphoblastic leukemia (ALL); Chronic myeloid leukemia; 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; Pediatric lymphoma; Childhood leukemia; Malignant lymphoma; A pharmaceutical composition, characterized in that it is at least one hematologic malignancy selected from the group consisting of gastric lymphoma and myeloproliferative syndrome.
  10. 제1항의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 예방 또는 개선용 건강기능식품 조성물.A health function for preventing or ameliorating a disease related to NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Food composition.
  11. 제1항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 NAE(NEDD8-Activating Enzyme) 또는 SAE(Sumo Activating Enzyme) 관련 질환의 치료 방법.A disease associated with NEDD8-Activating Enzyme (NAE) or Sum Activating Enzyme (SAE), comprising administering to a subject a therapeutically effective amount of a compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof Method of treatment.
  12. 제1항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 암의 치료 방법.A method of treating cancer comprising administering to a subject a therapeutically effective amount of a compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  13. 제12항에 있어서,The method of claim 12,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 교모세포종, 구강암, 구순암, 균상식육종, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 담낭암, 담도암, 대장암, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 흉선암, 및 두경부암으로부터 선택되는 1종 이상의 고형 종양인 것을 특징으로 하는 치료 방법.The cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, glioblastoma, oral cancer, cleft lip cancer, mycosis sarcoma, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, Pituitary Adenoma, Gallbladder Cancer, Biliary Cancer, Colorectal Cancer, Retinoblastoma, Choroidal Melanoma, Batterous Enlarged Cancer, Bladder Cancer, Peritoneal Cancer, Parathyroid Cancer, Adrenal Cancer, Non-sinus Cancer, Non-Small Cell Lung Cancer, Sublingual Cancer, Astrocytoma, Small Cell Lung Cancer, Childhood Brain cancer, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethra Cancer, Primary unknown cancer, Gastric cancer, Gastric carcinoma, Gastrointestinal stromal cancer, Wilm's cancer, Breast cancer, Sarcoma, Penis cancer, Pharyngeal cancer, Pregnancy in chorionic disease, Cervical cancer, Endometrial cancer, Uterine sarcoma, Prostate cancer, Metastatic bone cancer, Metastatic Brain cancer, mediastinal cancer, rectal cancer, Rectal carcinoma, vaginal cancer, spinal cord cancer, neural carcinoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, And at least one solid tumor selected from laryngeal cancer, pleural cancer, thymic cancer, and head and neck cancer.
  14. 제12항에 있어서,The method of claim 12,
    상기 암은 급성 골수 백혈병(AML); 만성적 골수성 백혈병(CML); 급성 림프아구성 백혈병(ALL); 만성골수성백혈병; 만성적 림프구성 백혈병(CLL); 호지킨 질환(HD); 비-호지킨 림프종(NHL); B-세포 림프종; T-세포 림프종; 다발성 골수종(MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군(MDS); 작은 림프구 림프종(SLL); 변연부 림프종; 무증상 다발성 골수종; 소아림프종; 소아백혈병; 악성림프종; 위림프종 및 골수증식성 증후군으로 이루어진 군으로부터 선택되는 1종 이상의 혈액성 악성 종양인 것을 특징으로 하는 치료 방법.The cancer includes acute myeloid leukemia (AML); Chronic myeloid leukemia (CML); Acute lymphoblastic leukemia (ALL); Chronic myeloid leukemia; 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; Pediatric lymphoma; Childhood leukemia; Malignant lymphoma; And at least one hematologic malignancy selected from the group consisting of gastric lymphoma and myeloproliferative syndrome.
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