WO2010032986A2 - Novel 5-(4-aminophenyl)-isoquinoline derivative, pharmaceutically acceptable salt thereof, production method for same, and composition containing same as active ingredient for prophylaxis and treatment of medical condition induced by raf kinase hyperactivity - Google Patents

Novel 5-(4-aminophenyl)-isoquinoline derivative, pharmaceutically acceptable salt thereof, production method for same, and composition containing same as active ingredient for prophylaxis and treatment of medical condition induced by raf kinase hyperactivity Download PDF

Info

Publication number
WO2010032986A2
WO2010032986A2 PCT/KR2009/005326 KR2009005326W WO2010032986A2 WO 2010032986 A2 WO2010032986 A2 WO 2010032986A2 KR 2009005326 W KR2009005326 W KR 2009005326W WO 2010032986 A2 WO2010032986 A2 WO 2010032986A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
formula
compound
trifluoromethyl
isoquinolin
Prior art date
Application number
PCT/KR2009/005326
Other languages
French (fr)
Korean (ko)
Other versions
WO2010032986A3 (en
Inventor
한철규
윤정혁
김남두
심은경
Original Assignee
주식회사 이큐스팜
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 이큐스팜 filed Critical 주식회사 이큐스팜
Publication of WO2010032986A2 publication Critical patent/WO2010032986A2/en
Publication of WO2010032986A3 publication Critical patent/WO2010032986A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom

Definitions

  • the present invention provides a novel 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a method for preventing or treating a disease caused by the overactivity of Raf kinase containing the same as an active ingredient. It relates to a composition.
  • Ras / Raf / MEK / ERK protein kinase signaling pathways play a very important role in the regulation of cell function and are specifically involved in cell proliferation, differentiation, survival and angiogenesis [Biology of the Cell, 2001, 93, 53-62].
  • GTP guanosine triphosphate
  • phosphorylation and activation of Raf protein in the plasma membrane proceed.
  • Activated Raf protein then phosphorylates and activates MEK protein, which MEK phosphorylates and activates ERK protein.
  • Translocation of the activated ERK from the cytoplasm to the nucleus results in the regulation and phosphorylation of the activity of transcription factors such as Elk-1 and Myc.
  • the Raf protocogene is a serine / threon protein kinase that transfers signals from activated growth factor receptors to cell transcription factors in the nucleus.
  • the activation of the Raf protein is accompanied by phosphorylation of tyrosine, serine, and threonine residues of the Raf protein, and direct phosphorylation by receptor tyrosine kinase or phosphorylation by protein kinase enzymes regulated by these receptors is a function of Raf activation. It is known by the mechanism. Of these, Ras is involved in the activation of Raf when regulated by the receptor.
  • Raf The signal reaching Raf is delivered to the nucleus via a signaling pathway leading back to Raf / MEK / ERK protein kinase.
  • a series of kinases are arranged in species to transmit signals, which play an essential role in cell growth and differentiation [Nature Rev. Mol. Cell. Biol., 2004, 5, 875-885.
  • Raf acts as a major breeder of Ras function, providing a theoretical background for anticancer therapies in cases where Ras mutations or activated cancers inhibit the action of this protein.
  • Raf proteins have three functional isoforms: A-raf, B-Raf, and C-Raf [Biochim. Biophys. Acta., 2003, 1653, 25-40], among which B-Raf plays an important role in linking MEK signaling in Ras. All three Raf genes are expressed in most tissues, with high expression of B-raf in neuronal tissues and A-raf in urogenital tissues.
  • Each Raf family has a very similar amino acid sequence, but biochemical activity and biological function are distinguished from one another [Exp. Cell. Res. 1999, 253, 34-46].
  • B-raf is an important isoform protein involved in cell proliferation and is an important target of tumorigenic Ras.
  • Abnormal mutations in the body have been identified only in the case of B-raf, occur in 30-60% of malignant skin melanoma [Nature, 2002, 417, 949-954], 30-50% in thyroid cancer, colorectal cancer 5 20% and 30% of ovarian cancers. Mol. Cell Biology, 2004, 5, 875-885.
  • more than 45 B-raf mutations have been known, but the most frequent mutations have been observed in more than 90% of human cancers, with valine 600 being mutated to glutamic acid.
  • This mutation increases B-raf's kinase activity and is believed to deliver Raf / MEK / ERK signals in a subsignal pathway that includes the structural activity of ERK as a result of Ras and growth factor receptor activation.
  • Mutated B-raf protein is transformed in NIH3T3 cells [Nature, 2002, 417, 949-954] and melanocytes [Cancer Res., 2004, 64, 2338-2342] and also survives and transforms melanoma. It appears to be essential for [Cancer Res., 2003, 63, 5198 ⁇ 5202]. Therefore, B-raf, which plays a key role in the continuous signaling of Raf / MEK / ERK, plays an essential role in tumor survival.
  • the present inventors conducted a long-term study to develop an inhibitor that can modulate the activity of B-raf kinase, and as a result, 5- (4-aminophenyl) -isoquinoline derivative has a superior B-raf kinase inhibitory effect.
  • 5- (4-aminophenyl) -isoquinoline derivative has a superior B-raf kinase inhibitory effect.
  • Another object of the present invention is to provide a method for preparing the 5- (4-aminophenyl) -isoquinoline derivative.
  • Another object of the present invention is for the prevention or treatment of diseases caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a composition.
  • the present invention provides a novel 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for preparing the 5- (4-aminophenyl) -isoquinoline derivative.
  • the present invention provides a composition for preventing or treating a disease caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • composition containing the 5- (4-aminophenyl) -isoquinoline derivative according to the present invention effectively regulates the activity of B-raf kinase and thus prevents cancer, melanoma, and the like, which is a disease caused by overactivity of Raf kinase. It can be usefully used as a therapeutic agent.
  • the present invention provides a 5- (4-aminophenyl) -isoquinoline derivative represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, cyano, amino or amide
  • R 2 is hydrogen or C 1-6 straight or branched alkyl
  • R 3 is R 4 or NHR 5 ,
  • R 4 or R 5 is unsubstituted or halogen, respectively; C 1-6 straight or branched alkyl; C 1-6 haloalkyl; C 1-6 alkoxy; 5 ⁇ C 12 aryloxy; 5 ⁇ C 12 aryl C 1 ⁇ 6 alkyl; C 1-6 alkylthio; C 3-12 heterocycloalkyl unsubstituted or substituted with one or more C 1-6 straight or branched alkyl or hydroxy; A C 5 ⁇ 12 unsubstituted or substituted by one or more C 1 ⁇ 6 straight or branched chain alkyl or hydroxy-heteroaryl; And C 1 ⁇ 6, and a C 5 ⁇ 12 aryl-aryl or C 5 ⁇ 12 heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl carboxylic acid, wherein the heterocycloalkyl or heteroaryl group consisting of N, O and S At least one hetero atom selected from
  • R 1 is hydrogen, cyano, amino or amide
  • R 2 is hydrogen or C 1-4 straight or branched alkyl
  • R 3 is R 4 or NHR 5 ,
  • R 4 or R 5 is unsubstituted or halogen, respectively; C 1-4 straight or branched alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; 5 ⁇ C 12 aryloxy; 5 ⁇ C 12 aryl C 1 ⁇ 4 alkyl; C 1-4 alkylthio; C 3-8 heterocycloalkyl unsubstituted or substituted with one or more C 1-4 straight or branched alkyl or hydroxy; C 5-8 heteroaryl unsubstituted or substituted with one or more C 1-4 straight or branched alkyl or hydroxy; And C 1 ⁇ 4, and a C 5 ⁇ 8 aryl aryl or C 5 ⁇ 12 heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl carboxylic acid, wherein the heterocycloalkyl or heteroaryl is a N, O or N, and O It contains a hetero atom.
  • R 1 is hydrogen, cyano, amino or amide
  • R 2 is hydrogen, methyl or ethyl
  • R 3 is R 4 or NHR 5 ,
  • R 4 or R 5 is unsubstituted or fluorine, chlorine, methyl, trifluoromethyl, methoxy, ethoxy, methylthio, phenyloxy, hydroxypiperidine, morpholine, N-methylpiperazine , Phenyl, indole or benzodi substituted with one or more substituents selected from the group consisting of imidazole, 3,5-dimethylimidazole, methylimidazole, piperazinylmethyl, benzyl, methylcarboxyl and ethylcarboxyl It's oxol.
  • R 1 is hydrogen, cyano, amino or amide
  • R 2 is hydrogen or methyl
  • R 3 is R 4 or NHR 5 ,
  • R 4 is phenyl substituted with one or more substituents selected from the group consisting of trifluoromethyl, morpholine, methylimidazole, piperazinylmethyl, hydroxypiperidine,
  • R 5 is unsubstituted or chlorine, methyl, trifluoromethyl, methoxy, methylthio, phenyloxy, N-methylpiperazinylethyl, 3,5-dimethylimidazole, piperazinylmethyl, benzyl, methylcar Phenyl, indole or benzodioxol substituted with one or more substituents selected from the group consisting of a compound.
  • the 5- (4-aminophenyl) -isoquinoline derivative of the present invention represented by the formula (1) may be used in the form of a pharmaceutically acceptable salt, and as a salt by a pharmaceutically acceptable free acid Acid addition salts formed are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
  • water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
  • Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
  • 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 silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
  • the 5- (4-aminophenyl) -isoquinoline derivative represented by Formula 1 of the present invention is not only a pharmaceutically acceptable salt, but also all salts, hydrates, and solvates that can be prepared by conventional methods. It includes everything.
  • the addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
  • a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • the present invention also provides a method for preparing the 5- (4-aminophenyl) -isoquinoline derivative.
  • step 1 Preparing a compound of formula 4 by reacting a starting compound with a compound of formula 3 under a palladium catalyst (step 1);
  • step 2 Reacting the compound of formula 4 prepared in step 1 in a solvent to prepare a compound of formula 1a (step 2).
  • Step 1 is a step of preparing a compound of formula 4 by reacting a compound of formula 2 as a starting material with a compound of formula 3 under a base and a palladium catalyst.
  • the starting material of the compound of formula (2) can be obtained by using a commercially available or synthesized by methods known in the art.
  • step 1 is commonly known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like.
  • reaction solvent dimethoxyethane
  • potassium carbonate was used as a base, and heated to reflux at 75 to 85 ° C. for 16 to 20 hours under a palladium catalyst to obtain a compound of Chemical Formula 4 above.
  • Step 2 is a step of preparing a compound of Formula 1a by reacting the compound of Formula 4 prepared in Step 1 in a solvent.
  • the compound of Formula 4 is dissolved in a suitable organic solvent under the conditions of an appropriate coupling reagent (e.g., EDCI, etc.) and a suitable base (e.g., DMAP, etc.), and then reacted with a compound of Formula 5 to The compound of can be prepared.
  • an appropriate coupling reagent e.g., EDCI, etc.
  • a suitable base e.g., DMAP, etc.
  • the compound of Formula 4 and the amine compound of Formula 6 may be dissolved in a suitable organic solvent, and then p-nitrochloroformate may be added to react at room temperature to prepare the compound of Formula 1a.
  • the compound of Formula 4 may be reacted with a compound of Formula 7 under an appropriate organic solvent to prepare a compound of Formula 1a.
  • the organic solvent used may include dichloromethane, methyl chloride, DMF and the like.
  • Step 2 ′ Preparing a compound of formula 10 by reacting the compound of formula 8 prepared in step 1 ′ with a compound of formula 9 in a solvent (step 2 ′);
  • step 4' Reducing the compound of formula 13 prepared in step 3 'under palladium catalytic hydrogen conditions to produce a compound of formula 1b (step 4').
  • Step 1 ′ is a step of preparing a compound of formula 8 into which nitro is introduced by reacting a compound of formula 2 as a starting material.
  • step 1 is commonly widely known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like.
  • the compound of formula 8 may be prepared by dissolving the compound of formula 2 in a DMSO solvent and then adding KNO 3 , Ac 2 O, and HMPA.
  • Step 2 ' is a step of preparing a compound of formula 10 by reacting the compound of formula 8 prepared in step 1' with a compound of formula 9 in a solvent.
  • the compound of Formula 8 is dissolved in dimethoxyethane as a reaction solvent, and then potassium carbonate and the compound of Formula 9 are added, and heated and refluxed at 75 to 85 ° C. for 16 to 20 hours under a palladium catalyst. The compound of was obtained.
  • Step 3 ' accordinging to the present invention dissolves the compound of Formula 10 and the amine compound of Formula 11 prepared in Step 2' in a solvent, and then reacts at room temperature by adding p-nitrochloroformate (12) Step 13 is to prepare the compound.
  • the organic solvent used may include methyl chloride, THF and the like.
  • Step 4 ' is a step of preparing the compound of Formula 1b by reducing the compound of Formula 13 prepared in Step 3' under palladium catalytic hydrogen conditions.
  • the compound of Formula 13 may be prepared by reducing the nitro group to an amine group using a palladium catalyst and hydrogen.
  • Step 2 Preparing a compound of Formula 15 by reacting the compound of Formula 14 prepared in Step 1 ′′ with the compound of Formula 2 (Step 2 ′′);
  • Step 3 ′′ Preparing a compound of Chemical Formula 16 using an oxidant to the compound of Chemical Formula 15 prepared in Step 2 ′′ (Step 3 ′′);
  • step 6 Reacting the compound of formula 19 prepared in step 5 "with a base to prepare a compound of formula 1c introducing an amide group (step 6").
  • Step 1 ′′ according to the present invention is a step of preparing a compound of Formula 14 having a protecting group introduced into an amino group of the compound of Formula 3.
  • the reaction for introducing the protecting group may be used a method commonly used in the art, but is not limited thereto.
  • the compound of Formula 14 having a protecting group introduced into an amino group may be prepared by adding and reacting sodium carbonate and Boc 2 O to a 1,4-dioxane / water mixed solvent.
  • Step 2 ′′ is a step of preparing the compound of Formula 15 by reacting the compound of Formula 14 prepared in Step 1 ′′ with the compound of Formula 2.
  • the compound of Formula 14 is dissolved in dimethoxyethane as a reaction solvent, and then potassium carbonate and the compound of Formula 2 are added, and heated and refluxed at 75 to 85 ° C. for 16 to 20 hours under a palladium catalyst to give the formula (15). The compound of was obtained.
  • Step 3 ′′ is a step of preparing a compound of Formula 16 by using an oxidant to the compound of Formula 15 prepared in Step 2 ′′.
  • 3-chlorobenzoic acid may be added as an oxidizing agent to prepare a compound of Formula 16 in which N-oxide is introduced into isoquinoline nitrogen of the compound of Formula 15. .
  • Step 4 ′′ is a step of preparing the compound of Formula 17 in which the amino group protecting group of the compound of Formula 16 prepared in Step 3 ′′ is removed and a cyano group is introduced.
  • reaction may be carried out by adding a compound of Formula 16 and trimethylsilyl cyanide in a tetrahydrofuran solvent and adding DBU to reflux stirring at 85 to 95 ° C. for about 2 hours.
  • Step 5 ′′ is a step of preparing a compound of Formula 19 by reacting an isocyanate compound 18 with the compound of Formula 17 prepared in Step 4 ′′.
  • methyl chloride may be used as the solvent.
  • Step 6 ′′ is a step of preparing a compound of Formula 1c introducing an amide group by reacting the compound of Formula 19 prepared in Step 5 ′′ with a base.
  • the compound of Formula 1c having an amide group introduced therein may be prepared by reacting the compound of Formula 19 with a ethanol / water mixed solvent as a solvent and potassium hydroxide as a base.
  • 5- (4-aminophenyl) -isoquinoline derivatives or intermediates prepared according to the present invention are prepared after infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, or beneficiation. Molecular structure can be confirmed by a figure measurement method and the comparison of the elemental analysis calculation value and the measured value of a typical compound.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
  • B-raf in Raf kinase is an important isoform protein involved in cell proliferation and is an important target of tumorigenic Ras.
  • Abnormal mutations in the body have been identified only in the case of B-raf, occur in 30-60% of malignant skin melanoma [Nature, 2002, 417, 949-954], 30-50% in thyroid cancer, colorectal cancer 5 20% and 30% of ovarian cancers. Mol. Cell Biology, 2004, 5, 875-885.
  • more than 45 B-raf mutations have been known, but the most frequent mutations have been observed in more than 90% of human cancers, with valine 600 being mutated to glutamic acid.
  • This mutation increases B-raf's kinase activity and is believed to deliver Raf / MEK / ERK signals in a subsignal pathway that includes the structural activity of ERK as a result of Ras and growth factor receptor activation.
  • Mutated B-raf protein is transformed in NIH3T3 cells [Nature, 2002, 417, 949-954] and melanocytes [Cancer Res., 2004, 64, 2338-2342], and also melanoma survival and transformation [ Cancer Res., 2003, 63, 5198-5202.
  • B-raf which plays a key role in the continuous signaling of Raf / MEK / ERK, plays an essential role in tumor survival.
  • composition according to the present invention significantly inhibits the activity of B-raf in in vitro experiments.
  • experiments in A375 cells were also shown to significantly inhibit the activity of B-raf (see Table 1 and Table 2). Therefore, the composition according to the present invention effectively inhibits the activity of B-raf kinase and thus can be usefully used as a prophylactic or therapeutic agent for diseases such as cancer and melanoma caused by the overactivity of B-raf kinase.
  • composition of the present invention When the composition of the present invention is used as a medicine, a pharmaceutical composition containing 5- (4-aminophenyl) -isoquinoline derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient is used during clinical administration. It may be formulated in various oral or parenteral dosage forms as follows, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like.
  • Rose 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 also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt.
  • Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixir
  • the pharmaceutical composition comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • 5- (4-aminophenyl) -isoquinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension. And can be prepared in ampule or vial unit dosage forms.
  • 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.
  • the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1,000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.
  • Step 2 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3,4,5-trimethoxyphenyl) urea
  • Step 2 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (4-phenyloxyphenyl) urea
  • 4-nitrophenyl chloroformate (24 mg, 0.12 mmol) and 4-phenyloxyaniline (20 mg, 0.11 mmol) were dissolved in a mixed solvent of tetrahydrofuran and dichloromethane (1: 1), followed by diisopropylethylamine ( 0.024 mL, 0.13 mmol) was added and stirred at room temperature for 0.5 hour.
  • 4- (isoquinolin-5-yl) aniline (25 mg, 0.11 mmol) prepared in step 1 was dissolved in a solvent and added to the reaction mixture, followed by adding diisopropylethylamine (0.019 mL, 0.11 mmol) at room temperature. Stir for hours.
  • Step 2 Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea
  • Step 2 Preparation of ethyl 3- (3- (4- (isoquinolin-5-yl) phenyl) ureido) benzoate
  • Step 2 Preparation of 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4- (isoquinolin-5-yl) phenyl) urea
  • Step 1 Preparation of t-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbonate
  • Step 2 Preparation of t-butyl 4- (isoquinolin-5-yl) phenylcarbonate
  • Step 3 Preparation of 5- (4- (t-butoxycarbonylamino) phenyl) isoquinoline 2-oxide
  • Step 5 Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea
  • Step 6 Preparation of 5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide
  • Step 1 to Step 4": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
  • step 4 5- (4-aminophenyl) isoquinoline-1-carbonitrile (42 mg, 0.17 mmol) prepared in step 4 " was dissolved and added to the reaction product, followed by diisopropylethylamine (0.03 mL, 0.17 mmol) After the reaction was completed, the product was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was concentrated by column chromatography (methanol: dichloromethane).
  • Step 1 to Step 4": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
  • Step 5 Preparation of 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide
  • Step 1 to Step 4": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
  • Step 5 Preparation of 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (3-phenyloxyphenyl) urea
  • Step 6 Preparation of 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide
  • Step 2 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (1-methyl-1H-indol-6-yl) urea
  • Step 1 Preparation of Benzyl 4- (isoquinolin-5-yl) phenylcarbamate
  • Step 2 Preparation of 5- (4- (benzyloxycarbonylamino) phenyl) isoquinoline 2-oxide
  • Step 3 Preparation of benzyl 4- (1-chloroisoquinolin-5-yl) phenylcarbamate
  • Step 4 Preparation of 5- (4-aminophenyl) -N- (3,4-dimethoxybenzyl) isoquinolin-1-amine
  • Step 5 ′′ 1- (4- (1- (3,4-Dimethoxybenzylamino) isoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl Preparation of) -3- (trifluoromethyl) phenyl) urea
  • step 4 To the mixed solvent was dissolved 5- (4-aminophenyl) -N- (3,4-dimethoxybenzyl) isoquinolin-1-amine (386 mg, 1.0 mmol) prepared in step 4 "and added to the reaction. After diisopropylethylamine (0.2 mL, 1.0 mmol) was added and stirred at room temperature for 7 hours, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Step 6 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl ) Phenyl) urea
  • Step 1 ′ Preparation of 5-bromo-1-nitroisoquinoline
  • Step 2 ′ Preparation of 4- (1-nitroisoquinolin-5-yl) aniline
  • Step 3 ' 1- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- (4- (1-nitroisoquinolin-5-yl Preparation of Phenyl) urea
  • Step 4 ' 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl Preparation of Phenyl) urea
  • Step 1 ′ Preparation of 5-bromo-1-nitroisoquinoline
  • Step 2 ′ Preparation of 3-methyl-4- (1-nitroisoquinolin-5-yl) aniline
  • Step 3 ' 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (3-methyl-4- (1-nitroisoquinoline Preparation of -5-yl) phenyl) urea
  • 3-methyl-4- (1-nitroisoquinolin-5-yl) aniline (48 mg, 0.17 mmol) prepared in step 2 ' was dissolved in the mixed solvent and added to the reaction product, followed by diisopropylethylamine (0.03 mL, 0.17 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Step 4 ' 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (tri Preparation of Fluoromethyl) phenyl) urea
  • Step 2 Preparation of N- (4-isoquinolin-5-yl) phenyl) -3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzamide
  • Step 2 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -3-morpholino-5- (trifluoromethyl) benzamide
  • Step 2 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -4-morpholino-3- (trifluoromethyl) benzamide
  • Step 2 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) benzamide
  • Step 2 Preparation of 3- (4-hydroxypiperidin-1-yl) -N- (4- (isoquinolin-5-yl) phenyl) -5- (trifluoromethyl) benzamide
  • Step 2 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) benzamide
  • Step 2 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) urea
  • Step 2 1- (4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl Production of urea
  • the 4-isoquinolin-5-yl) aniline (44 mg, 0.20 mmol) prepared in Step 1 was dissolved in the mixed solvent and added to the reaction product, followed by adding diisopropylethylamine (0.04 mL, 0.20 mmol) at room temperature. Stir for 5 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Step 2 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea Manufacture
  • Step 2 Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea
  • Step 2 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3- (methylthio) phenyl) urea
  • a dilution solvent (20 mM MOPS, pH 7.2, 25 mM ⁇ -glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol) in a centrifuge tube 20
  • Mg / ATP mixed solution 500 ⁇ M ATP, 75 mM magnesium chloride
  • the solutions in the tube were collected by centrifugation at the bottom, and then reacted at 30 ° C. for 30 minutes, and 4 ⁇ l of the mixed solution was taken to proceed to the next step test.
  • the compound according to the present invention exhibits an excellent inhibitory effect of B-raf activity in nM units with a B-raf activity inhibition rate of 206 to 510 nM.
  • the A375 cell line (ATCC) is derived from human melanoma patients and has a V599E mutation in the B-Raf gene so that the level of phosphorylated MEK is elevated due to the mutation of B-Raf.
  • Sub-confluent to confluent A375 cells were incubated with the compounds prepared in Examples 1-23 for 2 hours at 37 ° C. in serum-free medium. Cells were then washed once with cold PBS and lysed with lysis buffer containing 1% Triton X100. After centrifugation, the supernatants were subjected to SDS-PAGE and then transferred to nitro cellulose membranes. The membrane was then subjected to western blotting using anti-phospho-MEK antibody (ser217 / 221) (Cell Signaling). The amount of phosphorylated MEK was measured by the density of phospho-MEK bands in the nitrocellulose membrane to determine B-raf activity inhibition rate (IC 50 ). The results are shown in Table 2 below.
  • the compound according to the present invention has a B-raf activity inhibition rate of 0.12 to 19.0 ⁇ M and is excellent in inhibitory activity of B-raf, thus causing an abnormal disease such as cancer and black. It can be usefully used for the prevention and treatment of species.
  • the 5- (4-aminophenyl) -isoquinoline derivative represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the active ingredient After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.
  • Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

Abstract

The present invention relates to a novel 5-(4-aminophenyl)-isoquinoline derivative or a pharmaceutically acceptable salt thereof, a production method for the same, and a composition  containing the same as an active ingredient for the prophylaxis and treatment of a medical condition induced by the hyperactivity of Raf kinases. The composition containing a 5-(4-aminophenyl)-isoquinoline derivative according to the present invention effectively inhibits the activity of Raf kinases and particularly B-raf kinase, and thus can be used to good effect in the prophylaxis and treatment of such cancers or melanomas as are induced by the hyperactivity of Raf kinases.

Description

신규 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 RAF 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 조성물Novel 5- (4-aminophenyl) -isoquinoline derivative or pharmaceutically acceptable salt thereof, preparation method thereof, and composition for preventing or treating a disease caused by overactivity of RAF kinase containing the same as an active ingredient
본 발명은 신규 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 Raf 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention provides a novel 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a method for preventing or treating a disease caused by the overactivity of Raf kinase containing the same as an active ingredient. It relates to a composition.
Ras/Raf/MEK/ERK 단백질 키나제 신호전달 경로는 세포 기능의 조절에 매우 중요한 역할을 하며, 구체적으로 세포의 증식, 분화, 생존 및 혈관신생에 관여하고 있다[Biology of the Cell, 2001, 93, 53~62]. 상기 신호전달 경로에 있어서, Ras 단백질에 구아노신 3인산(GTP)이 결합되면, 원형질막에 있는 Raf 단백질의 인산화 및 활성화가 진행된다. 이어서 활성화된 Raf 단백질은 MEK 단백질을 인산화 및 활성화시키고, 상기 MEK 단백질은 ERK 단백질을 인산화 및 활성화시킨다. 활성화된 ERK의 세포질에서 핵으로의 전좌(translocation)는 Elk-1과 Myc와 같은 전사 인자의 활성을 조절하고, 인산화시키는 결과를 가져온다. Ras / Raf / MEK / ERK protein kinase signaling pathways play a very important role in the regulation of cell function and are specifically involved in cell proliferation, differentiation, survival and angiogenesis [Biology of the Cell, 2001, 93, 53-62]. In the signaling pathway, when guanosine triphosphate (GTP) is bound to Ras protein, phosphorylation and activation of Raf protein in the plasma membrane proceed. Activated Raf protein then phosphorylates and activates MEK protein, which MEK phosphorylates and activates ERK protein. Translocation of the activated ERK from the cytoplasm to the nucleus results in the regulation and phosphorylation of the activity of transcription factors such as Elk-1 and Myc.
Raf 원암 유전자(protooncogene)는 세린/쓰레오닌(Ser/Thr) 단백질 키나제로서, 세포막에서 활성화된 성장인자 수용체로부터 오는 신호를 핵내의 전사인자에 전달하는 물질이다. 상기 Raf 단백질의 활성화는 Raf 단백질의 티로신, 세린, 쓰레오닌 잔기에 인산화를 동반하며, 수용체 티로신 키나제에 의한 직접적인 인산화 또는 이들 수용체들에 의해 조절되는 단백질 인산화 효소들에 의한 인산화가 Raf 활성화의 작용기전으로 알려지고 있다. 이중, 수용체에 의해 조절되는 경우에 Ras가 Raf의 활성화에 관여하게 된다. Raf에 도달한 신호는 다시 Raf/MEK/ERK 단백질 키나제로 이어지는 신호전달 경로를 통해 핵으로 전달된다. 이러한 신호 전달 경로에는 일련의 키나제들이 종으로 배열되어 신호를 전달하게 되는데, 이는 세포의 성장과 분화에 필수적인 역할을 수행한다[Nature Rev. Mol. Cell. Biol., 2004, 5, 875~885].The Raf protocogene is a serine / threon protein kinase that transfers signals from activated growth factor receptors to cell transcription factors in the nucleus. The activation of the Raf protein is accompanied by phosphorylation of tyrosine, serine, and threonine residues of the Raf protein, and direct phosphorylation by receptor tyrosine kinase or phosphorylation by protein kinase enzymes regulated by these receptors is a function of Raf activation. It is known by the mechanism. Of these, Ras is involved in the activation of Raf when regulated by the receptor. The signal reaching Raf is delivered to the nucleus via a signaling pathway leading back to Raf / MEK / ERK protein kinase. In this signal transduction pathway, a series of kinases are arranged in species to transmit signals, which play an essential role in cell growth and differentiation [Nature Rev. Mol. Cell. Biol., 2004, 5, 875-885.
이처럼 Raf는 Ras 기능의 주요 번식자로서 작용하여, 이 단백질의 작용을 억제하는 것에 대한 Ras의 변이가 있거나 활성화되어 있는 암의 경우 항암치료에 대해 이론적인 배경을 제공해 주었다. Raf 단백질에는 A-raf, B-Raf, C-Raf의 세 가지 기능을 하는 이성질형태(isoform)가 있는데[Biochim. Biophys. Acta., 2003, 1653, 25~40], 그 중에서 B-Raf가 Ras에서 MEK 신호전달을 연결하는데 중요한 역할을 한다. 세 개의 Raf 유전자 모두 대부분의 조직에서 발현되며, 신경세포 조직 내에서는 B-raf 그리고 비뇨생식 조직 내에서는 A-raf의 고 발현이 일어난다. 각각의 Raf 패밀리들은 매우 유사한 아미노산 배열을 하고 있지만, 생화학적 활성 및 생물학적 기능은 서로 구분이 되는 특징을 가지고 있다[Exp. Cell. Res. 1999, 253, 34~46]. 지금까지 연구 결과에 의하면 B-raf는 세포증식에 관련된 중요한 이성형(isoform) 단백질로 종양 발생성 Ras의 중요한 표적이다. 체내 비정상적인 돌연변이는 B-raf의 경우에만 확인되어 왔고, 악성 피부 흑색종에서 30~60%의 빈도로 발생하고[Nature, 2002, 417, 949~954], 갑상선암에서 30~50%, 대장암 5~20%, 및 난소암에서 ~30%의 빈도로 발생하고 있는 것으로 알려져 있다[Nature Rev. Mol. Cell Biology, 2004, 5, 875~885]. 지금까지 B-raf 돌연변이는 45가지 이상 알려져 있으나, 가장 빈번한 돌연변이는 발린 600번이 글루탐산으로 변이가 일어나는 것으로 인간암의 90%이상에서 관찰되고 있다. 이 돌연변이는 B-raf의 키나제 활성을 증가시키고, Ras 및 성장 인자 수용체 활성화 결과 ERK의 구조적 활성을 포함하는 하위신호전달경로로 Raf/MEK/ERK 신호를 전달하는 것으로 여겨진다. 돌연변이화 된 B-raf 단백질은 NIH3T3 세포[Nature, 2002, 417, 949~954] 및 흑색세포[Cancer Res., 2004, 64, 2338~2342]에서 형질전환하고, 또한 흑색종의 생존 및 형질전환[Cancer Res., 2003, 63, 5198~5202]에 필수적인 것으로 나타났다. 따라서 Raf/MEK/ERK의 연속적인 신호전달에 있어서 핵심적인 역할을 하는 B-raf는 종양의 생존에 필수적인 역할을 하고 있다.Raf acts as a major breeder of Ras function, providing a theoretical background for anticancer therapies in cases where Ras mutations or activated cancers inhibit the action of this protein. Raf proteins have three functional isoforms: A-raf, B-Raf, and C-Raf [Biochim. Biophys. Acta., 2003, 1653, 25-40], among which B-Raf plays an important role in linking MEK signaling in Ras. All three Raf genes are expressed in most tissues, with high expression of B-raf in neuronal tissues and A-raf in urogenital tissues. Each Raf family has a very similar amino acid sequence, but biochemical activity and biological function are distinguished from one another [Exp. Cell. Res. 1999, 253, 34-46]. So far, B-raf is an important isoform protein involved in cell proliferation and is an important target of tumorigenic Ras. Abnormal mutations in the body have been identified only in the case of B-raf, occur in 30-60% of malignant skin melanoma [Nature, 2002, 417, 949-954], 30-50% in thyroid cancer, colorectal cancer 5 20% and 30% of ovarian cancers. Mol. Cell Biology, 2004, 5, 875-885. To date, more than 45 B-raf mutations have been known, but the most frequent mutations have been observed in more than 90% of human cancers, with valine 600 being mutated to glutamic acid. This mutation increases B-raf's kinase activity and is believed to deliver Raf / MEK / ERK signals in a subsignal pathway that includes the structural activity of ERK as a result of Ras and growth factor receptor activation. Mutated B-raf protein is transformed in NIH3T3 cells [Nature, 2002, 417, 949-954] and melanocytes [Cancer Res., 2004, 64, 2338-2342] and also survives and transforms melanoma. It appears to be essential for [Cancer Res., 2003, 63, 5198 ~ 5202]. Therefore, B-raf, which plays a key role in the continuous signaling of Raf / MEK / ERK, plays an essential role in tumor survival.
이에, 본 발명자들은 B-raf 키나제의 활성을 조절할 수 있는 저해제 개발을 하고자 오랜 기간 연구를 수행한 결과, 5-(4-아미노페닐)-이소퀴놀린 유도체가 우수한 B-raf 키나제 저해 효과가 있음을 발견하고 본 발명을 완성하였다.Accordingly, the present inventors conducted a long-term study to develop an inhibitor that can modulate the activity of B-raf kinase, and as a result, 5- (4-aminophenyl) -isoquinoline derivative has a superior B-raf kinase inhibitory effect. Discovered and completed the present invention.
본 발명의 목적은 B-raf 키나제의 활성을 조절할 수 있는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용 가능한 염을 제공하는 데 있다.It is an object of the present invention to provide a 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof that can modulate the activity of B-raf kinase.
또한, 본 발명의 다른 목적은 상기 5-(4-아미노페닐)-이소퀴놀린 유도체의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a method for preparing the 5- (4-aminophenyl) -isoquinoline derivative.
또한, 본 발명의 다른 목적은 상기 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 Raf 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 조성물을 제공하는 데 있다.In addition, another object of the present invention is for the prevention or treatment of diseases caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a composition.
상기 목적을 달성하기 위하여, 본 발명은 신규 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the above object, the present invention provides a novel 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 5-(4-아미노페닐)-이소퀴놀린 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing the 5- (4-aminophenyl) -isoquinoline derivative.
나아가, 본 발명은 상기 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 Raf 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 조성물을 제공한다.Furthermore, the present invention provides a composition for preventing or treating a disease caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. do.
본 발명에 따른 5-(4-아미노페닐)-이소퀴놀린 유도체를 함유하는 조성물은 B-raf 키나제의 활성을 효과적으로 조절하므로 Raf 키나제의 과활성에 의해 유발되는 질환인 암, 흑색종 등의 예방 또는 치료제로서 유용하게 사용될 수 있다.The composition containing the 5- (4-aminophenyl) -isoquinoline derivative according to the present invention effectively regulates the activity of B-raf kinase and thus prevents cancer, melanoma, and the like, which is a disease caused by overactivity of Raf kinase. It can be usefully used as a therapeutic agent.
본 발명은 하기 화학식 1로 표시되는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a 5- (4-aminophenyl) -isoquinoline derivative represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.
화학식 1
Figure PCTKR2009005326-appb-C000001
 Formula 1
Figure PCTKR2009005326-appb-C000001
상기 화학식 1에서In Chemical Formula 1
R1은 수소, 시아노, 아미노 또는 아미드이고,R 1 is hydrogen, cyano, amino or amide,
R2는 수소 또는 C1~6 직쇄 또는 측쇄 알킬이고,R 2 is hydrogen or C 1-6 straight or branched alkyl,
R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
이때, R4 또는 R5는 각각 비치환 또는 할로겐; C1~6직쇄 또는 측쇄 알킬; C1~6할로알킬; C1~6알콕시; C5~12아릴옥시; C5~12아릴C1~6알킬; C1~6알킬티오; 비치환 또는 1 이상의 C1~6직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C3~12헤테로사이클로알킬; 비치환 또는 1 이상의 C1~6직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C5~12헤테로아릴; 및 C1~6알킬카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환된 C5~12아릴 또는 C5~12헤테로아릴이고, 상기 헤테로사이클로알킬 또는 헤테로아릴은 N, O 및 S로 이루어지는 군으로부터 선택되는 1 이상의 헤테로 원자를 포함한다.In this case, R 4 or R 5 is unsubstituted or halogen, respectively; C 1-6 straight or branched alkyl; C 1-6 haloalkyl; C 1-6 alkoxy; 5 ~ C 12 aryloxy; 5 ~ C 12 aryl C 1 ~ 6 alkyl; C 1-6 alkylthio; C 3-12 heterocycloalkyl unsubstituted or substituted with one or more C 1-6 straight or branched alkyl or hydroxy; A C 5 ~ 12 unsubstituted or substituted by one or more C 1 ~ 6 straight or branched chain alkyl or hydroxy-heteroaryl; And C 1 ~ 6, and a C 5 ~ 12 aryl-aryl or C 5 ~ 12 heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl carboxylic acid, wherein the heterocycloalkyl or heteroaryl group consisting of N, O and S At least one hetero atom selected from
바람직하게는Preferably
상기 R1은 수소, 시아노, 아미노 또는 아미드이고,R 1 is hydrogen, cyano, amino or amide,
R2는 수소 또는 C1~4 직쇄 또는 측쇄 알킬이고,R 2 is hydrogen or C 1-4 straight or branched alkyl,
R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
이때, R4 또는 R5는 각각 비치환 또는 할로겐; C1~4직쇄 또는 측쇄 알킬; C1~4할로알킬; C1~4알콕시; C5~12아릴옥시; C5~12아릴C1~4알킬; C1~4알킬티오; 비치환 또는 1 이상의 C1~4직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C3~8헤테로사이클로알킬; 비치환 또는 1 이상의 C1~4직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C5~8헤테로아릴; 및 C1~4알킬카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환된 C5~8아릴 또는 C5~12헤테로아릴이고, 상기 헤테로사이클로알킬 또는 헤테로아릴은 N, O 또는 N 및 O의 헤테로 원자를 포함한다.In this case, R 4 or R 5 is unsubstituted or halogen, respectively; C 1-4 straight or branched alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; 5 ~ C 12 aryloxy; 5 ~ C 12 aryl C 1 ~ 4 alkyl; C 1-4 alkylthio; C 3-8 heterocycloalkyl unsubstituted or substituted with one or more C 1-4 straight or branched alkyl or hydroxy; C 5-8 heteroaryl unsubstituted or substituted with one or more C 1-4 straight or branched alkyl or hydroxy; And C 1 ~ 4, and a C 5 ~ 8 aryl aryl or C 5 ~ 12 heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl carboxylic acid, wherein the heterocycloalkyl or heteroaryl is a N, O or N, and O It contains a hetero atom.
더욱 바람직하게는, More preferably,
상기 R1은 수소, 시아노, 아미노 또는 아미드이고,R 1 is hydrogen, cyano, amino or amide,
R2는 수소, 메틸 또는 에틸이고,R 2 is hydrogen, methyl or ethyl,
R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
이때, R4 또는 R5는 각각 비치환 또는 플루오린, 염소, 메틸, 트리플루오로메틸, 메톡시, 에톡시, 메틸티오, 페닐옥시, 히드록시피페리딘, 모르폴린, N-메틸피페라진, 이미다졸, 3,5-디메틸이미다졸, 메틸이미다졸, 피페라지닐메틸, 벤질, 메틸카르복실 및 에틸카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환되는 페닐, 인돌 또는 벤조디옥솔이다.Wherein R 4 or R 5 is unsubstituted or fluorine, chlorine, methyl, trifluoromethyl, methoxy, ethoxy, methylthio, phenyloxy, hydroxypiperidine, morpholine, N-methylpiperazine , Phenyl, indole or benzodi substituted with one or more substituents selected from the group consisting of imidazole, 3,5-dimethylimidazole, methylimidazole, piperazinylmethyl, benzyl, methylcarboxyl and ethylcarboxyl It's oxol.
가장 바람직하게는,Most preferably,
상기 R1은 수소, 시아노, 아미노 또는 아미드이고,R 1 is hydrogen, cyano, amino or amide,
R2는 수소 또는 메틸이고,R 2 is hydrogen or methyl,
R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
이때, R4는 트리플루오로메틸, 모르폴린, 메틸이미다졸, 피페라지닐메틸, 히드록시피페리딘으로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환되는 페닐이고,Wherein R 4 is phenyl substituted with one or more substituents selected from the group consisting of trifluoromethyl, morpholine, methylimidazole, piperazinylmethyl, hydroxypiperidine,
R5는 비치환 또는 염소, 메틸, 트리플루오로메틸, 메톡시, 메틸티오, 페닐옥시, N-메틸피페라지닐에틸, 3,5-디메틸이미다졸, 피페라지닐메틸, 벤질, 메틸카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환되는 페닐, 인돌 또는 벤조디옥솔이다.R 5 is unsubstituted or chlorine, methyl, trifluoromethyl, methoxy, methylthio, phenyloxy, N-methylpiperazinylethyl, 3,5-dimethylimidazole, piperazinylmethyl, benzyl, methylcar Phenyl, indole or benzodioxol substituted with one or more substituents selected from the group consisting of a compound.
상기 화학식 1로 표시되는 5-(4-아미노페닐)-이소퀴놀린 유도체를 보다 구체적으로 예시하면 다음과 같다:More specifically exemplified 5- (4-aminophenyl) -isoquinoline derivative represented by Formula 1 is as follows:
(1) 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아;(1) 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) Phenyl) urea;
(2) 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-페닐옥시페닐)우레아;(2) 1- (4- (isoquinolin-5-yl) phenyl) -3- (4-phenyloxyphenyl) urea;
(3) 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아;(3) 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea;
(4) 에틸 3-(3-(4-(이소퀴놀린-5-일)페닐)우레이도)벤조에이트;(4) ethyl 3- (3- (4- (isoquinolin-5-yl) phenyl) ureido) benzoate;
(5) 1-(벤조[d][1,3]다이옥솔-5-일)-3-(4-(이소퀴놀린-5-일)페닐)우레아;(5) 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4- (isoquinolin-5-yl) phenyl) urea;
(6) 5-(4-(3-(4-클로로-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린- 1-카르복시아미드;(6) 5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide;
(7) 5-(4-(3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드;(7) 5- (4- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxy amides;
(8) 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드;(8) 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide;
(9) 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(1-시아노이소퀴놀린-5-일) 페닐)우레아;(9) 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea;
(10) 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아;(10) 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl ) Phenyl) urea;
(11) 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(3-페닐옥시페닐)우레아;(11) 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (3-phenyloxyphenyl) urea;
(12) 1-(3-벤질메틸)-3-(4-(1-시아노이소퀴놀린-5-일)페닐)우레아;(12) 1- (3-benzylmethyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea;
(13) 1-(4-(이소퀴놀린-5-일)페닐)-3-(1-메틸-1H-인돌-6-일)우레아;(13) 1- (4- (isoquinolin-5-yl) phenyl) -3- (1-methyl-1H-indol-6-yl) urea;
(14) 1-(4-(이소퀴놀린-5-일)페닐)-3-(5-메틸-2-(트리플루오로메틸)푸란-3-일)우레아;(14) 1- (4- (isoquinolin-5-yl) phenyl) -3- (5-methyl-2- (trifluoromethyl) furan-3-yl) urea;
(15) 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(3-메틸-4-(1-니트로이소퀴놀린-5-일)페닐)우레아;(15) 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (3-methyl-4- (1-nitroisoquinoline- 5-yl) phenyl) urea;
(16) 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)우레아;(16) 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoro Rhomethyl) phenyl) urea;
(17) 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아;(17) 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoro Rhomethyl) phenyl) urea;
(18) N-(4-이소퀴놀린-5-일)페닐)-3-(4-메틸-1H-이미다졸-1-일)-5 -(트리플루오로메틸)벤즈아미드;(18) N- (4-isoquinolin-5-yl) phenyl) -3- (4-methyl-1H-imidazol-1-yl) -5-(trifluoromethyl) benzamide;
(19) N-(4-(이소퀴놀린-5-일)페닐)-3-모르폴리노-5-(트리플루오로메틸)벤즈아미드;(19) N- (4- (isoquinolin-5-yl) phenyl) -3-morpholino-5- (trifluoromethyl) benzamide;
(20) N-(4-(이소퀴놀린-5-일)페닐)-4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)벤즈아미드;(20) N- (4- (isoquinolin-5-yl) phenyl) -4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) benzamide;
(21) N-(4-(이소퀴놀린-5-일)페닐)-4-모르폴리노-3-(트리플루오로메틸)벤즈아미드;(21) N- (4- (isoquinolin-5-yl) phenyl) -4-morpholino-3- (trifluoromethyl) benzamide;
(22) 3-(4-히드록시피페리딘-1-일)-N-(4-(이소퀴놀린-5-일)페닐)- 5-(트리플루오로메틸)벤즈아미드;(22) 3- (4-hydroxypiperidin-1-yl) -N- (4- (isoquinolin-5-yl) phenyl) -5 (trifluoromethyl) benzamide;
(23) N-(4-(이소퀴놀린-5-일)페닐)-3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤즈아미드;(23) N- (4- (isoquinolin-5-yl) phenyl) -3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) benzamide;
(24) 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)페닐)우레아;(24) 1- (4- (isoquinolin-5-yl) phenyl) -3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) urea;
(25) 1-(4-(2,4-디메틸-1H-이미다졸-1-일)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아;(25) 1- (4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl Urea;
(26) 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아; 및(26) 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea ; And
(27) 1-(4-(이소퀴놀린-5-일)페닐)-3-(3-(메틸티오)페닐)우레아.(27) 1- (4- (isoquinolin-5-yl) phenyl) -3- (3- (methylthio) phenyl) urea.
상기 화학식 1로 표시되는 본 발명의 5-(4-아미노페닐)-이소퀴놀린 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 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 또는 만델레이트를 포함한다.The 5- (4-aminophenyl) -isoquinoline derivative of the present invention represented by the formula (1) may be used in the form of a pharmaceutically acceptable salt, and as a salt by a pharmaceutically acceptable free acid Acid addition salts formed are useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenyl Butyrate, Citrate, Lactate, β-hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 유도체를 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다.The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
동량의 화학식 1의 유도체 및 물 중의 산 또는 알코올을 가열하고, 이어서 이 혼합물을 증발시켜서 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
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 은 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 silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
또한, 본 발명의 상기 화학식 1로 표시되는 5-(4-아미노페닐)-이소퀴놀린 유도체는 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.In addition, the 5- (4-aminophenyl) -isoquinoline derivative represented by Formula 1 of the present invention is not only a pharmaceutically acceptable salt, but also all salts, hydrates, and solvates that can be prepared by conventional methods. It includes everything.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
또한, 본 발명은 상기 5-(4-아미노페닐)-이소퀴놀린 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing the 5- (4-aminophenyl) -isoquinoline derivative.
본 발명에 따른 제조방법은 하기 반응식 1에 표시되는 바와 같이, The production method according to the present invention, as shown in Scheme 1 below,
출발물질인 화학식 2의 화합물을 팔라듐촉매하에서 화학식 3의 화합물과 반응시켜 화학식 4의 화합물을 제조하는 단계(단계 1); Preparing a compound of formula 4 by reacting a starting compound with a compound of formula 3 under a palladium catalyst (step 1);
상기 단계 1에서 제조된 화학식 4의 화합물을 용매하에서 반응시켜 화학식 1a의 화합물을 제조하는 단계(단계 2)를 포함한다.Reacting the compound of formula 4 prepared in step 1 in a solvent to prepare a compound of formula 1a (step 2).
[반응식 1]Scheme 1
Figure PCTKR2009005326-appb-I000001
Figure PCTKR2009005326-appb-I000001
(상기 식에서, R2 및 R3는 상기 화학식 1에서 정의한 바와 같으며, 화학식 1a는 화학식 1에 포함된다.)(Wherein R 2 and R 3 are as defined in Formula 1 above, and Formula 1a is included in Formula 1).
이하, 본 발명에 따른 제조방법을 단계별로 상세히 설명한다.Hereinafter, the manufacturing method according to the present invention will be described in detail step by step.
단계 1Step 1
본 발명에 따른 상기 단계 1은 출발물질인 화학식 2의 화합물을 염기 및 팔라듐촉매하에서 화학식 3의 화합물과 반응시켜 화학식 4의 화합물을 제조하는 단계이다.Step 1 according to the present invention is a step of preparing a compound of formula 4 by reacting a compound of formula 2 as a starting material with a compound of formula 3 under a base and a palladium catalyst.
상기 출발물질인 화학식 2의 화합물은 시판되는 것을 사용하거나 당업계에 알려진 방법으로 합성하여 얻을 수 있다.The starting material of the compound of formula (2) can be obtained by using a commercially available or synthesized by methods known in the art.
상기 단계 1의 반응은 유기화학 분야에서 통상적으로 널리 알려져 있으며, 반응 용매, 반응 온도, 반응 시간 등의 반응 조건은 반응물질, 생성물질 등을 고려하여 적절히 선택할 수 있다. 일례로 본 발명에서는 반응 용매로서 디메톡시에탄을 사용하였고, 염기로서 탄산칼륨을 사용하였으며, 팔라듐촉매하에서 75~85 ℃에서 16~20시간 동안 가열 환류시켜 상기 화학식 4의 화합물을 수득하였다.The reaction of step 1 is commonly known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like. For example, in the present invention, dimethoxyethane was used as a reaction solvent, potassium carbonate was used as a base, and heated to reflux at 75 to 85 ° C. for 16 to 20 hours under a palladium catalyst to obtain a compound of Chemical Formula 4 above.
단계 2Step 2
본 발명에 따른 상기 단계 2는 상기 단계 1에서 제조된 화학식 4의 화합물을 용매하에서 반응시켜 화학식 1a의 화합물을 제조하는 단계이다.Step 2 according to the present invention is a step of preparing a compound of Formula 1a by reacting the compound of Formula 4 prepared in Step 1 in a solvent.
본 발명에 따른 제조방법에 있어서, 상기 화학식 4의 화합물에서 화학식 1a의 화합물을 제조하는 방법으로 다양한 방법을 사용할 수 있다.In the preparation method according to the present invention, various methods may be used as a method for preparing the compound of Formula 1a from the compound of Formula 4.
일례로서, 상기 화학식 4의 화합물을 적절한 커플링 시약(예를 들면 EDCI 등) 및 적절한 염기(예를 들면 DMAP 등)의 조건 하에서 적절한 유기용매에 용해시킨 후, 화학식 5의 화합물과 반응시켜 화학식 1a의 화합물을 제조할 수 있다.As an example, the compound of Formula 4 is dissolved in a suitable organic solvent under the conditions of an appropriate coupling reagent (e.g., EDCI, etc.) and a suitable base (e.g., DMAP, etc.), and then reacted with a compound of Formula 5 to The compound of can be prepared.
또한, 상기 화학식 4의 화합물과 화학식 6의 아민화합물을 적절한 유기용매에 용해시킨 후, p-니트로클로로포메이트를 첨가하여 실온에서 반응시켜 상기 화학식 1a의 화합물을 제조할 수 있다.In addition, the compound of Formula 4 and the amine compound of Formula 6 may be dissolved in a suitable organic solvent, and then p-nitrochloroformate may be added to react at room temperature to prepare the compound of Formula 1a.
나아가, 상기 화학식 4의 화합물을 화학식 7의 화합물과 적절한 유기용매 하에서 반응시켜 화학식 1a의 화합물을 제조할 수 있다.Furthermore, the compound of Formula 4 may be reacted with a compound of Formula 7 under an appropriate organic solvent to prepare a compound of Formula 1a.
이때, 사용되는 유기용매는 디클로로메탄, 메틸클로라이드, DMF 등을 들 수 있다.At this time, the organic solvent used may include dichloromethane, methyl chloride, DMF and the like.
또한, 본 발명에 따른 제조방법은 하기 반응식 2에 표시되는 바와 같이, In addition, the production method according to the present invention, as shown in Scheme 2 below,
화학식 2의 화합물을 반응시켜 니트로가 도입된 화학식 8의 화합물을 제조하는 단계(단계 1');Reacting the compound of Formula 2 to prepare a compound of Formula 8 into which nitro is introduced (step 1 ′);
상기 단계 1'에서 제조된 화학식 8의 화합물을 용매하에서 화학식 9의 화합물과 반응시켜 화학식 10의 화합물을 제조하는 단계(단계 2');Preparing a compound of formula 10 by reacting the compound of formula 8 prepared in step 1 ′ with a compound of formula 9 in a solvent (step 2 ′);
상기 단계 2'에서 제조된 화학식 10의 화합물과 화학식 11의 아민 화합물을 용매에 용해시킨 후, p-니트로클로로포메이트(12)를 첨가하여 실온에서 반응시켜 화학식 13의 화합물을 제조하는 단계(단계 3'); 및Preparing a compound of Chemical Formula 13 by dissolving the compound of Chemical Formula 10 and the amine compound of Chemical Formula 11 prepared in Step 2 'in a solvent, and then reacting at room temperature by adding p-nitrochloroformate (12) (step 3 '); And
상기 단계 3'에서 제조된 화학식 13의 화합물을 팔라듐 촉매 수소 조건하에서 환원반응시켜 화학식 1b의 화합물을 제조하는 단계(단계 4')를 포함한다.Reducing the compound of formula 13 prepared in step 3 'under palladium catalytic hydrogen conditions to produce a compound of formula 1b (step 4').
[반응식 2]Scheme 2
Figure PCTKR2009005326-appb-I000002
Figure PCTKR2009005326-appb-I000002
(상기 식에서, R2 및 R5는 상기 화학식 1에서 정의한 바와 같으며, 화학식 1b는 화학식 1에 포함된다.)(Wherein R 2 and R 5 are as defined in Formula 1 above, and Formula 1b is included in Formula 1).
단계 1'Step 1 '
본 발명에 따른 상기 단계 1'은 출발물질인 화학식 2의 화합물을 화학식 2의 화합물을 반응시켜 니트로가 도입된 화학식 8의 화합물을 제조하는 단계이다.Step 1 ′ according to the present invention is a step of preparing a compound of formula 8 into which nitro is introduced by reacting a compound of formula 2 as a starting material.
상기 단계 1'의 반응은 유기화학 분야에서 통상적으로 널리 알려져 있으며, 반응 용매, 반응 온도, 반응 시간 등의 반응 조건은 반응물질, 생성물질 등을 고려하여 적절히 선택할 수 있다. 일례로 본 발명에서는 화학식 2의 화합물을 DMSO 용매에 용해시킨 후 KNO3, Ac2O 및 HMPA를 첨가하여 니트로가 도입된 화학식 8의 화합물을 제조할 수 있다.The reaction of step 1 'is commonly widely known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like. In one embodiment of the present invention, the compound of formula 8 may be prepared by dissolving the compound of formula 2 in a DMSO solvent and then adding KNO 3 , Ac 2 O, and HMPA.
단계 2'Step 2 '
본 발명에 따른 상기 단계 2'는 상기 단계 1'에서 제조된 화학식 8의 화합물을 용매하에서 화학식 9의 화합물과 반응시켜 화학식 10의 화합물을 제조하는 단계이다.Step 2 'according to the present invention is a step of preparing a compound of formula 10 by reacting the compound of formula 8 prepared in step 1' with a compound of formula 9 in a solvent.
구체적으로, 상기 화학식 8의 화합물을 반응 용매로서 디메톡시에탄에 용해시킨 후, 탄산칼륨과 화학식 9의 화합물을 첨가하고, 팔라듐촉매하에서 75~85 ℃에서 16~20시간 동안 가열 환류시켜 상기 화학식 10의 화합물을 수득하였다.Specifically, the compound of Formula 8 is dissolved in dimethoxyethane as a reaction solvent, and then potassium carbonate and the compound of Formula 9 are added, and heated and refluxed at 75 to 85 ° C. for 16 to 20 hours under a palladium catalyst. The compound of was obtained.
단계 3'Step 3 '
본 발명에 따른 상기 단계 3'는 상기 단계 2'에서 제조된 화학식 10의 화합물과 화학식 11의 아민 화합물을 용매에 용해시킨 후, p-니트로클로로포메이트(12)를 첨가하여 실온에서 반응시켜 화학식 13의 화합물을 제조하는 단계이다.Step 3 'according to the present invention dissolves the compound of Formula 10 and the amine compound of Formula 11 prepared in Step 2' in a solvent, and then reacts at room temperature by adding p-nitrochloroformate (12) Step 13 is to prepare the compound.
이때, 사용되는 유기용매는 메틸클로라이드, THF 등을 들 수 있다.At this time, the organic solvent used may include methyl chloride, THF and the like.
단계 4'Step 4 '
본 발명에 따른 상기 단계 4'는 상기 단계 3'에서 제조된 화학식 13의 화합물을 팔라듐 촉매 수소 조건하에서 환원반응시켜 화학식 1b의 화합물을 제조하는 단계이다.Step 4 'according to the present invention is a step of preparing the compound of Formula 1b by reducing the compound of Formula 13 prepared in Step 3' under palladium catalytic hydrogen conditions.
상기 화학식 13의 화합물은 팔라듐 촉매와 수소를 사용하여 니트로기를 아민기로 환원시킴으로써 화학식 1b의 화합물을 제조할 수 있다.The compound of Formula 13 may be prepared by reducing the nitro group to an amine group using a palladium catalyst and hydrogen.
또한, 본 발명에 따른 제조방법은 하기 반응식 3에 표시되는 바와 같이, In addition, the production method according to the present invention, as shown in Scheme 3 below,
화학식 3의 화합물의 아미노기에 보호기를 도입한 화학식 14의 화합물을 제조하는 단계(단계 1");Preparing a compound of formula 14 having a protecting group introduced into an amino group of a compound of formula 3 (step 1 ″);
상기 단계 1"에서 제조된 화학식 14의 화합물을 화학식 2의 화합물과 반응시켜 화학식 15의 화합물을 제조하는 단계(단계 2");Preparing a compound of Formula 15 by reacting the compound of Formula 14 prepared in Step 1 ″ with the compound of Formula 2 (Step 2 ″);
상기 단계 2"에서 제조된 화학식 15의 화합물에 산화제를 이용하여 화학식 16의 화합물을 제조하는 단계(단계 3"); Preparing a compound of Chemical Formula 16 using an oxidant to the compound of Chemical Formula 15 prepared in Step 2 ″ (Step 3 ″);
상기 단계 3"에서 제조된 화학식 16의 화합물의 아미노기 보호기를 제거하고 시아노기를 도입한 화학식 17의 화합물을 제조하는 단계(단계 4");Removing the amino group protecting group of the compound of Formula 16 prepared in step 3 ″ and preparing a compound of formula 17 incorporating a cyano group (step 4 ″);
상기 단계 4"에서 제조된 화학식 17의 화합물에 이소시아네이트 화합물(18)을 반응시켜 화학식 19의 화합물을 제조하는 단계(단계 5"); 및Preparing a compound of formula 19 by reacting an isocyanate compound 18 with the compound of formula 17 prepared in step 4 ″ (step 5 ″); And
상기 단계 5"에서 제조된 화학식 19의 화합물을 염기와 반응시켜 아미드기를 도입한 화학식 1c의 화합물을 제조하는 단계(단계 6")를 포함한다.Reacting the compound of formula 19 prepared in step 5 "with a base to prepare a compound of formula 1c introducing an amide group (step 6").
[반응식 3]Scheme 3
Figure PCTKR2009005326-appb-I000003
Figure PCTKR2009005326-appb-I000003
(상기 식에서, R2 및 R5는 상기 화학식 1에서 정의한 바와 같으며, 화학식 1c는 화학식 1에 포함된다.)(Wherein R 2 and R 5 are as defined in Formula 1 above, and Formula 1c is included in Formula 1).
단계 1"Step 1 "
본 발명에 따른 상기 단계 1"은 화학식 3의 화합물의 아미노기에 보호기를 도입한 화학식 14의 화합물을 제조하는 단계이다.Step 1 ″ according to the present invention is a step of preparing a compound of Formula 14 having a protecting group introduced into an amino group of the compound of Formula 3.
상기 보호기를 도입시키는 반응은 당업계에서 통상적으로 사용하는 방법을 이용할 수 있으나, 이에 제한되지는 않는다. 일례로, 1,4-디옥산/물의 혼합용매에 탄산나트륨 및 Boc2O를 첨가하여 반응시킴으로써 아미노기에 보호기를 도입한 화학식 14의 화합물을 제조할 수 있다.The reaction for introducing the protecting group may be used a method commonly used in the art, but is not limited thereto. For example, the compound of Formula 14 having a protecting group introduced into an amino group may be prepared by adding and reacting sodium carbonate and Boc 2 O to a 1,4-dioxane / water mixed solvent.
단계 2"Step 2 "
본 발명에 따른 상기 단계 2"는 상기 단계 1"에서 제조된 화학식 14의 화합물을 화학식 2의 화합물과 반응시켜 화학식 15의 화합물을 제조하는 단계이다.Step 2 ″ according to the present invention is a step of preparing the compound of Formula 15 by reacting the compound of Formula 14 prepared in Step 1 ″ with the compound of Formula 2.
구체적으로, 상기 화학식 14의 화합물을 반응 용매로서 디메톡시에탄에 용해시킨 후, 탄산칼륨과 화학식 2의 화합물을 첨가하고, 팔라듐촉매하에서 75~85 ℃에서 16~20시간 동안 가열 환류시켜 상기 화학식 15의 화합물을 수득하였다.Specifically, the compound of Formula 14 is dissolved in dimethoxyethane as a reaction solvent, and then potassium carbonate and the compound of Formula 2 are added, and heated and refluxed at 75 to 85 ° C. for 16 to 20 hours under a palladium catalyst to give the formula (15). The compound of was obtained.
단계 3"Step 3 "
본 발명에 따른 상기 단계 3"는 상기 단계 2"에서 제조된 화학식 15의 화합물에 산화제를 이용하여 화학식 16의 화합물을 제조하는 단계이다.Step 3 ″ according to the present invention is a step of preparing a compound of Formula 16 by using an oxidant to the compound of Formula 15 prepared in Step 2 ″.
구체적으로, 클로로포름과 같은 용매에 화학식 15의 화합물을 용해시킨 후, 산화제로서 3-클로로벤조산을 첨가하여 화학식 15의 화합물의 이소퀴놀린 질소에 N-옥사이드를 도입한 화학식 16의 화합물을 제조할 수 있다.Specifically, after dissolving the compound of Formula 15 in a solvent such as chloroform, 3-chlorobenzoic acid may be added as an oxidizing agent to prepare a compound of Formula 16 in which N-oxide is introduced into isoquinoline nitrogen of the compound of Formula 15. .
단계 4"Step 4 "
본 발명에 따른 상기 단계 4"는 상기 단계 3"에서 제조된 화학식 16의 화합물의 아미노기 보호기를 제거하고 시아노기를 도입한 화학식 17의 화합물을 제조하는 단계이다.Step 4 ″ according to the present invention is a step of preparing the compound of Formula 17 in which the amino group protecting group of the compound of Formula 16 prepared in Step 3 ″ is removed and a cyano group is introduced.
구체적으로 상기 반응은 테트라히드로퓨란 용매에 화학식 16의 화합물과 트라이메틸실릴시아나이드를 넣고 DBU를 첨가하여 85~95 ℃에서 2시간 정도 환류 교반시킴으로써 수행될 수 있다.Specifically, the reaction may be carried out by adding a compound of Formula 16 and trimethylsilyl cyanide in a tetrahydrofuran solvent and adding DBU to reflux stirring at 85 to 95 ° C. for about 2 hours.
단계 5"Step 5 "
본 발명에 따른 상기 단계 5"는 상기 단계 4"에서 제조된 화학식 17의 화합물에 이소시아네이트 화합물(18)을 반응시켜 화학식 19의 화합물을 제조하는 단계이다.Step 5 ″ according to the present invention is a step of preparing a compound of Formula 19 by reacting an isocyanate compound 18 with the compound of Formula 17 prepared in Step 4 ″.
이때, 용매로는 메틸클로라이드를 사용할 수 있다.In this case, methyl chloride may be used as the solvent.
단계 6"Step 6 "
본 발명에 따른 상기 단계 6"는 상기 단계 5"에서 제조된 화학식 19의 화합물을 염기와 반응시켜 아미드기를 도입한 화학식 1c의 화합물을 제조하는 단계이다.Step 6 ″ according to the present invention is a step of preparing a compound of Formula 1c introducing an amide group by reacting the compound of Formula 19 prepared in Step 5 ″ with a base.
구체적으로 상기 화학식 19의 화합물에 용매로서 에탄올/물 혼합용매를 사용하고 염기로서 수산화칼륨을 사용하여 반응시킴으로써 아미드기가 도입된 화학식 1c의 화합물을 제조할 수 있다.Specifically, the compound of Formula 1c having an amide group introduced therein may be prepared by reacting the compound of Formula 19 with a ethanol / water mixed solvent as a solvent and potassium hydroxide as a base.
상기와 같이 본 발명에 따라 제조된 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 중간체들은 제조 후, 적외선 분광법, 핵자기 공명 스펙트럼, 질량 분광법, 액체 크로마토그래피법, X-선 구조결정법, 선광도 측정법 및 대표적인 화합물의 원소분석 계산치와 실측치의 비교에 의해 분자구조를 확인할 수 있다. As described above, 5- (4-aminophenyl) -isoquinoline derivatives or intermediates prepared according to the present invention are prepared after infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, or beneficiation. Molecular structure can be confirmed by a figure measurement method and the comparison of the elemental analysis calculation value and the measured value of a typical compound.
나아가, 본 발명은 상기 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 Raf 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
Raf 키나제 중 B-raf는 세포증식에 관련된 중요한 이성형(isoform) 단백질로 종양 발생성 Ras의 중요한 표적이다. 체내 비정상적인 돌연변이는 B-raf의 경우에만 확인되어 왔고, 악성 피부 흑색종에서 30~60%의 빈도로 발생하고[Nature, 2002, 417, 949~954], 갑상선암에서 30~50%, 대장암 5~20%, 및 난소암에서 ~30%의 빈도로 발생하고 있는 것으로 알려져 있다[Nature Rev. Mol. Cell Biology, 2004, 5, 875~885]. 지금까지 B-raf 돌연변이는 45가지 이상 알려져 있으나, 가장 빈번한 돌연변이는 발린 600번이 글루탐산으로 변이가 일어나는 것으로 인간암의 90%이상에서 관찰되고 있다. 이 돌연변이는 B-raf의 키나제 활성을 증가시키고, Ras 및 성장 인자 수용체 활성화 결과 ERK의 구조적 활성을 포함하는 하위신호전달경로로 Raf/MEK/ERK 신호를 전달하는 것으로 여겨진다. 돌연변이화된 B-raf 단백질은 NIH3T3 세포[Nature, 2002, 417, 949~954] 및 흑색세포[Cancer Res., 2004, 64, 2338~2342]에서 형질전환하고, 또한 흑색종 생존 및 형질전환[Cancer Res., 2003, 63, 5198~5202]에 필수적인 것으로 나타났다. Raf/MEK/ERK의 연속적인 신호전달에 있어서 핵심적인 역할을 하는 B-raf는 종양의 생존에 필수적인 역할을 하고 있다.B-raf in Raf kinase is an important isoform protein involved in cell proliferation and is an important target of tumorigenic Ras. Abnormal mutations in the body have been identified only in the case of B-raf, occur in 30-60% of malignant skin melanoma [Nature, 2002, 417, 949-954], 30-50% in thyroid cancer, colorectal cancer 5 20% and 30% of ovarian cancers. Mol. Cell Biology, 2004, 5, 875-885. To date, more than 45 B-raf mutations have been known, but the most frequent mutations have been observed in more than 90% of human cancers, with valine 600 being mutated to glutamic acid. This mutation increases B-raf's kinase activity and is believed to deliver Raf / MEK / ERK signals in a subsignal pathway that includes the structural activity of ERK as a result of Ras and growth factor receptor activation. Mutated B-raf protein is transformed in NIH3T3 cells [Nature, 2002, 417, 949-954] and melanocytes [Cancer Res., 2004, 64, 2338-2342], and also melanoma survival and transformation [ Cancer Res., 2003, 63, 5198-5202. B-raf, which plays a key role in the continuous signaling of Raf / MEK / ERK, plays an essential role in tumor survival.
본 발명에 따른 조성물에 유효성분으로 함유되는 5-(4-아미노페닐)-이소퀴놀린 유도체 및 이의 약학적으로 허용가능함 염은 세포 외(in vitro) 실험에서 B-raf의 활성을 유의적으로 억제하는 것으로 나타났으며, A375 세포 내(in vivo)에서의 실험에서도 B-raf의 활성을 유의적으로 억제하는 것으로 나타났다(표 1 및 표 2 참조). 따라서, 본 발명에 따른 조성물은 B-raf 키나제의 활성을 효과적으로 억제하므로 B-raf 키나제의 과활성에 의해 유발되는 암, 흑색종 등의 질병의 예방 또는 치료제로서 유용하게 사용될 수 있다.5- (4-aminophenyl) -isoquinoline derivatives and pharmaceutically acceptable salts thereof contained as an active ingredient in the composition according to the present invention significantly inhibit the activity of B-raf in in vitro experiments. In addition, experiments in A375 cells (in vivo) were also shown to significantly inhibit the activity of B-raf (see Table 1 and Table 2). Therefore, the composition according to the present invention effectively inhibits the activity of B-raf kinase and thus can be usefully used as a prophylactic or therapeutic agent for diseases such as cancer and melanoma caused by the overactivity of B-raf kinase.
본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1로 표시되는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a medicine, a pharmaceutical composition containing 5- (4-aminophenyl) -isoquinoline derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient is used during clinical administration. It may be formulated in various oral or parenteral dosage forms as follows, but is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 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 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 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, and the like. Rose, 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 also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
상기 화학식 1로 표시되는 유도체를 유효 성분으로 하는 약학 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. The pharmaceutical composition comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용되는 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, in order to formulate into a formulation for parenteral administration, 5- (4-aminophenyl) -isoquinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension. And can be prepared in ampule or vial unit dosage forms. 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.
또한, 본 발명의 화합물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.1 ~ 1,000 ㎎/일이며, 바람직하게는 1 ~ 500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1,000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.
이하, 본 발명을 더욱 상세하게 설명하기 위한 실시예 및 실험예를 제시한다. 그러나 하기의 실시예 및 실험예는 본 발명을 보다 쉽게 설명하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, examples and experimental examples for explaining the present invention in more detail. However, the following Examples and Experimental Examples are provided only to explain the present invention more easily, and the content of the present invention is not limited by the Examples.
<실시예 1> 1-(4-(이소퀴놀린-5-일)페닐)-3-(3,4,5-트리메톡시페닐)우레아의 제조Example 1 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3,4,5-trimethoxyphenyl) urea
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
Figure PCTKR2009005326-appb-I000004
Figure PCTKR2009005326-appb-I000004
디메톡시에탄 용매에 5-브로모이소퀴놀린(3.1 g, 15 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-디옥사자보로란-2-일)아닐린(3.9 g, 18 mmol), PdCl2(dppf)(857 mg, 1.05 mmol)와 탄산칼륨(10.4 g, 75 mmol)을 넣고 80 ℃에서 18시간 동안 환류교반하였다. 반응물을 물과 소금물로 씻어준 후 에틸아세테이트로 추출하고 무수 황산 마그네슘 건조 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:2)로 정제하여 4-(이소퀴놀린-5-일)아닐린(2.7 g, 83 %)을 얻었다. 5-bromoisoquinoline (3.1 g, 15 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxazaborolan-2-yl) aniline in dimethoxyethane solvent (3.9 g, 18 mmol), PdCl 2 (dppf) (857 mg, 1.05 mmol) and potassium carbonate (10.4 g, 75 mmol) were added thereto, and the mixture was stirred under reflux at 80 ° C. for 18 hours. The reaction was washed with water and brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain 4- (isoquinolin-5-yl) aniline (2.7 g, 83%).
1H NMR (400MHz, CDCl3): δ 3.79 (bs, 2H), 6.83 (m, 2H), 7.28 (m, 2H), 7.62 (m, 2H), 7.79 (d, J = 6.0 Hz, 1H), 7.92 (t, J = 4.4 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 3.79 (bs, 2H), 6.83 (m, 2H), 7.28 (m, 2H), 7.62 (m, 2H), 7.79 (d, J = 6.0 Hz, 1H) , 7.92 (t, J = 4.4 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H).
단계 2: 1-(4-(이소퀴놀린-5-일)페닐)-3-(3,4,5-트리메톡시페닐)우레아의 제조Step 2: Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3,4,5-trimethoxyphenyl) urea
Figure PCTKR2009005326-appb-I000005
Figure PCTKR2009005326-appb-I000005
테트라히드로퓨란과 디클로로메탄(1:1) 혼합 용매에 4-니트로페닐 클로로포메이트(24 mg, 0.12 mmol)와 상기 단계 1에서 수득한 4-(이소퀴놀린-5-일)아닐린 (25 mg, 0.11 mmol)을 녹인 후 디이소프로필에틸아민(0.024 mL, 0.13 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 용매에 4-(이소퀴놀린-5-일)아닐린 (25 mg, 0.11 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.019 mL, 0.11 mmol)을 넣고 실온에서 5시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(이소퀴놀린-5-일)페닐)-3-(3,4,5-트리메톡시페닐)우레아(43 mg, 90 %)를 얻었다. 4-nitrophenyl chloroformate (24 mg, 0.12 mmol) in tetrahydrofuran and dichloromethane (1: 1) mixed solvent and 4- (isoquinolin-5-yl) aniline (25 mg, 0.11 mmol) was dissolved, diisopropylethylamine (0.024 mL, 0.13 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. 4- (isoquinolin-5-yl) aniline (25 mg, 0.11 mmol) was dissolved in the solvent, added to the reaction product, and then diisopropylethylamine (0.019 mL, 0.11 mmol) was added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (isoquinolin-5-yl) phenyl) -3- (3,4,5-trimethoxyphenyl Urea (43 mg, 90%) was obtained.
1H NMR (400MHz, CDCl3): δ 6.71 ( s, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.11 (d, J= 9.0 Hz, 1H), 8.39 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H), 3.81 (s, 3H), 3.77 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.71 (s, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.8 Hz , 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.11 (d, J = 9.0 Hz , 1H), 8.39 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H), 3.81 (s, 3H), 3.77 (s, 6H).
<실시예 2> 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-페닐옥시페닐)우레아의 제조Example 2 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (4-phenyloxyphenyl) urea
Figure PCTKR2009005326-appb-I000006
Figure PCTKR2009005326-appb-I000006
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-페닐옥시페닐)우레아의 제조Step 2: Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (4-phenyloxyphenyl) urea
테트라히드로퓨란과 디클로로메탄(1:1) 혼합 용매에 4-니트로페닐 클로로포메이트(24 mg, 0.12 mmol)와 4-페닐옥시아닐린(20 mg, 0.11 mmol)을 녹인 후 디이소프로필에틸아민(0.024 mL, 0.13 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 용매에 상기 단계 1에서 제조한 4-(이소퀴놀린-5-일)아닐린(25 mg, 0.11 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.019 mL, 0.11 mmol)을 넣고 실온에서 5시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-페닐옥시페닐)우레아(41 mg, 87 %)를 얻었다. 4-nitrophenyl chloroformate (24 mg, 0.12 mmol) and 4-phenyloxyaniline (20 mg, 0.11 mmol) were dissolved in a mixed solvent of tetrahydrofuran and dichloromethane (1: 1), followed by diisopropylethylamine ( 0.024 mL, 0.13 mmol) was added and stirred at room temperature for 0.5 hour. 4- (isoquinolin-5-yl) aniline (25 mg, 0.11 mmol) prepared in step 1 was dissolved in a solvent and added to the reaction mixture, followed by adding diisopropylethylamine (0.019 mL, 0.11 mmol) at room temperature. Stir for hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1:10) to give 1- (4- (isoquinolin-5-yl) phenyl) -3- (4-phenyloxyphenyl) urea (41 mg). , 87%).
1H NMR (400MHz, CDCl3): δ 6.83 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.4 Hz, 2H), 7.28 (bs, 2H), 7.45 (d, J = 6.0 Hz, 3H), 7.52 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 4.9 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 8.10 (s, 1H), 8.29 (bs, 2H), 9.24 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.83 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 7.19 (t , J = 7.4 Hz, 2H), 7.28 (bs, 2H), 7.45 (d, J = 6.0 Hz, 3H), 7.52 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 4.9 Hz, 1H ), 7.88 (d, J = 7.4 Hz, 1H), 8.10 (s, 1H), 8.29 (bs, 2H), 9.24 (s, 1H).
<실시예 3> 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일) 페닐)우레아의 제조Example 3 Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea
Figure PCTKR2009005326-appb-I000007
Figure PCTKR2009005326-appb-I000007
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일) 페닐)우레아의 제조Step 2: Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea
디클로로메탄 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(10 mg, 0.05 mmol)과 1-클로로-4-이소시아네이토-2-(트리플루오로메틸)벤젠(11 mg, 0.05 mmol)을 넣고 실온에서 0.5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하였다. 무수 황산마그네슘으로 건조 후 감압 농축하고 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아(21 mg, 93 %)를 얻었다.4- (isoquinolin-5-yl) aniline (10 mg, 0.05 mmol) and 1-chloro-4-isocyanato-2- (trifluoromethyl) benzene prepared in step 1 in dichloromethane solvent ( 11 mg, 0.05 mmol) were added and reacted at room temperature for 0.5 hour. After the reaction was washed with water and brine and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was purified by column chromatography (methanol: dichloromethane = 1:10) to give 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4 -(Isoquinolin-5-yl) phenyl) urea (21 mg, 93%) was obtained.
1H NMR (400MHz, CD3OD): δ 7.44 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 3H), 7.75 (m, 2H), 7.84 (d, J = 5.9 Hz, 1H), 8.05 (s, 1H), 8.11 (dd, J = 5.5, 3.4 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 9.29 (s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 7.44 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 3H), 7.75 ( m, 2H), 7.84 (d, J = 5.9 Hz, 1H), 8.05 (s, 1H), 8.11 (dd, J = 5.5, 3.4 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 9.29 (s, 1 H).
<실시예 4> 에틸 3-(3-(4-(이소퀴놀린-5-일)페닐)우레이도)벤조에이트의 제조Example 4 Preparation of Ethyl 3- (3- (4- (isoquinolin-5-yl) phenyl) ureido) benzoate
Figure PCTKR2009005326-appb-I000008
Figure PCTKR2009005326-appb-I000008
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 에틸 3-(3-(4-(이소퀴놀린-5-일)페닐)우레이도)벤조에이트의 제조Step 2: Preparation of ethyl 3- (3- (4- (isoquinolin-5-yl) phenyl) ureido) benzoate
디클로로메탄 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(10 mg, 0.05 mmol)과 3-이소시아네이토 벤조에이트(8.3 μl, 0.05 mmol)를 넣고 실온에서 0.5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하였다. 무수 황산마그네슘으로 건조 후 감압 농축하고 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 에틸 3-(3-(4-(이소퀴놀린-5-일)페닐)우레이도)벤조에이트(19 mg, 98 %)를 얻었다. 4- (isoquinolin-5-yl) aniline (10 mg, 0.05 mmol) and 3-isocyanato benzoate (8.3 μl, 0.05 mmol) prepared in step 1 were added to a dichloromethane solvent for 0.5 hour at room temperature. Reacted for a while. After the reaction was washed with water and brine and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was purified by column chromatography (methanol: dichloromethane = 1:10) to give ethyl 3- (3- (4- (isoquinolin-5-yl) phenyl) ureido). Benzoate (19 mg, 98%) was obtained.
1H NMR (400MHz, CD3OD): δ 1.27 (bs, 3H), 4.35 (bs, 2H), 7.40 (m, 3H), 7.62-7.81 (m, 7H), 8.08 (bs, 1H), 8.16 (s, 1H), 8.37 (bs, 1H), 9.26(s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 1.27 (bs, 3H), 4.35 (bs, 2H), 7.40 (m, 3H), 7.62-7.81 (m, 7H), 8.08 (bs, 1H), 8.16 (s, 1 H), 8.37 (bs, 1 H), 9.26 (s, 1 H).
<실시예 5> 1-(벤조[d][1,3]다이옥솔-5-일)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Example 5 Preparation of 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4- (isoquinolin-5-yl) phenyl) urea
Figure PCTKR2009005326-appb-I000009
Figure PCTKR2009005326-appb-I000009
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(벤조[d][1,3]다이옥솔-5-일)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Step 2: Preparation of 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4- (isoquinolin-5-yl) phenyl) urea
디클로로메탄 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(10 mg, 0.05 mmol)과 3,4-(메틸렌디옥시)페닐이소시아네이트(8 mg, 0.05 mmol)를 넣고 실온에서 0.5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하였다. 무수 황산마그네슘으로 건조 후 감압 농축하고 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(벤조[d][1,3]다이옥솔-5-일)-3-(4-(이소퀴놀린-5-일)페닐)우레아(18 mg, 91 %)를 얻었다. 4- (isoquinolin-5-yl) aniline (10 mg, 0.05 mmol) and 3,4- (methylenedioxy) phenyl isocyanate (8 mg, 0.05 mmol) prepared in step 1 were added to a dichloromethane solvent. The reaction was carried out for 0.5 hours at. After the reaction was washed with water and brine and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was purified by column chromatography (methanol: dichloromethane = 1:10) to give 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4- (isoquinolin-5-yl) phenyl) urea (18 mg, 91%) was obtained.
1H NMR (400MHz, CD3OD): δ 5.92 (s, 2H), 6.78 (s, 2H), 7.16 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 8.12 (m, 1H), 8.41 (d, J = 7.4 Hz, 1H), 9.30 (s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 5.92 (s, 2H), 6.78 (s, 2H), 7.16 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 8.12 (m, 1H), 8.41 (d, J = 7.4 Hz, 1 H), 9.30 (s, 1 H).
<실시예 6> 5-(4-(3-(4-클로로-3-(트리플루오로메틸)페닐)우레이도)페닐) 이소퀴놀린-1-카르복시아미드의 제조Example 6 Preparation of 5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide
단계 1": t-부틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일) 페닐카르보네이트의 제조Step 1 ″: Preparation of t-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbonate
Figure PCTKR2009005326-appb-I000010
Figure PCTKR2009005326-appb-I000010
1,4-디옥산과 물(2:1)의 혼합 용매에 4-4,4,5,5-테트라메틸-1,3,2-디옥사자보로란-2-일)아닐린(219.1 mg, 1 mmol)과 탄산나트륨(212.0 mg, 2 mmol)을 녹인 후 디-t-부틸 디카르보네이트(262 mg, 1.2 mmol)를 넣고 상온에서 15시간 반응시켰다. 반응 종료 후 포화 탄산수소나트륨 수용액과 물로 씻어주고 디클로로메탄으로 추출 한 후 무수 황산마그네슘 건조하고 감압 농축하였다. 농축 후 잔여물은 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 t-부틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)페닐카르보네이트(284 mg, 89 %)를 얻었다. 4-4,4,5,5-tetramethyl-1,3,2-dioxazaborolan-2-yl) aniline (219.1 mg) in a mixed solvent of 1,4-dioxane and water (2: 1) , 1 mmol) and sodium carbonate (212.0 mg, 2 mmol) were dissolved, and then di-t-butyl dicarbonate (262 mg, 1.2 mmol) was added thereto and reacted at room temperature for 15 hours. After completion of the reaction, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to give t-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl) phenylcarbonate (284 mg, 89%) was obtained.
1H NMR (400MHz,CDCl3): δ 1.35 (s, 12H), 1.53 (s, 9H), 6.54 (s, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.35 (s, 12H), 1.53 (s, 9H), 6.54 (s, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H).
단계 2": t-부틸 4-(이소퀴놀린-5-일)페닐카르보네이트의 제조Step 2 ": Preparation of t-butyl 4- (isoquinolin-5-yl) phenylcarbonate
Figure PCTKR2009005326-appb-I000011
Figure PCTKR2009005326-appb-I000011
디메톡시에탄 용매에 5-브로모이소퀴놀린(50 mg, 0.24 mmol), 상기 단계 1"에서 제조된 t-부틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)페닐카르보네이트(84 mg, 0.26 mmol), PdCl2(dppf)(19.6 mg, 0.024 mmol)와 탄산칼륨(166 g, 1.2 mmol)을 넣고 80 ℃에서 18시간 동안 환류 교반하였다. 반응물을 물과 소금물로 씻어준 후 에틸아세테이트로 추출하고 무수 황산 마그네슘 건조 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:2)로 정제하여 t-부틸 4-(이소퀴놀린-5-일)페닐카르보네이트(65 mg, 84 %)를 얻었다. 5-bromoisoquinoline (50 mg, 0.24 mmol) in dimethoxyethane solvent, t-butyl-4- (4,4,5,5-tetramethyl-1,3,2- prepared in step 1 "above Dioxaborolan-2-yl) phenylcarbonate (84 mg, 0.26 mmol), PdCl 2 (dppf) (19.6 mg, 0.024 mmol) and potassium carbonate (166 g, 1.2 mmol) were added and the mixture was heated at 80 ° C. to 18 The reaction mixture was washed with water and brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. tert-Butyl 4- (isoquinolin-5-yl) phenylcarbonate (65 mg, 84%) was obtained.
1H NMR (400MHz,CDCl3): δ 1.55 (s, 9H), 6.87 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.65 (m, 2H), 7.75 (d, J = 6.0 Hz, 1H), 7.97 (dd, J = 6.0, 3.2 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 9.30 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.55 (s, 9H), 6.87 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.65 (m, 2H), 7.75 (d, J = 6.0 Hz, 1H), 7.97 (dd, J = 6.0, 3.2 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 9.30 (s, 1H) .
단계 3": 5-(4-(t-부톡시카르보닐아미노)페닐)이소퀴놀린 2-옥사이드의 제조Step 3 ″: Preparation of 5- (4- (t-butoxycarbonylamino) phenyl) isoquinoline 2-oxide
Figure PCTKR2009005326-appb-I000012
Figure PCTKR2009005326-appb-I000012
클로로포름 용매에 단계 2"에서 제조된 t-부틸 4-(이소퀴놀린-5-일)페닐카르보네이트 (20 mg, 0.06 mmol)을 녹인 후 0 ℃에서 3-클로로퍼벤조산(28 mg, 0.12 mmol)을 첨가하였다. 이 후 반응 온도를 실온으로 상승시키고 이 온도에서 12시간 동안 교반시켰다. 반응 후 생성된 고체를 감압 여과하여 제거하고 감압 농축하여 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 5-(4-(t-부톡시카르보닐아미노)페닐)이소퀴놀린 2-옥사이드(19 mg, 92 %)를 얻었다. Dissolve t-butyl 4- (isoquinolin-5-yl) phenylcarbonate (20 mg, 0.06 mmol) prepared in step 2 "in chloroform solvent and then 3-chloroperbenzoic acid (28 mg, 0.12 mmol) at 0 ° C. The reaction temperature was then raised to room temperature and stirred at this temperature for 12 hours The resulting solid was removed by filtration under reduced pressure and concentrated under reduced pressure to give column chromatography (methanol: dichloromethane = 1: 10). Purification with 5 gave 4- (4- (t-butoxycarbonylamino) phenyl) isoquinoline 2-oxide (19 mg, 92%).
1H NMR (400MHz, CD3OD): δ 1.56 (s, 9H), 7.40 (d, J = 6.7 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.81 (t, J = 8.2 Hz, 2H), 7.98 (m, 2H), 8.18 (dd, J = 7.2, 2.0 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 1.56 (s, 9H), 7.40 (d, J = 6.7 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.81 (t, J = 8.2 Hz, 2H), 7.98 (m, 2H), 8.18 (dd, J = 7.2, 2.0 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H).
단계 4": 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴의 제조Step 4 ": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
Figure PCTKR2009005326-appb-I000013
Figure PCTKR2009005326-appb-I000013
테트라히드로퓨란 용매에 상기 단계 3"에서 제조된 5-(4-(t-부톡시카르보닐아미노)페닐)이소퀴놀린 2-옥사이드(100 mg, 0.3 mmol)와 트라이메틸실릴시아나이드(48 μl, 0.4 mmol)를 넣고 반응물에 DBU(99 μl)를 천천히 가한 후, 90 ℃에서 2시간 동안 환류 교반하였다. 반응 종료 후 감압 농축하여 용매를 제거하고 재결정하여 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴(48 mg, 65 %)을 얻었다. In tetrahydrofuran solvent, 5- (4- (t-butoxycarbonylamino) phenyl) isoquinoline 2-oxide (100 mg, 0.3 mmol) and trimethylsilyl cyanide (48 μl, 0.4 mmol) was added and DBU (99 μl) was slowly added to the reaction, followed by stirring under reflux for 2 hours at 90 ° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent and recrystallized to obtain 5- (4-aminophenyl) isoquinoline- 1-carbonitrile (48 mg, 65%) was obtained.
1H NMR (400MHz, CD3OD): δ 7.64 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.92 (dd, J = 7.2, 1.0 Hz, 1H), 7.99 (m, 2H), 8.43 (dt, J = 8.4, 1.0 Hz, 1H), 8.64 (d, J = 5.9 Hz, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 7.64 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.92 (dd, J = 7.2, 1.0 Hz, 1H), 7.99 (m, 2H), 8.43 (dt, J = 8.4, 1.0 Hz, 1H), 8.64 (d, J = 5.9 Hz, 1H).
단계 5": 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(1-시아노이소퀴놀린-5-일)페닐)우레아의 제조Step 5 ″: Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea
Figure PCTKR2009005326-appb-I000014
Figure PCTKR2009005326-appb-I000014
디클로로메탄 용매에 상기 단계 4"에서 제조된 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴(15 mg, 0.06 mmol)과 1-클로로-4-이소시아네이토-2-(트리플루오로메틸)벤젠(15 mg, 0.07 mmol)을 넣고 실온에서 2시간 동안 반응시켰다. 반응 후 생성된 고체를 감압 여과하고 여과한 고체를 디클로로메탄과 디에틸에테르로 세척하고 건조하여 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(1-시아노이소퀴놀린-5-일)페닐)우레아(24 mg, 86 %)를 얻었다. 5- (4-aminophenyl) isoquinoline-1-carbonitrile (15 mg, 0.06 mmol) and 1-chloro-4-isocyanato-2- (trifluoro) prepared in step 4 "in dichloromethane solvent Chloromethyl) benzene (15 mg, 0.07 mmol) was added and reacted at room temperature for 2 hours The resulting solid was filtered under reduced pressure and the filtered solid was washed with dichloromethane and diethyl ether and dried to obtain 1- (4- Chloro-3- (trifluoromethyl) phenyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea (24 mg, 86%) was obtained.
1H NMR (400MHz, DMSO-d6): δ 7.47 (d, J = 8.3 Hz, 2H), 7.67 (m, 4H), 7.90 (d, J = 7.1 Hz, 1H), 7.99 (m, 1H), 8.08 (d, J = 5.8 Hz, 1H), 8.13 (s, 1H), 8.28 (d J = 8.4 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 9.15 (s, 1H), 9.29 (s, 1H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.47 (d, J = 8.3 Hz, 2H), 7.67 (m, 4H), 7.90 (d, J = 7.1 Hz, 1H), 7.99 (m, 1H) , 8.08 (d, J = 5.8 Hz, 1H), 8.13 (s, 1H), 8.28 (d J = 8.4 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 9.15 (s, 1H), 9.29 (s, 1 H).
단계 6": 5-(4-(3-(4-클로로-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드의 제조Step 6 ″: Preparation of 5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide
Figure PCTKR2009005326-appb-I000015
Figure PCTKR2009005326-appb-I000015
에탄올과 물(20:1)의 혼합 용매에 상기 단계 5"에서 제조된 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(1-시아노이소퀴놀린-5-일)페닐)우레아(15 mg, 0.03 mmol)와 수산화칼륨(83 mg, 1.5 mmol)을 넣고 90 ℃에서 2시간 동안 환류 교반하였다. 반응 종료 후 1 N 염산 수용액으로 중화하고 생성된 고체를 감압 여과하여 물과 디에틸에테르로 세척하고 건조시켜 5-(4-(3-(4-클로로-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드(14 mg, 93 %)를 얻었다. In a mixed solvent of ethanol and water (20: 1), 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1-cyanoisoquinoline- 5-yl) phenyl) urea (15 mg, 0.03 mmol) and potassium hydroxide (83 mg, 1.5 mmol) were added and stirred under reflux for 2 hours at 90 ° C. After completion of the reaction, the reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, and the resulting solid was solid Filtration under reduced pressure, washing with water and diethyl ether, and drying to give 5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide (14 mg, 93%).
1H NMR (400MHz, DMSO-d6): δ 7.43 (d, J = 8.4 Hz, 2H), 7.84-7.62 (m, 8H), 8.13 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 8.84 (d, J = 8.1 Hz, 1H), 9.18 (s,1H), 9.36 (s, 1H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.43 (d, J = 8.4 Hz, 2H), 7.84-7.62 (m, 8H), 8.13 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 8.84 (d, J = 8.1 Hz, 1H), 9.18 (s, 1H), 9.36 (s, 1H).
<실시예 7> 5-(4-(3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드의 제조Example 7 5- (4- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1 Preparation of Carboxyamide
제조예: 4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)아닐린의 제조Preparation Example: Preparation of 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline
Figure PCTKR2009005326-appb-I000016
Figure PCTKR2009005326-appb-I000016
1-메틸-4-니트로-2-트리플루오로메틸벤젠(2.0 g, 9.7 mmol), N-브로모석신이미드(1.7 g, 9.7 mmol) 및 AIBN(160 mg, 0.97 mmol)을 사염화탄소 용매에 용해시킨 후 15시간 동안 환류 교반하였다. 반응 종료 후 물과 소금물로 씻어주고 디클로로메탄으로 추출한 후 무수 황산 마그네슘으로 건조 후 감압 농축하였다. 농축 후 생성된 고체를 여과하여 건조 후 디클로로메탄 용매에 녹였다. 반응 용액에 디이소프로필에틸아민(1.7 mL, 9.7 mmol)과 N-에틸피페라진(1.2 mL, 9.7 mmol)을 가한 후 실온에서 0.5시간 동안 교반하였다. 반응물을 물로 씻어주고 디클로로메탄으로 추출 후 무수 황산 마그네슘으로 건조시킨 후 감압 농축하고 컬럼 크로마토그래피 (헥산:에틸아세테이트 = 1:1)로 정제하여 1-에틸-4-(4-니트로-2-(트리플루오로메틸)벤질)피페라진 (2.9 g, 95 %)을 얻었다. 상기 1-에틸-4-(4-니트로-2-(트리플루오로메틸)벤질)피페라진(2.9 g, 9.2 mmol)을 메탄올에 용해시킨 후 팔라듐 챠콜과 수소 압력 하에서 12시간 동안 교반하였다. 반응물을 셀라이트로 여과하고 감압 농축한 후 디에틸에테르와 헥산으로 재결정하여 4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)아닐린(2.6 g, 97 %)을 얻었다. 1-methyl-4-nitro-2-trifluoromethylbenzene (2.0 g, 9.7 mmol), N-bromosuccinimide (1.7 g, 9.7 mmol) and AIBN (160 mg, 0.97 mmol) were added to a carbon tetrachloride solvent. After dissolution, the mixture was stirred at reflux for 15 hours. After completion of the reaction, the mixture was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The solid produced after concentration was filtered, dried and dissolved in dichloromethane solvent. Diisopropylethylamine (1.7 mL, 9.7 mmol) and N-ethylpiperazine (1.2 mL, 9.7 mmol) were added to the reaction solution, followed by stirring at room temperature for 0.5 hour. The reaction was washed with water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by column chromatography (hexane: ethyl acetate = 1: 1) and purified by 1-ethyl-4- (4-nitro-2- ( Trifluoromethyl) benzyl) piperazine (2.9 g, 95%) was obtained. The 1-ethyl-4- (4-nitro-2- (trifluoromethyl) benzyl) piperazine (2.9 g, 9.2 mmol) was dissolved in methanol and stirred for 12 hours under palladium charcoal and hydrogen pressure. The reaction was filtered through celite, concentrated under reduced pressure, and recrystallized with diethyl ether and hexane to give 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (2.6 g, 97 %) Was obtained.
1H NMR (400MHz, CDCl3): δ 1.09 (t, J = 6.8 Hz, 3H), 2.39-2.50 (m, 10 H), 3.53 (s, 2H), 3.76 (bs, 2H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.09 (t, J = 6.8 Hz, 3H), 2.39-2.50 (m, 10H), 3.53 (s, 2H), 3.76 (bs, 2H), 6.79 (dd , J = 8.4, 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H).
단계 1"~단계 4": 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴의 제조Step 1 "to Step 4": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
실시예 6의 단계 1"~단계 4"와 동일한 방법으로 수행하여 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴을 제조하였다.5- (4-aminophenyl) isoquinoline-1-carbonitrile was prepared in the same manner as in Step 1 "-Step 4" of Example 6.
단계 5": 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아의 제조Step 5 ″: 1- (4- (1-Cyanoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoro Preparation of Methyl) phenyl) urea
Figure PCTKR2009005326-appb-I000017
Figure PCTKR2009005326-appb-I000017
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐클로로포메이트(38 mg, 0.20 mmol)와 제조예에서 제조된 4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)아닐린(50 mg, 0.17 mmol)을 용해시킨 후 디이소프로필에틸아민(0.04 mL, 0.21 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 상기 혼합 용매에 단계 4"에서 제조된 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴(42 mg, 0.17 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.03 mL, 0.17 mmol)을 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 생성물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아(75 mg, 79 %)를 얻었다. 4-((4-ethylpiperazin-1-yl) methyl prepared in the preparation example with 4-nitrophenylchloroformate (38 mg, 0.20 mmol) in a mixed solvent of tetrahydrofuran and dichloromethane (1: 1) ) -3- (trifluoromethyl) aniline (50 mg, 0.17 mmol) was dissolved, diisopropylethylamine (0.04 mL, 0.21 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. In the mixed solvent, 5- (4-aminophenyl) isoquinoline-1-carbonitrile (42 mg, 0.17 mmol) prepared in step 4 "was dissolved and added to the reaction product, followed by diisopropylethylamine (0.03 mL, 0.17 mmol After the reaction was completed, the product was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was concentrated by column chromatography (methanol: dichloromethane). = 1:10) to give 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (Trifluoromethyl) phenyl) urea (75 mg, 79%) was obtained.
1H NMR (400MHz, CDCl3): δ 1.09 (t, J = 7.2 Hz, 3H), 2.44 (m, 10H), 7.36 (d, J = 8.4 Hz, 2H), 7.70-7.53 (m, 8H), 7.81 (m, 1H), 7.89 (d, J = 5.8 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 5.8 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.09 (t, J = 7.2 Hz, 3H), 2.44 (m, 10H), 7.36 (d, J = 8.4 Hz, 2H), 7.70-7.53 (m, 8H) , 7.81 (m, 1H), 7.89 (d, J = 5.8 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 5.8 Hz, 1H).
단계 6": 5-(4-(3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드의 제조Step 6 ": 5- (4- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1- Preparation of Carboxamides
Figure PCTKR2009005326-appb-I000018
Figure PCTKR2009005326-appb-I000018
에탄올과 물(20:1)의 혼합 용매에 상기 단계 5"에서 제조된 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아(17 mg, 0.03 mmmol)와 수산화칼륨(83 mg, 1.5 mmol)을 넣고 90 ℃에서 1시간 동안 환류 교반하였다. 반응 종료 후 1 N 염산 수용액으로 중화하고, 생성된 고체를 감압 여과하여 물과 디에틸에테르로 세척하고 건조한 후 5-(4-(3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드(16 mg, 96 %)를 얻었다. To a mixed solvent of ethanol and water (20: 1) 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpipepea) prepared in step 5 "above. Razin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea (17 mg, 0.03 mmmol) and potassium hydroxide (83 mg, 1.5 mmol) were added thereto, and the mixture was stirred under reflux at 90 ° C. for 1 hour. After completion, the solution was neutralized with 1N aqueous hydrochloric acid solution, the resulting solid was filtered under reduced pressure, washed with water and diethyl ether, and dried. 5- (4- (3- (4-((4-ethylpiperazin-1-yl) Methyl) -3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide (16 mg, 96%) was obtained.
1H NMR (400MHz, CD3OD): δ 1.11 (t, J = 7.2 Hz, 3H), 2.45 (m, 10H), 3.64 (s, 2H), 7.41 (m, 2H), 7.79-7.63 (m, 7H), 7.95 (m, 2H), 8.46 (d, J = 5.9 Hz, 1H), 8.56 (s, 1H), 8.91 (m, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 1.11 (t, J = 7.2 Hz, 3H), 2.45 (m, 10H), 3.64 (s, 2H), 7.41 (m, 2H), 7.79-7.63 (m , 7H), 7.95 (m, 2H), 8.46 (d, J = 5.9 Hz, 1H), 8.56 (s, 1H), 8.91 (m, 1H).
<실시예 8> 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드의 제조Example 8 Preparation of 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide
단계 1"~단계 4": 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴의 제조Step 1 "to Step 4": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
실시예 6의 단계 1"~단계 4"와 동일한 방법으로 수행하여 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴을 제조하였다.5- (4-aminophenyl) isoquinoline-1-carbonitrile was prepared in the same manner as in Step 1 "-Step 4" of Example 6.
단계 5": 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드의 제조Step 5 ″: Preparation of 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide
Figure PCTKR2009005326-appb-I000019
Figure PCTKR2009005326-appb-I000019
디클로로메탄 용매에 상기 단계 4"에서 제조된 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴(15 mg, 0.06 mmol)과 1-벤질-3-이소시아네이토벤젠(15 mg, 0.07 mmol)을 넣고 실온에서 2시간 동안 반응시켰다. 반응 후 생성된 고체를 감압 여과하고 여과한 고체를 디클로로메탄과 디에틸에테르로 세척하고 건조하여 1-(3-벤질메틸)-3-(4-(1-시아노이소퀴놀린-5-일)페닐)우레아(26 mg, 96 %)를 얻었다. 5- (4-aminophenyl) isoquinoline-1-carbonitrile (15 mg, 0.06 mmol) and 1-benzyl-3-isocyanatobenzene (15 mg, 0.07) prepared in step 4 "in dichloromethane solvent mmol), and the resulting solid was filtered under reduced pressure, and the filtered solid was washed with dichloromethane and diethyl ether and dried to obtain 1- (3-benzylmethyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea (26 mg, 96%) was obtained.
1H NMR (400MHz, CDCl3): δ 3.98 (s, 2H), 6.71 (s, 1H), 6.90 (s, 1H), 7.02 (d, J = 7.4 Hz, 1H), 7.32-7.10 (m, 8H), 7.38 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 7.1, 1.0 Hz, 1H), 7.83 (m, 1H), 7.94 (d, J = 5.9 Hz, 1H), 8.37 (d, J = 8.4 Hz, 2H), 8.57 (d, J = 5.9 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 3.98 (s, 2H), 6.71 (s, 1H), 6.90 (s, 1H), 7.02 (d, J = 7.4 Hz, 1H), 7.32-7.10 (m, 8H), 7.38 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 7.1, 1.0 Hz, 1H), 7.83 (m, 1H), 7.94 ( d, J = 5.9 Hz, 1H), 8.37 (d, J = 8.4 Hz, 2H), 8.57 (d, J = 5.9 Hz, 1H).
<실시예 9> 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드의 제조Example 9 Preparation of 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide
단계 1"~단계 4": 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴의 제조Step 1 "to Step 4": Preparation of 5- (4-aminophenyl) isoquinoline-1-carbonitrile
실시예 6의 단계 1"~단계 4"와 동일한 방법으로 수행하여 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴을 제조하였다.5- (4-aminophenyl) isoquinoline-1-carbonitrile was prepared in the same manner as in Step 1 "-Step 4" of Example 6.
단계 5": 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(3-페닐옥시페닐)우레아의 제조Step 5 ″: Preparation of 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (3-phenyloxyphenyl) urea
Figure PCTKR2009005326-appb-I000020
Figure PCTKR2009005326-appb-I000020
디클로로메탄 용매에 5-(4-아미노페닐)이소퀴놀린-1-카르보니트릴 (15 mg, 0.06 mmol)과 1-이소시아네이토-3-페닐옥시벤젠 (15 mg, 0.07 mmol)을 넣고 실온에서 2 시간 반응시켰다. 반응 후 생성된 고체를 감압 여과하고 여과 한 고체를 디클로로메탄과 디에틸에테르로 씻어주고 건조하여 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(3-페닐옥시페닐)우레아 (25 mg, 92 %)를 얻었다.5- (4-aminophenyl) isoquinoline-1-carbonitrile (15 mg, 0.06 mmol) and 1-isocyanato-3-phenyloxybenzene (15 mg, 0.07 mmol) were added to a dichloromethane solvent at room temperature. The reaction was carried out for 2 hours. After the reaction, the produced solid was filtered under reduced pressure, and the filtered solid was washed with dichloromethane and diethyl ether and dried to obtain 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (3-phenyl Oxyphenyl) urea (25 mg, 92%) was obtained.
1H NMR (400MHz, CDCl3): δ 6.75 (dd, J = 8.2, 1.8 Hz, 1H), 6.94 (s, 1H), 7.01 (m, 2H), 7.11(m, 3H), 7.30 (m, 3H), 7.38 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 7.2, 0.9 Hz, 1H), 7.82 (m, 1H), 7.92 (d, J = 5.9 Hz, 1H), 8.36 (d, J = 8.4 Hz, 2H), 8.56 (d, J = 5.8 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.75 (dd, J = 8.2, 1.8 Hz, 1H), 6.94 (s, 1H), 7.01 (m, 2H), 7.11 (m, 3H), 7.30 (m, 3H), 7.38 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 7.2, 0.9 Hz, 1H), 7.82 (m, 1H), 7.92 ( d, J = 5.9 Hz, 1H), 8.36 (d, J = 8.4 Hz, 2H), 8.56 (d, J = 5.8 Hz, 1H).
단계 6": 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드의 제조Step 6 ": Preparation of 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide
Figure PCTKR2009005326-appb-I000021
Figure PCTKR2009005326-appb-I000021
에탄올과 물(20:1)의 혼합 용매에 상기 단계 5"에서 제조된 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(3-페닐옥시페닐)우레아(14 mg, 0.03 mmmol)와 수산화칼륨(83 mg, 1.5 mmol)을 넣고 90 ℃에서 1시간 동안 환류 교반하였다. 반응 종료 후 1 N 염산 수용액으로 중화하고, 생성된 고체를 감압 여과하여 물과 디에틸에테르로 세척하고 건조시켜 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드(13 mg, 90 %)를 얻었다. 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (3-phenyloxyphenyl) urea prepared in step 5 "in a mixed solvent of ethanol and water (20: 1) 14 mg, 0.03 mmmol) and potassium hydroxide (83 mg, 1.5 mmol) were added thereto, and the mixture was stirred under reflux for 1 hour at 90 ° C. After completion of the reaction, the mixture was neutralized with an aqueous solution of 1 N hydrochloric acid, and the resulting solid was filtered under reduced pressure to obtain water and diethyl. Washing with ether and drying gave 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide (13 mg, 90%).
1H NMR (400MHz, DMSO-d6): δ 6.61 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 7.15 (m, 2H), 7.28 (m, 2H), 7.40 (m, 4H), 7.61 (d, J = 7.7 Hz, 2H), 7.83-7.71 (m, 4H), 8.25 (s, 1H), 8.48 (d, J = 5.7 Hz, 1H), 8.82 (d, J = 7.7 Hz, 1H), 8.97 (d, J = 4.8 Hz, 2H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 6.61 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 7.15 (m, 2H), 7.28 (m, 2H) , 7.40 (m, 4H), 7.61 (d, J = 7.7 Hz, 2H), 7.83-7.71 (m, 4H), 8.25 (s, 1H), 8.48 (d, J = 5.7 Hz, 1H), 8.82 ( d, J = 7.7 Hz, 1H), 8.97 (d, J = 4.8 Hz, 2H).
<실시예 10> 1-(4-(이소퀴놀린-5-일)페닐)-3-(1-메틸-1H-인돌-6-일)우레아의 제조Example 10 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (1-methyl-1H-indol-6-yl) urea
Figure PCTKR2009005326-appb-I000022
Figure PCTKR2009005326-appb-I000022
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-(이소퀴놀린-5-일)페닐)-3-(1-메틸-1H-인돌-6-일)우레아의 제조Step 2: Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (1-methyl-1H-indol-6-yl) urea
디클로로메탄 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(10 mg, 0.05 mmol)과 6-이소시아네이토-1-메틸-1H-인돌(8.6 mg, 0.05 mmol)을 넣고 실온에서 0.5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하였다. 무수 황산마그네슘으로 건조한 후 감압 농축하고 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(이소퀴놀린-5-일)페닐)-3-(1-메틸-1H-인돌-6-일)우레아(18 mg, 91 %)를 얻었다. 4- (isoquinolin-5-yl) aniline (10 mg, 0.05 mmol) and 6-isocyanato-1-methyl-1H-indole (8.6 mg, 0.05 mmol) prepared in step 1 above in dichloromethane solvent Was added and reacted at room temperature for 0.5 hour. After the reaction was washed with water and brine and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (isoquinolin-5-yl) phenyl) -3- (1-methyl -1H-indol-6-yl) urea (18 mg, 91%) was obtained.
1H NMR (400MHz, DMSO-d6): δ 3.73 (s, 3H), 6.34 (bs, 1H), 6.91 (d, J = 8.4 Hz, 1H), 7.21 (m, 1H), 7.43 (d, J = 8.2 Hz, 3H), 7.66-7.81 (m, 6H), 8.12 (d, J = 7.5 Hz, 1H), 8.49 (dd, J = 5.9, 1.5 Hz, 1H), 8.69 (s, 1H), 8.84 (s, 1H), 9.38 (s, 1H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.73 (s, 3H), 6.34 (bs, 1H), 6.91 (d, J = 8.4 Hz, 1H), 7.21 (m, 1H), 7.43 (d, J = 8.2 Hz, 3H), 7.66-7.81 (m, 6H), 8.12 (d, J = 7.5 Hz, 1H), 8.49 (dd, J = 5.9, 1.5 Hz, 1H), 8.69 (s, 1H), 8.84 (s, 1 H), 9.38 (s, 1 H).
<실시예 11> 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아의 제조Example 11 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- ( Preparation of Trifluoromethyl) phenyl) urea
단계 1": 벤질 4-(이소퀴놀린-5-일)페닐카바메이트의 제조Step 1 ″: Preparation of Benzyl 4- (isoquinolin-5-yl) phenylcarbamate
Figure PCTKR2009005326-appb-I000023
Figure PCTKR2009005326-appb-I000023
물과 디에틸에테르(1:1)의 혼합용매에 4-(이소퀴놀린-5-일)아닐린(1.0 g, 4.5 mmol)과 탄산수소나트륨을 녹인 후 벤질 클로로포메이트(0.7 mL, 5.0 mmol)를 넣고 실온에서 5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하고 유기층을 무수 황산마그네슘으로 건조 후 감압 여과하여 농축하였다. 농축 후 남은 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 벤질 4-(이소퀴놀린-5-일)페닐카바메이트(1.3 g, 89 %)를 얻었다. 4- (isoquinolin-5-yl) aniline (1.0 g, 4.5 mmol) and sodium bicarbonate were dissolved in a mixed solvent of water and diethyl ether (1: 1), followed by benzyl chloroformate (0.7 mL, 5.0 mmol). Was added and reacted at room temperature for 5 hours. After completion of the reaction, the mixture was washed with water and brine, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue remaining after concentration was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain benzyl 4- (isoquinolin-5-yl) phenylcarbamate (1.3 g, 89%).
1H NMR (600MHz, CDCl3): δ 5.25 (s, 2H), 6.94 (s, 1H), 7.64-7.67 (m, 7H), 7.56 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.98 (dd, J = 2.4, 6.6 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H), 9.31 (s, 1H). 1 H NMR (600 MHz, CDCl 3 ): δ 5.25 (s, 2H), 6.94 (s, 1H), 7.64-7.67 (m, 7H), 7.56 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.98 (dd, J = 2.4, 6.6 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H), 9.31 (s, 1H).
단계 2": 5-(4-(벤질옥시카르보닐아미노)페닐)이소퀴놀린 2-옥사이드의 제조Step 2 ″: Preparation of 5- (4- (benzyloxycarbonylamino) phenyl) isoquinoline 2-oxide
Figure PCTKR2009005326-appb-I000024
Figure PCTKR2009005326-appb-I000024
클로로포름 용매에 상기 단계 1"에서 제조된 벤질 4-(이소퀴놀린-5-일)페닐카바메이트(700 mg, 1.98 mmol)을 녹인 후 0 ℃에서 3-클로로퍼벤조산(682 mg, 3.95 mmol)을 첨가하였다. 이 후 반응 온도를 실온으로 올리고 이 온도에서 12시간 동안 교반하였다. 반응 후 생성된 고체를 감압 여과하여 제거하고 감압 농축하여 컬럼 크로마토그래피(메탄올:디틀로로메탄 = 1:10)로 정제하여 5-(4-(벤질옥시카르보닐아미노)페닐)이소퀴놀린 2-옥사이드(682 mg, 93 %)를 얻었다. Benzyl 4- (isoquinolin-5-yl) phenylcarbamate (700 mg, 1.98 mmol) prepared in step 1 "was dissolved in chloroform solvent, and 3-chloroperbenzoic acid (682 mg, 3.95 mmol) was added at 0 ° C. The reaction temperature was then raised to room temperature and stirred at this temperature for 12 hours, after which the resulting solid was removed by filtration under reduced pressure and concentrated under reduced pressure by column chromatography (methanol: dithromethane = 1: 10). Purification gave 5- (4- (benzyloxycarbonylamino) phenyl) isoquinoline 2-oxide (682 mg, 93%).
1H NMR (400MHz, CD3OD): δ 5.21 (s, 2H), 7.31-7.45 (m, 7H), 7.63-7.76 (m, 3H), 7.80 (t, J = 8.0 Hz , 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.98(d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.0, 7.2 Hz, 1H), 9.08 (d, J = 1.6 Hz, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 5.21 (s, 2H), 7.31-7.45 (m, 7H), 7.63-7.76 (m, 3H), 7.80 (t, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.0, 7.2 Hz, 1H), 9.08 (d, J = 1.6 Hz, 1H).
단계 3": 벤질 4-(1-클로로이소퀴놀린-5-일)페닐카바메이트의 제조Step 3 ": Preparation of benzyl 4- (1-chloroisoquinolin-5-yl) phenylcarbamate
Figure PCTKR2009005326-appb-I000025
Figure PCTKR2009005326-appb-I000025
클로로포름 용매에 상기 단계 2"에서 제조된 5-(4-(벤질옥시카르보닐아미노)페닐)이소퀴놀린 2-옥사이드(370 mg, 1 mmol)와 포스포러스 옥시클로라이드(1.5 mL,16.9 mmol)을 넣고 3시간 동안 환류 교반하였다. 반응 종료 후 온도를 낮추고 포화 탄산수소나트륨수용액을 넣어 pH를 염기성으로 맞추고 물로 씻어주고 클로로포름으로 추출한 후 무수 황산마그네슘으로 건조하여 감압 농축하였다. 농축 후 남은 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 벤질 4-(1-클로로이소퀴놀린-5-일)페닐카바메이트(369 mg, 95 %)를 얻었다. In a chloroform solvent, 5- (4- (benzyloxycarbonylamino) phenyl) isoquinoline 2-oxide (370 mg, 1 mmol) and phosphorus oxychloride (1.5 mL, 16.9 mmol) prepared in step 2 "were added thereto. After the reaction was completed, the mixture was stirred at reflux for 3 hours, lowered in temperature, added with saturated aqueous sodium hydrogen carbonate solution, adjusted to basic pH, washed with water, extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by chromatography (ethylacetate: hexane = 1: 1) yielded benzyl 4- (1-chloroisoquinolin-5-yl) phenylcarbamate (369 mg, 95%).
1H NMR (600MHz, DMSO-d6): δ 5.16 (s, 1H), 7.31-7.43 (m, 7H), 7.62 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 6.0Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H ), 7.84 (t, J = 8.4 Hz, 1H), 8.24 (d, J = 6.0 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 9.98 (s, 1H). 1 H NMR (600 MHz, DMSO-d 6 ): δ 5.16 (s, 1H), 7.31-7.43 (m, 7H), 7.62 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.84 (t, J = 8.4 Hz, 1H), 8.24 (d, J = 6.0 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H) , 9.98 (s, 1 H).
단계 4": 5-(4-아미노페닐)-N-(3,4-다이메톡시벤질)이소퀴놀린-1-아민의 제조Step 4 ": Preparation of 5- (4-aminophenyl) -N- (3,4-dimethoxybenzyl) isoquinolin-1-amine
Figure PCTKR2009005326-appb-I000026
Figure PCTKR2009005326-appb-I000026
상기 단계 3"에서 제조된 벤질 4-(1-클로로이소퀴놀린-5-일)페닐카바메이트 (389 mg, 1 mmol)와 베라트릴아민을 반응 용기에 넣고 150 ℃에서 2시간 동안 교반하였다. 이후, 실온으로 온도를 낮추고 에틸아세테이트로 희석시킨 후 물과 소금물로 씻어주고 무수 황산 마그네슘으로 건조한 다음 감압 농축하였다. 농축 후 남은 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1.5:1)로 정제하여 5-(4-아미노페닐)-N-(3,4-다이메톡시벤질)이소퀴놀린-1-아민 (238 mg, 62 %)을 얻었다. Benzyl 4- (1-chloroisoquinolin-5-yl) phenylcarbamate (389 mg, 1 mmol) and verratrylamine prepared in step 3 ″ were added to a reaction vessel and stirred at 150 ° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The remaining residue was purified by column chromatography (ethyl acetate: hexane = 1.5: 1). 5- (4-aminophenyl) -N- (3,4-dimethoxybenzyl) isoquinolin-1-amine (238 mg, 62%) was obtained.
1H NMR (600MHz, CDCl3): δ 3.87 (s, 3H), 3.88 (s, 3H), 4.43 (s, 2H), 5.14 (s, 1H), 6.60 (s, 1H), 6.83-6.90 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H ), 7.71 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 6.0 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H). 1 H NMR (600 MHz, CDCl 3 ): δ 3.87 (s, 3H), 3.88 (s, 3H), 4.43 (s, 2H), 5.14 (s, 1H), 6.60 (s, 1H), 6.83-6.90 ( m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 6.0 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H).
단계 5": 1-(4-(1-(3,4-디메톡시벤질아미노)이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아의 제조Step 5 ″: 1- (4- (1- (3,4-Dimethoxybenzylamino) isoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl Preparation of) -3- (trifluoromethyl) phenyl) urea
Figure PCTKR2009005326-appb-I000027
Figure PCTKR2009005326-appb-I000027
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐 클로로포메이트(222 mg, 1.1 mmol)와 상기 실시예 7의 제조예에서 제조된 4-((4-에틸피페라진-1-일)메틸)-3-(트리클로로메틸)아닐린(287 mg, 1.0 mmol)을 용해시킨 후 디이소프로필에틸아민(0.2 mL, 1.2 mmol)을 넣고 실온에서 0.5시간 동알 교반하였다. 상기 혼합 용매에 상기 단계 4"에서 제조된 5-(4-아미노페닐)-N-(3,4-다이메톡시벤질)이소퀴놀린-1-아민(386 mg, 1.0 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.2 mL, 1.0 mmol)을 넣고 실온에서 7시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(1-(3,4-디메톡시벤질아미노)이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아(384 mg, 55 %)를 얻었다. 4-nitrophenyl chloroformate (222 mg, 1.1 mmol) in a mixed solvent of tetrahydrofuran and dichloromethane (1: 1) and 4-((4-ethylpiperazine-) 1-yl) methyl) -3- (trichloromethyl) aniline (287 mg, 1.0 mmol) was dissolved, diisopropylethylamine (0.2 mL, 1.2 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. To the mixed solvent was dissolved 5- (4-aminophenyl) -N- (3,4-dimethoxybenzyl) isoquinolin-1-amine (386 mg, 1.0 mmol) prepared in step 4 "and added to the reaction. After diisopropylethylamine (0.2 mL, 1.0 mmol) was added and stirred at room temperature for 7 hours, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue after concentration was purified by column chromatography (methanol: dichloromethane = 1:10) to give 1- (4- (1- (3,4-dimethoxybenzylamino) isoquinolin-5-yl) phenyl) -3 -(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea (384 mg, 55%) was obtained.
1H NMR (600MHz, CD3OD): δ 1.17 (t, J = 7.2 Hz, 3H), 2.60-2.77 (m, 10H), 3.64 (s, 2H), 3.78 (s, 6H), 4.71 (s, 2H), 6.87 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.53 (bs, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.65 (bs, 2H), 7.71 (d, J = 6.6 Hz, 1H), 7.92 (s, 1H), 8.16 (s, 1H). 1 H NMR (600 MHz, CD 3 OD): δ 1.17 (t, J = 7.2 Hz, 3H), 2.60-2.77 (m, 10H), 3.64 (s, 2H), 3.78 (s, 6H), 4.71 (s , 2H), 6.87 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 7.34 (d , J = 8.4 Hz, 2H), 7.53 (bs, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.65 (bs, 2H), 7.71 (d, J = 6.6 Hz, 1H), 7.92 (s , 1H), 8.16 (s, 1H).
단계 6": 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아Step 6 ": 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl ) Phenyl) urea
Figure PCTKR2009005326-appb-I000028
Figure PCTKR2009005326-appb-I000028
트리플루오로아세트산에 상기 단계 5"에서 제조된 1-(4-(1-(3,4-디메톡시벤질아미노)이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아(5 mg, 0.007 mmol)를 넣고 80 ℃에서 1시간 동안 교반하였다. 반응 종료 후, 실온으로 온도를 낮추고 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아(3.2 mg, 83 %)를 얻었다. 1- (4- (1- (3,4-dimethoxybenzylamino) isoquinolin-5-yl) phenyl) -3- (4-((4-ethyl Piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea (5 mg, 0.007 mmol) was added and stirred for 1 hour at 80 ° C. After the reaction was completed, the temperature was reduced to room temperature and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea (3.2 mg, 83%) was obtained.
1H NMR (400MHz, CDCl3): δ 1.28 (t, J = 6.6 Hz, 3H), 2.65-3.36 (m, 10H), 3.69 (s, 2H), 7.12 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.47 (m, 1H), 7.58-7.74 (m, 5H), 7.19 (d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.28 (t, J = 6.6 Hz, 3H), 2.65-3.36 (m, 10H), 3.69 (s, 2H), 7.12 (d, J = 6.8 Hz, 1H) , 7.36 (d, J = 7.6 Hz, 2H), 7.47 (m, 1H), 7.58-7.74 (m, 5H), 7.19 (d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 8.26 ( d, J = 8.4 Hz, 1H).
<실시예 12> 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)우레아의 제조Example 12 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoro Preparation of Methyl) phenyl) urea
단계 1': 5-브로모-1-니트로이소퀴놀린의 제조Step 1 ′: Preparation of 5-bromo-1-nitroisoquinoline
Figure PCTKR2009005326-appb-I000029
Figure PCTKR2009005326-appb-I000029
디메틸술폭사이드 용매에 3-브로모이소퀴놀린(208 mg, 1 mmol), 포타슘니트레이트(510 mg, 6 mmol)와 HMPA(2 mL)를 넣고 교반하였다. 이후, 무수아세트산(567 μl, 6 mmol), HMPA(2 mL)와 디메틸술폭사이드(4 mL)를 교반한 것을 반응 용기에 천천히 가하여 주었다. 반응 종료 후 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산마그네슘 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:4)로 정제하여 5-브로모-1-니트로이소퀴놀린 (197 mg, 73 %)을 얻었다.3-bromoisoquinoline (208 mg, 1 mmol), potassium nitrate (510 mg, 6 mmol) and HMPA (2 mL) were added and stirred in a dimethyl sulfoxide solvent. After stirring, acetic anhydride (567 μl, 6 mmol), HMPA (2 mL) and dimethyl sulfoxide (4 mL) were slowly added to the reaction vessel. After completion of the reaction, the mixture was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After concentration, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 4) to give 5-bromo-1-nitroisoquinoline (197 mg, 73%).
1H NMR (400MHz, CDCl3): δ 7.65 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 5.8 Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.65 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.38 (d , J = 5.8 Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H).
단계 2': 4-(1-니트로이소퀴놀린-5-일)아닐린의 제조Step 2 ′: Preparation of 4- (1-nitroisoquinolin-5-yl) aniline
Figure PCTKR2009005326-appb-I000030
Figure PCTKR2009005326-appb-I000030
디메톡시에탄 용매에 상기 단계 1'에서 제조된 5-브로모-1-니트로이소퀴놀린(61 mg, 0.24 mmol), t-부틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)페닐카르보네이트(84 mg, 0.26 mmol), PdCl2(dppf)(19.6 mg, 0.024 mmol)와 탄산칼륨(166 g, 1.2 mmol)을 넣고 80 ℃에서 18시간 동안 환류 교반하였다. 생성된 물질을 물과 소금물로 씻어준 후 에틸아세테이트로 추출하고 무수 황산 마그네슘 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:4)로 정제하여 4-(1-니트로이소퀴놀린-5-일)아닐린(57 mg, 89 %)을 얻었다. 5-bromo-1-nitroisoquinoline (61 mg, 0.24 mmol), t-butyl-4- (4,4,5,5-tetramethyl-1, prepared in step 1 'in dimethoxyethane solvent, Add 3,2-dioxaborolan-2-yl) phenylcarbonate (84 mg, 0.26 mmol), PdCl 2 (dppf) (19.6 mg, 0.024 mmol) and potassium carbonate (166 g, 1.2 mmol) Stirring at reflux at 80 ° C. for 18 h. The resulting material was washed with water and brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 4) to give 4- (1-nitroisoquinolin-5-yl) aniline (57 mg, 89%).
1H NMR (400MHz, CDCl3): δ 6.85 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.76 (m, 2H), 8.22 (d, J = 8.3 Hz, 1H), 8.36 (d, J = 5.8 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.85 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.76 (m, 2H), 8.22 (d, J = 8.3 Hz , 1H), 8.36 (d, J = 5.8 Hz, 1H).
단계 3': 1-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)-3-(4-(1-니트로이소퀴놀린-5-일)페닐)우레아의 제조Step 3 ': 1- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- (4- (1-nitroisoquinolin-5-yl Preparation of Phenyl) urea
Figure PCTKR2009005326-appb-I000031
Figure PCTKR2009005326-appb-I000031
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐 클로로포메이트(38 mg, 0.20 mmol)와 3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)아닐린(41 mg, 0.17 mmol)을 녹인 후 디이소프로필에틸아민(0.04 mL, 0.21 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 상기 혼합 용매에 상기 단계 2'에서 제조된 4-(1-니트로이소퀴놀린-5-일)아닐린(45 mg, 0.17 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.03 mL, 0.17 mmol)을 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:30)로 정제하여 1-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)-3-(4-(1-니트로이소퀴놀린-5-일)페닐)우레아(73 mg, 81 %)를 얻었다. In a mixed solvent of tetrahydrofuran and dichloromethane (1: 1) 4-nitrophenyl chloroformate (38 mg, 0.20 mmol) and 3- (4-methyl-1H-imidazol-1-yl) -5- ( After dissolving trifluoromethyl) aniline (41 mg, 0.17 mmol), diisopropylethylamine (0.04 mL, 0.21 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. 4- (1-nitroisoquinolin-5-yl) aniline (45 mg, 0.17 mmol) prepared in step 2 'was dissolved in the mixed solvent and added to the reaction solution, followed by diisopropylethylamine (0.03 mL, 0.17 mmol). ) Was added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1:30) to give 1- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl ) -3- (4- (1-nitroisoquinolin-5-yl) phenyl) urea (73 mg, 81%) was obtained.
1H NMR (400MHz, CD3OD): δ 2.27 (s, 3H), 7.36 (s, 1H), 7.46 (m, 3H), 7.70 (d, J = 8.3 Hz, 2H), 7.81 (s, 1H), 7.86 (m, 2H), 7.99 (s, 1H), 8.11 (d, J = 5.6 Hz, 2H), 8.12 (s, 1H), 8.35 (d, J = 5.8 Hz, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 2.27 (s, 3H), 7.36 (s, 1H), 7.46 (m, 3H), 7.70 (d, J = 8.3 Hz, 2H), 7.81 (s, 1H ), 7.86 (m, 2H), 7.99 (s, 1H), 8.11 (d, J = 5.6 Hz, 2H), 8.12 (s, 1H), 8.35 (d, J = 5.8 Hz, 1H).
단계 4': 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)우레아의 제조Step 4 ': 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl Preparation of Phenyl) urea
Figure PCTKR2009005326-appb-I000032
Figure PCTKR2009005326-appb-I000032
메탄올 용매에 상기 단계 3'에서 제조된 1-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)-3-(4-(1-니트로이소퀴놀린-5-일)페닐)우레아(20 mg, 0.04 mmol)를 용해시키고 수소 압력 하에서 팔라듐 챠콜과 실온에서 7시간 동안 반응시켰다. 반응물을 셀라이트로 여과하고 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:20)로 정제하여 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)우레아(18 mg, 91 %)를 얻었다. 1- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- (4- (1-nitro) prepared in step 3 'in methanol solvent Isoquinolin-5-yl) phenyl) urea (20 mg, 0.04 mmol) was dissolved and reacted with palladium charcoal under hydrogen pressure at room temperature for 7 hours. The reaction was filtered through celite and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1:20) to give 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (3- (4-methyl- 1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) urea (18 mg, 91%) was obtained.
1H NMR (400MHz, CD3OD): δ 2.28 (s, 3H), 6.99 (d, J = 6.2 Hz, 1H), 7.40 (m, 3H), 7.49 (s, 1H), 7.61 (m, 4H), 7.70 (d, J = 6.2 Hz, 1H), 7.81 (s, 1H), 8.02 (s, 1H), 8.13 (m, 2H). 1 H NMR (400 MHz, CD 3 OD): δ 2.28 (s, 3H), 6.99 (d, J = 6.2 Hz, 1H), 7.40 (m, 3H), 7.49 (s, 1H), 7.61 (m, 4H ), 7.70 (d, J = 6.2 Hz, 1H), 7.81 (s, 1H), 8.02 (s, 1H), 8.13 (m, 2H).
<실시예 13> 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아의 제조Example 13 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- ( Preparation of Trifluoromethyl) phenyl) urea
단계 1': 5-브로모-1-니트로이소퀴놀린의 제조Step 1 ′: Preparation of 5-bromo-1-nitroisoquinoline
상기 실시예 12의 단계 1'의 방법과 동일한 방법으로 수행하여 5-브로모-1-니트로이소퀴놀린을 제조하였다.5-Bromo-1-nitroisoquinoline was prepared in the same manner as in step 1 ′ of Example 12.
단계 2': 3-메틸-4-(1-니트로이소퀴놀린-5-일)아닐린의 제조Step 2 ′: Preparation of 3-methyl-4- (1-nitroisoquinolin-5-yl) aniline
Figure PCTKR2009005326-appb-I000033
Figure PCTKR2009005326-appb-I000033
t-부틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)페닐카르보네이트 대신 3-메틸-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로란-2-일)아닐린(61 mg, 0.26 mmol)을 사용하는 것을 제외하고는 상기 실시예 12의 단계 2'의 방법과 동일한 방법으로 수행하여 3-메틸-4-(1-니트로이소퀴놀린-5-일)아닐린(48 mg, 72 %)을 얻었다. 3-methyl-4- (4,4, instead of t-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbonate Same method as in step 2 'of Example 12, except that 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (61 mg, 0.26 mmol) is used 3-methyl-4- (1-nitroisoquinolin-5-yl) aniline (48 mg, 72%) was obtained.
1H NMR (400MHz, CDCl3): δ 2.01 (s, 3H), 6.96 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.76 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.36 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ): δ 2.01 (s, 3H), 6.96 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.76 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.36 (m, 2H).
단계 3': 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(3-메틸-4-(1-니트로이소퀴놀린-5-일)페닐)우레아의 제조Step 3 ': 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (3-methyl-4- (1-nitroisoquinoline Preparation of -5-yl) phenyl) urea
Figure PCTKR2009005326-appb-I000034
Figure PCTKR2009005326-appb-I000034
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐 클로로포메이트(38 mg, 0.20 mmol)와 실시예 7의 제조예에서 제조된 4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)아닐린(50 mg, 0.17 mmol)을 녹인 후 디이소프로필에틸아민(0.04 mL, 0.21 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 상기 혼합 용매에 상기 단계 2'에서 제조된 3-메틸-4-(1-니트로이소퀴놀린-5-일)아닐린(48 mg, 0.17 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.03 mL, 0.17 mmol)을 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(3-메틸-4-(1-니트로이소퀴놀린-5-일)페닐)우레아(77 mg, 76 %)를 얻었다. 4-((4-ethylpiperazin-1) prepared in the preparation of Example 7 with 4-nitrophenyl chloroformate (38 mg, 0.20 mmol) in a mixed solvent of tetrahydrofuran and dichloromethane (1: 1) -Yl) methyl) -3- (trifluoromethyl) aniline (50 mg, 0.17 mmol) was dissolved, diisopropylethylamine (0.04 mL, 0.21 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. 3-methyl-4- (1-nitroisoquinolin-5-yl) aniline (48 mg, 0.17 mmol) prepared in step 2 'was dissolved in the mixed solvent and added to the reaction product, followed by diisopropylethylamine (0.03 mL, 0.17 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl ) -3- (3-methyl-4- (1-nitroisoquinolin-5-yl) phenyl) urea (77 mg, 76%) was obtained.
1H NMR (400MHz, CDCl3): δ 1.12 (t, J = 7.3 Hz, 3H), 2.00 (s, 3H), 2.54 (m, 10H), 3.63 (s, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.46 (m, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.67 (m, 3H), 7.77 (d, J = 7.1 Hz, 1H), 7.90 (m, 2H), 8.16 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 5.8 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.12 (t, J = 7.3 Hz, 3H), 2.00 (s, 3H), 2.54 (m, 10H), 3.63 (s, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.46 (m, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.67 (m, 3H), 7.77 (d, J = 7.1 Hz, 1H), 7.90 (m, 2H) , 8.16 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 5.8 Hz, 1H).
단계 4': 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아의 제조Step 4 ': 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (tri Preparation of Fluoromethyl) phenyl) urea
Figure PCTKR2009005326-appb-I000035
Figure PCTKR2009005326-appb-I000035
메탄올 용매에 상기 단계 3'에서 제조된 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(3-메틸-4-(1-니트로이소퀴놀린-5-일)페닐)우레아(20 mg, 0.03 mmol)를 용해시키고 수소 압력 하에서 팔라듐 챠콜과 실온에서 12시간 동안 반응시켰다. 생성물을 셀라이트로 여과하고 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아(13 mg, 77 %)를 얻었다. 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (3-methyl-4- in the methanol solvent prepared in step 3 ' (1-nitroisoquinolin-5-yl) phenyl) urea (20 mg, 0.03 mmol) was dissolved and reacted with palladium charcoal under hydrogen pressure at room temperature for 12 hours. The product was filtered through celite and concentrated under reduced pressure. After concentration, the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-(( 4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea (13 mg, 77%) was obtained.
1H NMR (400MHz, CDCl3): δ 1.13 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H), 2.52 (m, 10H), 3.64 (s, 2H), 5.54 (d, J = 7.4 Hz, 2H), 6.76 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 7.42-7.24 (m, 4H), 7.89 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.13 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H), 2.52 (m, 10H), 3.64 (s, 2H), 5.54 (d, J = 7.4 Hz, 2H), 6.76 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 7.42-7.24 (m, 4H), 7.89 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H).
<실시예 14> N-(4-이소퀴놀린-5-일)페닐)-3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)벤즈아미드의 제조Example 14 Preparation of N- (4-isoquinolin-5-yl) phenyl) -3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzamide
Figure PCTKR2009005326-appb-I000036
Figure PCTKR2009005326-appb-I000036
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: N-(4-이소퀴놀린-5-일)페닐)-3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)벤즈아미드의 제조Step 2: Preparation of N- (4-isoquinolin-5-yl) phenyl) -3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzamide
디클로로메탄 용매에 3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)벤조산(54 mg, 0.20 mmol), 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(50 mg, 0.23 mmol), EDCI(66 mg, 0.35 mmol) 및 DMAP(9 mg, 0.07 mmol)를 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어 주고 디클로로메탄으로 추출하고 무수 황산마그네슘 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:20)로 정제하여 N-(4-이소퀴놀린-5-일)페닐)-3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)벤즈아미드(89 mg, 94 %)를 얻었다. 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid (54 mg, 0.20 mmol) in dichloromethane solvent, 4- (isoquinoline- prepared in step 1 above. 5-yl) aniline (50 mg, 0.23 mmol), EDCI (66 mg, 0.35 mmol) and DMAP (9 mg, 0.07 mmol) were added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1:20) to give N- (4-isoquinolin-5-yl) phenyl) -3- (4-methyl-1H-imidazol-1- Il) -5- (trifluoromethyl) benzamide (89 mg, 94%) was obtained.
1H NMR (400MHz, CDCl3): δ 1.47 (s, 3H), 6.72 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.96 (s, 1H), 7.02 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.32 (m, 2H), 7.48 (m, 2H), 7.59 (d, J = 6.0 Hz, 1H), 7.63 (s, 1H), 8.48 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.47 (s, 3H), 6.72 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.96 (s, 1H), 7.02 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.32 (m, 2H), 7.48 (m, 2H), 7.59 (d, J = 6.0 Hz, 1H), 7.63 (s, 1 H), 8.48 (s, 1 H).
<실시예 15> N-(4-(이소퀴놀린-5-일)페닐)-3-모르폴리노-5-(트리플루오로메틸)벤즈아미드Example 15 N- (4- (isoquinolin-5-yl) phenyl) -3-morpholino-5- (trifluoromethyl) benzamide
Figure PCTKR2009005326-appb-I000037
Figure PCTKR2009005326-appb-I000037
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: N-(4-(이소퀴놀린-5-일)페닐)-3-모르폴리노-5-(트리플루오로메틸)벤즈아미드의 제조Step 2: Preparation of N- (4- (isoquinolin-5-yl) phenyl) -3-morpholino-5- (trifluoromethyl) benzamide
디클로로메탄 용매에 3-모르폴리노-5-(트리플루오로메틸)벤조산(55 mg, 0.20 mmol), 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(50 mg, 0.23 mmol), EDCI(66 mg, 0.35 mmol) 및 DMAP(9 mg, 0.07 mmol)를 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어 주고 디클로로메탄으로 추출하고 무수 황산마그네슘 건조한 후 감압농축 하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 2:1)로 정제하여 N-(4-(이소퀴놀린-5-일)페닐)-3-모르폴리노-5-(트리플루오로메틸)벤즈아미드(85 mg, 91 %)를 얻었다. 3-morpholino-5- (trifluoromethyl) benzoic acid (55 mg, 0.20 mmol) in dichloromethane solvent, 4- (isoquinolin-5-yl) aniline (50 mg, 0.23 mmol) prepared in step 1 above. ), EDCI (66 mg, 0.35 mmol) and DMAP (9 mg, 0.07 mmol) were added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (ethyl acetate: hexane = 2: 1) to give N- (4- (isoquinolin-5-yl) phenyl) -3-morpholino-5- (trifluoromethyl Benzamide (85 mg, 91%) was obtained.
1H NMR (400MHz, CD3OD): δ 3.34 (t, J = 4.8 Hz, 4H), 3.90 (t, J = 4.8 Hz, 4H), 7.41 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.80 (m, 3H), 7.86 (d, J = 6.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 8.15 (m, 1H), 8.44 (d, J = 6.0 Hz, 1H), 9.32 (s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 3.34 (t, J = 4.8 Hz, 4H), 3.90 (t, J = 4.8 Hz, 4H), 7.41 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.80 (m, 3H), 7.86 (d, J = 6.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 8.15 (m, 1H), 8.44 (d, J = 6.0 Hz, 1 H), 9.32 (s, 1 H).
<실시예 16> N-(4-(이소퀴놀린-5-일)페닐)-4-모르폴리노-3-(트리플루오로메틸)벤즈아미드의 제조Example 16 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -4-morpholino-3- (trifluoromethyl) benzamide
Figure PCTKR2009005326-appb-I000038
Figure PCTKR2009005326-appb-I000038
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: N-(4-(이소퀴놀린-5-일)페닐)-4-모르폴리노-3-(트리플루오로메틸)벤즈아미드의 제조Step 2: Preparation of N- (4- (isoquinolin-5-yl) phenyl) -4-morpholino-3- (trifluoromethyl) benzamide
디클로로메탄 용매에 4-모르폴리노-3-(트리플루오로메틸)벤조산(55 mg, 0.20 mmol), 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(50 mg, 0.23 mmol), EDCI(66 mg, 0.35 mmol) 및 DMAP(9 mg, 0.07 mmol)를 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어 주고 디클로로메탄으로 추출하고 무수 황산마그네슘 건조한 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 2:1)로 정제하여 N-(4-(이소퀴놀린-5-일)페닐)-4-모르폴리노-3-(트리플루오로메틸)벤즈아미드(98 mg, 97 %)를 얻었다.4-morpholino-3- (trifluoromethyl) benzoic acid (55 mg, 0.20 mmol) in dichloromethane solvent, 4- (isoquinolin-5-yl) aniline (50 mg, 0.23 mmol) prepared in step 1 above. ), EDCI (66 mg, 0.35 mmol) and DMAP (9 mg, 0.07 mmol) were added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (ethyl acetate: hexane = 2: 1) to give N- (4- (isoquinolin-5-yl) phenyl) -4-morpholino-3- (trifluoromethyl Benzamide (98 mg, 97%) was obtained.
1H NMR (400MHz, CD3OD): δ 3.02 (t, J = 4.0 Hz, 4H), 3.82 (t, J = 4.0 Hz, 4H), 7.49 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 6.8 Hz, 2H), 8.44 (m, 1H), 8.22 (dd, J = 8.4, 2.4 Hz, 1H), 8.29 (s, 1H), 8.40 (d, J = 6.4 Hz, 1H), 9.28 (s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 3.02 (t, J = 4.0 Hz, 4H), 3.82 (t, J = 4.0 Hz, 4H), 7.49 (d, J = 6.8 Hz, 2H), 7.58 ( d, J = 8.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 6.8 Hz, 2H), 8.44 (m, 1H), 8.22 (dd, J = 8.4, 2.4 Hz, 1H), 8.29 (s, 1H), 8.40 (d, J = 6.4 Hz, 1H), 9.28 (s, 1H).
<실시예 17> N-(4-(이소퀴놀린-5-일)페닐)-4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)벤즈아미드의 제조 Example 17 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -4- (4-methylpiperazin-1-yl) -3- ( trifluoromethyl ) benzamide
Figure PCTKR2009005326-appb-I000039
Figure PCTKR2009005326-appb-I000039
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: N-(4-(이소퀴놀린-5-일)페닐)-4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)벤즈아미드의 제조Step 2: Preparation of N- (4- (isoquinolin-5-yl) phenyl) -4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) benzamide
클로로포름과 톨루엔(1:4)의 혼합 용매에 4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)벤조산(100 mg, 0.35 mmol)을 용해시킨 후 포스포러스 옥시클로라이드를 천천히 가하였다. 반응용액을 3시간 동안 환류 교반시킨 후 반응 온도를 실온으로 내리고 감압 농축하였다. 농축 후 잔여물을 디클로로메탄에 녹이고 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(62 mg, 0.28 mmol)과 트리에틸아민(0.11 mL, 0.84 mmol)을 가하고 실온에서 18시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출한 다음 무수 황산마그네슘으로 건조시킨 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:20)로 정제하여 N-(4-(이소퀴놀린-5-일)페닐)-4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)벤즈아미드 (98 mg, 71 %)를 얻었다. Phosphorus oxychloride after 4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) benzoic acid (100 mg, 0.35 mmol) was dissolved in a mixed solvent of chloroform and toluene (1: 4). Was added slowly. The reaction solution was stirred under reflux for 3 hours, and then the reaction temperature was lowered to room temperature and concentrated under reduced pressure. After concentration, the residue was dissolved in dichloromethane, and 4- (isoquinolin-5-yl) aniline (62 mg, 0.28 mmol) and triethylamine (0.11 mL, 0.84 mmol) prepared in Step 1 were added thereto, and 18 hours at room temperature. Was stirred. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1:20) to give N- (4- (isoquinolin-5-yl) phenyl) -4- (4-methylpiperazin-1-yl) 3- (trifluoromethyl) benzamide (98 mg, 71%) was obtained.
1H NMR (600MHz, CD3OD): δ 2.54 (s, 3H), 2.83 (bs, 4H), 3.19 (bs, 4H), 7.46 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.67 (m, 2H), 7.75 (d, J = 6.6 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 2H), 7.99 (t, J = 5.0 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.27 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.56 (s, 1H), 9.31 (s, 1H). 1 H NMR (600 MHz, CD 3 OD): δ 2.54 (s, 3H), 2.83 (bs, 4H), 3.19 (bs, 4H), 7.46 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.67 (m, 2H), 7.75 (d, J = 6.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.99 (t, J = 5.0 Hz, 1H) , 8.20 (d, J = 7.8 Hz, 1H), 8.27 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.56 (s, 1H), 9.31 (s, 1H).
<실시예 18> 3-(4-히드록시피페리딘-1-일)-N-(4-(이소퀴놀린-5-일)페닐)-5-(트리플루오로메틸)벤즈아미드의 제조Example 18 Preparation of 3- (4-hydroxypiperidin-1-yl) -N- (4- (isoquinolin-5-yl) phenyl) -5- (trifluoromethyl) benzamide
Figure PCTKR2009005326-appb-I000040
Figure PCTKR2009005326-appb-I000040
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 3-(4-히드록시피페리딘-1-일)-N-(4-(이소퀴놀린-5-일)페닐)-5-(트리플루오로메틸)벤즈아미드의 제조Step 2: Preparation of 3- (4-hydroxypiperidin-1-yl) -N- (4- (isoquinolin-5-yl) phenyl) -5- (trifluoromethyl) benzamide
디클로로메탄 용매에 3-(4-히드록시피페리딘-1-일)-5-(트리플루오로메틸)벤조산(58 mg, 0.20 mmol), 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(50 mg, 0.23 mmol), EDCI(66 mg, 0.35 mmol) 및 DMAP(9 mg, 0.07 mmol)를 넣고 실온에서 10시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어 주고 디클로로메탄으로 추출한 다음 무수 황산마그네슘으로 건조시킨 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(에틸아세테이트:헥산 = 2:1)로 정제하여 3-(4-히드록시피페리딘-1-일)-N-(4-(이소퀴놀린-5-일)페닐)-5-(트리플루오로메틸)벤즈아미드 (81 mg, 82 %)를 얻었다. 3- (4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) benzoic acid (58 mg, 0.20 mmol) in dichloromethane solvent, 4- (isoquinoline-5 prepared in step 1 above -Yl) aniline (50 mg, 0.23 mmol), EDCI (66 mg, 0.35 mmol) and DMAP (9 mg, 0.07 mmol) were added and stirred at room temperature for 10 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration, the residue was purified by column chromatography (ethylacetate: hexane = 2: 1) to give 3- (4-hydroxypiperidin-1-yl) -N- (4- (isoquinolin-5-yl) Phenyl) -5- (trifluoromethyl) benzamide (81 mg, 82%) was obtained.
1H NMR (600MHz, CD3OD): δ 1.69 (m, 4H), 3.09 (m, 2H), 3.69 (m, 2H), 3.96 (m, 1H), 7.28 (s, 1H), 7.44 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 8.01 (m, 1H), 8.08 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 9.32 (s, 1H). 1 H NMR (600 MHz, CD 3 OD): δ 1.69 (m, 4H), 3.09 (m, 2H), 3.69 (m, 2H), 3.96 (m, 1H), 7.28 (s, 1H), 7.44 (s , 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.79 (d, J = 6.0 Hz , 1H), 7.83 (d, J = 8.4 Hz, 2H), 8.01 (m, 1H), 8.08 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 9.32 (s, 1H).
<실시예 19> N-(4-(이소퀴놀린-5-일)페닐)-3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤즈아미드의 제조Example 19 Preparation of N- (4- (isoquinolin-5-yl) phenyl) -3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) benzamide
Figure PCTKR2009005326-appb-I000041
Figure PCTKR2009005326-appb-I000041
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: N-(4-(이소퀴놀린-5-일)페닐)-3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤즈아미드의 제조Step 2: Preparation of N- (4- (isoquinolin-5-yl) phenyl) -3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) benzamide
디클로로메탄 용매에 3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤조산(58 mg, 0.20 mmol), 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(50 mg, 0.23 mmol), DCC(72 mg, 0.35 mmol) 및 DMAP(9 mg, 0.07 mmol)을 넣고 실온에서 12시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어 주고 디클로로메탄으로 추출하고 무수 황산마그네슘으로 건조시킨 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로메탄 = 1:20)로 정제하여 N-(4-(이소퀴놀린-5-일)페닐)-3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤즈아미드(72 mg, 73 %)를 얻었다. 3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) benzoic acid (58 mg, 0.20 mmol) in dichloromethane solvent, 4- (isoquinolin-5-yl prepared in step 1 above ) Aniline (50 mg, 0.23 mmol), DCC (72 mg, 0.35 mmol) and DMAP (9 mg, 0.07 mmol) were added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1:20) to give N- (4- (isoquinolin-5-yl) phenyl) -3- (4-methylpiperazin-1-yl ) -5- (trifluoromethyl) benzamide (72 mg, 73%) was obtained.
1H NMR (400MHz, CDCl3): δ 2.44 (s, 3H), 2.67 (bs, 4H), 3.41 (t, J = 5.2 Hz, 4H), 7.28 (s, 1H), 7.47 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.67 (m, 3H), 7.76 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 8.00 (m, 2H), 8.50 (d, J = 4.8 Hz, 1H), 9.32 (s, 1H) 1 H NMR (400 MHz, CDCl 3 ): δ 2.44 (s, 3H), 2.67 (bs, 4H), 3.41 (t, J = 5.2 Hz, 4H), 7.28 (s, 1H), 7.47 (s, 1H) , 7.52 (d, J = 8.8 Hz, 2H), 7.67 (m, 3H), 7.76 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 8.00 (m, 2H) , 8.50 (d, J = 4.8 Hz, 1H), 9.32 (s, 1H)
<실시예 20> 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)페닐)우레아의 제조Example 20 of 1- (4- (isoquinolin-5-yl) phenyl) -3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) urea Produce
Figure PCTKR2009005326-appb-I000042
Figure PCTKR2009005326-appb-I000042
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)페닐)우레아의 제조Step 2: Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) urea
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐 클로로포메이트(93 mg, 0.46 mmol)과 4-(4-메틸피페라진-1-일)-3-(트리플루오로메닐)아닐린(100 mg, 0.39 mmol)을 녹인 후 디이소프로필에틸아민(0.08 mL, 0.47 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 상기 혼합 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(86 mg, 0.39 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.08 mL, 0.39 mmol)을 넣고 실온에서 5시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조시킨 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)페닐)우레아(163 mg, 76 %)를 얻었다. In a mixed solvent of tetrahydrofuran and dichloromethane (1: 1) 4-nitrophenyl chloroformate (93 mg, 0.46 mmol) and 4- (4-methylpiperazin-1-yl) -3- (trifluorome Nil) aniline (100 mg, 0.39 mmol) was dissolved, diisopropylethylamine (0.08 mL, 0.47 mmol) was added and stirred at room temperature for 0.5 hour. 4- (isoquinolin-5-yl) aniline (86 mg, 0.39 mmol) prepared in Step 1 was dissolved in the mixed solvent, added to the reaction product, and then diisopropylethylamine (0.08 mL, 0.39 mmol) was added thereto. Stirred for 5 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (isoquinolin-5-yl) phenyl) -3- (4- (4-methylpiperazin-1 -Yl) -3- (trifluoromethyl) phenyl) urea (163 mg, 76%) was obtained.
1H NMR (600MHz, CD3OD): δ 2.36 (s, 3H), 2.56 (bs, 4H), 2.85 (bs, 4H), 7.26 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 6.0 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.66 (s, 2H), 7.93 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 8.16 (s, 1H), 8.38 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H). 1 H NMR (600 MHz, CD 3 OD): δ 2.36 (s, 3H), 2.56 (bs, 4H), 2.85 (bs, 4H), 7.26 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H ), 7.50 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 6.0 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.66 (s, 2H), 7.93 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 8.16 (s, 1H), 8.38 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H).
<실시예 21> 1-(4-(2,4-디메틸-1H-이미다졸-1-일)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Example 21 1- (4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl Preparation of Phenyl) urea
Figure PCTKR2009005326-appb-I000043
Figure PCTKR2009005326-appb-I000043
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-(2,4-디메틸-1H-이미다졸-1-일)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Step 2: 1- (4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl Production of urea
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐 클로로포메이트(44 mg, 0.22 mmol)와 4-(2,4-디메틸-1H-이미다졸-1-일)-3-(트리플루오로메틸)아닐린(50 mg, 0.20 mmol)을 녹인 후 디이소프로필에틸아민(0.04 mL, 0.24 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 상기 혼합 용매에 상기 단계 1에서 제조된 4-이소퀴놀린-5-일)아닐린(44 mg, 0.20 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.04 mL, 0.20 mmol)을 넣고 실온에서 5시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조시킨 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(2,4-디메틸-1H-이미다졸-1-일)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아(79 mg, 79 %)를 얻었다. 4-nitrophenyl chloroformate (44 mg, 0.22 mmol) and 4- (2,4-dimethyl-1H-imidazol-1-yl) -3 in a mixed solvent of tetrahydrofuran and dichloromethane (1: 1) -3 -(Trifluoromethyl) aniline (50 mg, 0.20 mmol) was dissolved, diisopropylethylamine (0.04 mL, 0.24 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. The 4-isoquinolin-5-yl) aniline (44 mg, 0.20 mmol) prepared in Step 1 was dissolved in the mixed solvent and added to the reaction product, followed by adding diisopropylethylamine (0.04 mL, 0.20 mmol) at room temperature. Stir for 5 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl ) Phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea (79 mg, 79%) was obtained.
1H NMR (600MHz, CDCl3): δ 2.22 (s, 3H), 2.33 (s, 3H), 6.78 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.66 (m, 5H), 7.77 (d, J = 6.0 Hz, 1H), 7.98 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 9.27 (bs, 1H), 9.31 (s, 1H), 9.74 (bs, 1H). 1 H NMR (600 MHz, CDCl 3 ): δ 2.22 (s, 3H), 2.33 (s, 3H), 6.78 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.66 (m, 5H), 7.77 (d, J = 6.0 Hz, 1H), 7.98 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 9.27 (bs, 1H), 9.31 (s, 1H), 9.74 (bs, 1H).
<실시예 22> 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Example 22 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl Production of urea
Figure PCTKR2009005326-appb-I000044
Figure PCTKR2009005326-appb-I000044
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Step 2: 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea Manufacture
테트라히드로퓨란과 디클로로메탄(1:1)의 혼합 용매에 4-니트로페닐 클로로포메이트(38 mg, 0.20 mmol)와 4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)아닐린(50 mg, 0.17 mmol)을 녹인 후 디이소프로필에틸아민(0.04 mL, 0.21 mmol)을 넣고 실온에서 0.5시간 동안 교반하였다. 상기 혼합 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(38 mg, 0.17 mmol)을 녹여 반응물에 첨가한 후 디이소프로필에틸아민(0.03 mL, 0.17 mmol)을 넣고 실온에서 5시간 동안 교반하였다. 반응 종료 후 반응물을 물과 소금물로 씻어주고 디클로로메탄으로 추출하고 무수 황산 마그네슘으로 건조시킨 후 감압 농축하였다. 농축 후 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아(62 mg, 68 %)를 얻었다. In a mixed solvent of tetrahydrofuran and dichloromethane (1: 1), 4-nitrophenyl chloroformate (38 mg, 0.20 mmol) and 4-((4-ethylpiperazin-1-yl) methyl) -3- ( Trifluoromethyl) aniline (50 mg, 0.17 mmol) was dissolved, diisopropylethylamine (0.04 mL, 0.21 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. 4- (isoquinolin-5-yl) aniline (38 mg, 0.17 mmol) prepared in Step 1 was dissolved in the mixed solvent, added to the reaction product, and then diisopropylethylamine (0.03 mL, 0.17 mmol) was added thereto to room temperature. Stirred for 5 hours. After the reaction was completed, the reaction was washed with water and brine, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After concentration the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl ) -3- (4- (isoquinolin-5-yl) phenyl) urea (62 mg, 68%) was obtained.
1H NMR (400MHz, CDCl3): δ 1.11 (t, J = 7.6 Hz, 3H), 2.47 (m, 10H), 3.55 (s, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.62 (m, 3H), 7.67 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.18 (s, 1H), 8.39 (d, J = 6.0 Hz, 1H), 9.28 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): δ 1.11 (t, J = 7.6 Hz, 3H), 2.47 (m, 10H), 3.55 (s, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.62 (m, 3H), 7.67 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 8.11 (s, 1 H), 8.18 (s, 1 H), 8.39 (d, J = 6.0 Hz, 1 H), 9.28 (s, 1 H).
<실시예 23> 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Example 23 Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea
Figure PCTKR2009005326-appb-I000045
Figure PCTKR2009005326-appb-I000045
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아의 제조Step 2: Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea
디클로로메탄 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(10 mg, 0.05 mmol)과 1-클로로-4-이소시아네이토-2-(트리플루오로메틸)벤젠(11 mg, 0.05 mmol)을 넣고 실온에서 0.5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하였다. 무수 황산마그네슘으로 건조시킨 후 감압 농축하고 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아(21 mg, 93 %)를 얻었다.4- (isoquinolin-5-yl) aniline (10 mg, 0.05 mmol) and 1-chloro-4-isocyanato-2- (trifluoromethyl) benzene prepared in step 1 in dichloromethane solvent ( 11 mg, 0.05 mmol) were added and reacted at room temperature for 0.5 hour. After the reaction was washed with water and brine and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- ( 4- (isoquinolin-5-yl) phenyl) urea (21 mg, 93%) was obtained.
1H NMR (400MHz, CD3OD): δ 7.44 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 3H), 7.75 (m, 2H), 7.84 (d, J = 5.9 Hz, 1H), 8.05 (s, 1H), 8.11 (dd, J = 5.5, 3.4 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 9.29 (s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 7.44 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 3H), 7.75 ( m, 2H), 7.84 (d, J = 5.9 Hz, 1H), 8.05 (s, 1H), 8.11 (dd, J = 5.5, 3.4 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 9.29 (s, 1 H).
<실시예 24> 1-(4-(이소퀴놀린-5-일)페닐)-3-(3-(메틸티오)페닐)우레아의 제조Example 24 Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3- (methylthio) phenyl) urea
Figure PCTKR2009005326-appb-I000046
Figure PCTKR2009005326-appb-I000046
단계 1: 4-(이소퀴놀린-5-일)아닐린의 제조Step 1: Preparation of 4- (isoquinolin-5-yl) aniline
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2: 1-(4-(이소퀴놀린-5-일)페닐)-3-(3-(메틸티오)페닐)우레아의 제조Step 2: Preparation of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3- (methylthio) phenyl) urea
디클로로메탄 용매에 상기 단계 1에서 제조된 4-(이소퀴놀린-5-일)아닐린(10 mg, 0.05 mmol)과 3-(메틸티오)페닐 이소시아네이트(7.5 μl, 0.05 mmol)를 넣고 실온에서 0.5시간 동안 반응시켰다. 반응 종료 후 물과 소금물로 씻어주고 에틸아세테이트로 추출하였다. 무수 황산마그네슘으로 건조시킨 후 감압 농축하여 잔여물을 컬럼 크로마토그래피(메탄올:디클로로메탄 = 1:10)로 정제하여 1-(4-(이소퀴놀린-5-일)페닐)-3-(3-(메틸티오)페닐)우레아(19 mg, 98 %)를 얻었다.4- (isoquinolin-5-yl) aniline (10 mg, 0.05 mmol) and 3- (methylthio) phenyl isocyanate (7.5 μl, 0.05 mmol) prepared in step 1 were added to a dichloromethane solvent for 0.5 hour at room temperature. Reacted for a while. After the reaction was washed with water and brine and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was purified by column chromatography (methanol: dichloromethane = 1: 10) to give 1- (4- (isoquinolin-5-yl) phenyl) -3- (3- (Methylthio) phenyl) urea (19 mg, 98%) was obtained.
1H NMR (400MHz, CD3OD): δ 2.48 (s, 3H), 6.92 (d, J = 7.4 Hz, 1H), 7.20 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.50(s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.73 (m, 2H), 7.82 (d, J = 6.0Hz, 1H), 8.09 (d, J = 6.6 Hz, 2.7 Hz, 1H), 8.38 (d, J = 6.0 Hz, 1H), 9.27 (s, 1H). 1 H NMR (400 MHz, CD 3 OD): δ 2.48 (s, 3H), 6.92 (d, J = 7.4 Hz, 1H), 7.20 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.50 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.73 (m, 2H), 7.82 (d, J = 6.0 Hz, 1H), 8.09 (d, J = 6.6 Hz, 2.7 Hz, 1H), 8.38 (d, J = 6.0 Hz, 1H), 9.27 (s, 1H).
<실험예 1> B-raf 키나제 활성효과 시험 Experimental Example 1 B-raf Kinase Activity Test
본 발명의 화합물들에 대한 B-raf 키나제 저해 활성을 알아보기 위하여 하기와 같은 실험을 실시하였다.In order to determine the B-raf kinase inhibitory activity of the compounds of the present invention, the following experiment was performed.
(1) 연쇄 신호전달 반응(1) chain signaling reaction
구체적으로 원심분리튜브에 희석용매(20 mM MOPS, pH 7.2, 25 mM β-글리세롤포스페이트, 5 mM EGTA, 1 mM 나트륨 오르토바나드산염(sodium orthovanadate), 1 mM 디티오트레이톨(dithiothreitol)) 20 ㎕와 Mg/ATP 혼합용액(500 μM ATP, 75 mM 염화마그네슘) 10 ㎕을 넣고, 실시예 11 또는 12의 화합물을 넣거나 대조군으로는 상기 실시예의 화합물을 넣지 않고, 활성화된 B-raf 1 ng, 비활성화된 MEK1 0.4 ng, 비활성화된 MAPK2 1 ㎍을 첨가하였다. 원심분리를 통해 튜브 안의 용액들을 바닥으로 모이게 한 다음, 30 ℃에서 30분간 반응시키고, 이 혼합용액 4 ㎕를 취하여 다음 단계시험을 진행하였다. Specifically, a dilution solvent (20 mM MOPS, pH 7.2, 25 mM β-glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol) in a centrifuge tube 20 Add 10 μl of Mg / ATP mixed solution (500 μM ATP, 75 mM magnesium chloride), add the compound of Example 11 or 12, or add the compound of Example 1 as a control, and activate activated B-raf 1 ng, 0.4 ng of inactivated MEK1 and 1 μg of inactivated MAPK2 were added. The solutions in the tube were collected by centrifugation at the bottom, and then reacted at 30 ° C. for 30 minutes, and 4 μl of the mixed solution was taken to proceed to the next step test.
(2) MAPK2에 의한 기질 단백질 MBP의 인산화 반응(2) Phosphorylation of Substrate Protein MBP by MAPK2
상기 (1)에서 취한 4 ㎕의 혼합용액에 희석용매 10 ㎕와 기질로 쓰이는 MBP 20 ㎍, 희석된 [γ-32P]ATP(1 μCi/μL) 10 ㎕를 첨가하였다. 원심분리를 통해 튜브 안의 용액들을 바닥으로 모이게 한 다음, 30 ℃에서 10분간 반응시켰다. 이 반응액 25 ㎕를 조심스레 2 cm × 2 cm P81 여과지 중앙에 30초간 올려놓았다. 이후, 상기 여과지를 0.75% 인산용액(phosphoric acid)으로 10분 단위로 3회, 아세톤(acetone)으로 5분간 1회 세척하였다. 다음으로 신틸레이션 바이알(scintillation vial)에 상기 여과지를 옮겨 넣고 5 ml의 신틸레이션 칵테일(scintillation cocktail)을 넣었다. 대조군과 비교하며 신틸레이션 카운터(scintillation counter)로 방사능을 읽음으로써 B-raf 활성 억제율(IC50)을 측정하였다. 그 결과를 하기 표 1에 나타내었다.To 4 μl of the mixed solution taken in (1), 10 μl of the diluted solvent and 20 μg of MBP used as a substrate and 10 μl of diluted [γ-32P] ATP (1 μCi / μL) were added. The solutions in the tube were collected at the bottom by centrifugation and then reacted at 30 ° C. for 10 minutes. 25 μl of the reaction solution was carefully placed in the center of a 2 cm × 2 cm P81 filter paper for 30 seconds. Thereafter, the filter paper was washed three times in 10 minute increments with 0.75% phosphoric acid solution, and once for 5 minutes with acetone. Next, the filter paper was transferred to a scintillation vial, and 5 ml of scintillation cocktail was added. B-raf activity inhibition rate (IC 50 ) was measured by reading the radioactivity with a scintillation counter compared to the control. The results are shown in Table 1 below.
표 1 B-raf 키나아제 활성 억제효과
화합물 B-raf 활성 억제율; IC50 (nM)
실시예 11 206
실시예 12 610
Table 1 <u> B-raf kinase activity inhibitory effect </ u>
compound Inhibition of B-raf activity; IC 50 (nM)
Example 11 206
Example 12 610
표 1에 나타낸 바와 같이, 본 발명에 따른 화합물은 B-raf 활성 억제율이 206~510 nM로서 nM 단위의 우수한 B-raf 활성 억제 효과를 나타냄을 알 수 있다.As shown in Table 1, it can be seen that the compound according to the present invention exhibits an excellent inhibitory effect of B-raf activity in nM units with a B-raf activity inhibition rate of 206 to 510 nM.
<실험예 2> B-raf 세포활성 저해 시험Experimental Example 2 B-raf Cell Activity Inhibition Test
본 발명의 화합물의 B-raf 세포활성 저해능력을 알아보기 위하여 A375 세포주(ATCC)에서 다음과 같은 시험을 수행하였다. A375 세포주(ATCC)는 인간 흑색종 환자로부터 유래한 것이고, B-Raf 유전자에 V599E 돌연변이를 가지므로 인산화된 MEK의 수치가 B-Raf의 돌연변이로 인하여 상승한다. In order to determine the ability of the compound of the present invention to inhibit B-raf cell activity, the following test was performed in the A375 cell line (ATCC). The A375 cell line (ATCC) is derived from human melanoma patients and has a V599E mutation in the B-Raf gene so that the level of phosphorylated MEK is elevated due to the mutation of B-Raf.
서브-컨플루언트 내지 컨플루언트 A375 세포를 무혈청 배지 중 37 ℃에서 2시간 동안 실시예 1~23에서 제조된 화합물과 인큐베이션시켰다. 이어서 세포를 냉 PBS로 1회 세척하고, 1％ 트리톤(Triton) X100을 함유하는 용해 완충액으로 용해시켰다. 원심분리 후, 상청액을 SDS-PAGE에 적용한 후, 니트로 셀룰로스 막으로 옮겼다. 이어서 항-포스포-MEK 항체(ser217/221)(셀 시그널링(Cell Signaling))를 이용하여 상기 막을 웨스턴 블라팅(western blotting)에 적용하였다. 인산화된 MEK의 양은 니트로셀룰로스 막에서의 포스포-MEK 밴드의 밀도로 모니터링함으로써 B-raf 활성 억제율(IC50)을 측정하였다. 그 결과를 하기 표 2에 나타내었다.Sub-confluent to confluent A375 cells were incubated with the compounds prepared in Examples 1-23 for 2 hours at 37 ° C. in serum-free medium. Cells were then washed once with cold PBS and lysed with lysis buffer containing 1% Triton X100. After centrifugation, the supernatants were subjected to SDS-PAGE and then transferred to nitro cellulose membranes. The membrane was then subjected to western blotting using anti-phospho-MEK antibody (ser217 / 221) (Cell Signaling). The amount of phosphorylated MEK was measured by the density of phospho-MEK bands in the nitrocellulose membrane to determine B-raf activity inhibition rate (IC 50 ). The results are shown in Table 2 below.
표 2 B-raf 세포저해 활성
화합물 B-raf 활성 억제율; IC50 (μM)
실시예 1 6.8
실시예 2 8.5
실시예 3 4.2
실시예 4 18.5
실시예 5 14.0
실시예 6 2.8
실시예 7 7.0
실시예 8 2.7
실시예 9 22.1
실시예 10 5.7
실시예 11 0.12
실시예 12 0.6
실시예 13 1.13
실시예 14 14.0
실시예 15 13.0
실시예 16 13.6
실시예 17 3.7
실시예 18 0.57
실시예 19 19.0
실시예 20 3.7
실시예 21 8.6
실시예 22 1.0
실시예 23 8.3
TABLE 2 <u> B-raf cytotoxic activity </ u>
compound Inhibition of B-raf activity; IC 50 (μM)
Example 1 6.8
Example 2 8.5
Example 3 4.2
Example 4 18.5
Example 5 14.0
Example 6 2.8
Example 7 7.0
Example 8 2.7
Example 9 22.1
Example 10 5.7
Example 11 0.12
Example 12 0.6
Example 13 1.13
Example 14 14.0
Example 15 13.0
Example 16 13.6
Example 17 3.7
Example 18 0.57
Example 19 19.0
Example 20 3.7
Example 21 8.6
Example 22 1.0
Example 23 8.3
표 2에 나타낸 바와 같이, 본 발명에 따른 화합물은 B-raf 활성 억제율이 0.12~19.0 μM로서 B-raf의 저해활성이 뛰어나므로 비정상적으로 B-raf 활성이 나타나는 관련 질환, 예를 들면 암, 흑색종 등의 예방 및 치료에 유용하게 사용될 수 있다.As shown in Table 2, the compound according to the present invention has a B-raf activity inhibition rate of 0.12 to 19.0 μM and is excellent in inhibitory activity of B-raf, thus causing an abnormal disease such as cancer and black. It can be usefully used for the prevention and treatment of species.
한편, 본 발명에 따른 상기 화학식 1로 표시되는 5-(4-아미노페닐)-이소퀴놀린 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the 5- (4-aminophenyl) -isoquinoline derivative represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
<제제예 1> 정제(직접 가압)Preparation Example 1 Tablet (Direct Pressurization)
활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 제조하였다.After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.
<제제예 2> 정제(습식 조립)Preparation Example 2 Tablet (Wet Assembly)
활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 제조하였다.After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.
<제제예 3> 분말과 캡슐제Preparation Example 3 Powder and Capsule
활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 혼합하였다. 상기 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.
<제제예 4> 주사제<Example 4> Injection
활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

Claims (11)

  1. 하기 화학식 1로 표시되는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염:5- (4-aminophenyl) -isoquinoline derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2009005326-appb-I000047
    .
    Figure PCTKR2009005326-appb-I000047
    .
    (상기 화학식 1에서(In Chemical Formula 1)
    R1은 수소, 시아노, 아미노 또는 아미드이고,R 1 is hydrogen, cyano, amino or amide,
    R2는 수소 또는 C1~6 직쇄 또는 측쇄 알킬이고,R 2 is hydrogen or C 1-6 straight or branched alkyl,
    R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
    이때, R4 또는 R5는 각각 비치환 또는 할로겐; C1~6직쇄 또는 측쇄 알킬; C1~6할로알킬; C1~6알콕시; C5~12아릴옥시; C5~12아릴C1~6알킬; C1~6알킬티오; 비치환 또는 1 이상의 C1~6직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C3~12헤테로사이클로알킬; 비치환 또는 1 이상의 C1~6직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C5~12헤테로아릴; 및 C1~6알킬카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환된 C5~12아릴 또는 C5~12헤테로아릴이고, 상기 헤테로사이클로알킬 또는 헤테로아릴은 N, O 및 S로 이루어지는 군으로부터 선택되는 1 이상의 헤테로 원자를 포함한다.)In this case, R 4 or R 5 is unsubstituted or halogen, respectively; C 1-6 straight or branched alkyl; C 1-6 haloalkyl; C 1-6 alkoxy; 5 ~ C 12 aryloxy; 5 ~ C 12 aryl C 1 ~ 6 alkyl; C 1-6 alkylthio; C 3-12 heterocycloalkyl unsubstituted or substituted with one or more C 1-6 straight or branched alkyl or hydroxy; A C 5 ~ 12 unsubstituted or substituted by one or more C 1 ~ 6 straight or branched chain alkyl or hydroxy-heteroaryl; And C 1 ~ 6, and a C 5 ~ 12 aryl-aryl or C 5 ~ 12 heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl carboxylic acid, wherein the heterocycloalkyl or heteroaryl group consisting of N, O and S At least one hetero atom selected from
  2. 제1항에 있어서, 상기 R1은 수소, 시아노, 아미노 또는 아미드이고,The compound of claim 1, wherein R 1 is hydrogen, cyano, amino or amide,
    R2는 수소 또는 C1~4 직쇄 또는 측쇄 알킬이고,R 2 is hydrogen or C 1-4 straight or branched alkyl,
    R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
    이때, R4 또는 R5는 각각 비치환 또는 할로겐; C1~4직쇄 또는 측쇄 알킬; C1~4할로알킬; C1~4알콕시; C5~12아릴옥시; C5~12아릴C1~4알킬; C1~4알킬티오; 비치환 또는 1 이상의 C1~4직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C3~8헤테로사이클로알킬; 비치환 또는 1 이상의 C1~4직쇄 또는 측쇄 알킬 또는 히드록시로 치환된 C5~8헤테로아릴; 및 C1~4알킬카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환된 C5~8아릴 또는 C5~12헤테로아릴이고, 상기 헤테로사이클로알킬 또는 헤테로아릴은 N, O 또는 N 및 O의 헤테로 원자를 포함하는 것을 특징으로 하는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염.In this case, R 4 or R 5 is unsubstituted or halogen, respectively; C 1-4 straight or branched alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; 5 ~ C 12 aryloxy; 5 ~ C 12 aryl C 1 ~ 4 alkyl; C 1-4 alkylthio; C 3-8 heterocycloalkyl unsubstituted or substituted with one or more C 1-4 straight or branched alkyl or hydroxy; C 5-8 heteroaryl unsubstituted or substituted with one or more C 1-4 straight or branched alkyl or hydroxy; And C 1 ~ 4, and a C 5 ~ 8 aryl aryl or C 5 ~ 12 heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl carboxylic acid, wherein the heterocycloalkyl or heteroaryl is a N, O or N, and O 5- (4-aminophenyl) -isoquinoline derivative, or a pharmaceutically acceptable salt thereof, comprising a hetero atom.
  3. 제1항에 있어서, 상기 R1은 수소, 시아노, 아미노 또는 아미드이고,The compound of claim 1, wherein R 1 is hydrogen, cyano, amino or amide,
    R2는 수소, 메틸 또는 에틸이고,R 2 is hydrogen, methyl or ethyl,
    R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
    이때, R4 또는 R5는 각각 비치환 또는 플루오린, 염소, 메틸, 트리플루오로메틸, 메톡시, 에톡시, 메틸티오, 페닐옥시, 히드록시피페리딘, 모르폴린, N-메틸피페라진, 이미다졸, 3,5-디메틸이미다졸, 메틸이미다졸, 피페라지닐메틸, 벤질, 메틸카르복실 및 에틸카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환되는 페닐, 인돌 또는 벤조디옥솔인 것을 특징으로 하는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염.Wherein R 4 or R 5 is unsubstituted or fluorine, chlorine, methyl, trifluoromethyl, methoxy, ethoxy, methylthio, phenyloxy, hydroxypiperidine, morpholine, N-methylpiperazine , Phenyl, indole or benzodi substituted with one or more substituents selected from the group consisting of imidazole, 3,5-dimethylimidazole, methylimidazole, piperazinylmethyl, benzyl, methylcarboxyl and ethylcarboxyl 5- (4-aminophenyl) -isoquinoline derivative, or a pharmaceutically acceptable salt thereof, characterized in that it is an oxol.
  4. 제1항에 있어서, 상기 R1은 수소, 시아노, 아미노 또는 아미드이고,The compound of claim 1, wherein R 1 is hydrogen, cyano, amino or amide,
    R2는 수소 또는 메틸이고,R 2 is hydrogen or methyl,
    R3는 R4 또는 NHR5이며,R 3 is R 4 or NHR 5 ,
    이때, R4는 트리플루오로메틸, 모르폴린, 메틸이미다졸, 피페라지닐메틸, 히드록시피페리딘으로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환되는 페닐이고,Wherein R 4 is phenyl substituted with one or more substituents selected from the group consisting of trifluoromethyl, morpholine, methylimidazole, piperazinylmethyl, hydroxypiperidine,
    R5는 비치환 또는 염소, 메틸, 트리플루오로메틸, 메톡시, 메틸티오, 페닐옥시, N-메틸피페라지닐에틸, 3,5-디메틸이미다졸, 피페라지닐메틸, 벤질, 메틸카르복실로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환되는 페닐, 인돌 또는 벤조디옥솔인 것을 특징으로 하는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염.R 5 is unsubstituted or chlorine, methyl, trifluoromethyl, methoxy, methylthio, phenyloxy, N-methylpiperazinylethyl, 3,5-dimethylimidazole, piperazinylmethyl, benzyl, methylcar 5- (4-aminophenyl) -isoquinoline derivative, or a pharmaceutically acceptable salt thereof, characterized in that it is phenyl, indole or benzodioxol substituted with one or more substituents selected from the group consisting of carboxyl.
  5. 제1항에 있어서, 상기 5-(4-아미노페닐)-이소퀴놀린 유도체는The method of claim 1, wherein the 5- (4-aminophenyl) -isoquinoline derivative is
    (1) 1-(4-(1-아미노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아;(1) 1- (4- (1-aminoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) Phenyl) urea;
    (2) 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-페닐옥시페닐)우레아;(2) 1- (4- (isoquinolin-5-yl) phenyl) -3- (4-phenyloxyphenyl) urea;
    (3) 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아;(3) 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea;
    (4) 에틸 3-(3-(4-(이소퀴놀린-5-일)페닐)우레이도)벤조에이트;(4) ethyl 3- (3- (4- (isoquinolin-5-yl) phenyl) ureido) benzoate;
    (5) 1-(벤조[d][1,3]다이옥솔-5-일)-3-(4-(이소퀴놀린-5-일)페닐)우레아;(5) 1- (benzo [d] [1,3] dioxol-5-yl) -3- (4- (isoquinolin-5-yl) phenyl) urea;
    (6) 5-(4-(3-(4-클로로-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린- 1-카르복시아미드;(6) 5- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxyamide;
    (7) 5-(4-(3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레이도)페닐)이소퀴놀린-1-카르복시아미드;(7) 5- (4- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenyl) isoquinoline-1-carboxy amides;
    (8) 5-(4-(3-(3-페닐옥시페닐)우레이도)페닐)이소퀴놀린-1-카르보아미드;(8) 5- (4- (3- (3-phenyloxyphenyl) ureido) phenyl) isoquinoline-1-carboamide;
    (9) 1-(4-클로로-3-(트리플루오로메틸)페닐)-3-(4-(1-시아노이소퀴놀린-5-일) 페닐)우레아;(9) 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea;
    (10) 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아;(10) 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl ) Phenyl) urea;
    (11) 1-(4-(1-시아노이소퀴놀린-5-일)페닐)-3-(3-페닐옥시페닐)우레아;(11) 1- (4- (1-cyanoisoquinolin-5-yl) phenyl) -3- (3-phenyloxyphenyl) urea;
    (12) 1-(3-벤질메틸)-3-(4-(1-시아노이소퀴놀린-5-일)페닐)우레아;(12) 1- (3-benzylmethyl) -3- (4- (1-cyanoisoquinolin-5-yl) phenyl) urea;
    (13) 1-(4-(이소퀴놀린-5-일)페닐)-3-(1-메틸-1H-인돌-6-일)우레아;(13) 1- (4- (isoquinolin-5-yl) phenyl) -3- (1-methyl-1H-indol-6-yl) urea;
    (14) 1-(4-(이소퀴놀린-5-일)페닐)-3-(5-메틸-2-(트리플루오로메틸)푸란-3-일)우레아;(14) 1- (4- (isoquinolin-5-yl) phenyl) -3- (5-methyl-2- (trifluoromethyl) furan-3-yl) urea;
    (15) 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(3-메틸-4-(1-니트로이소퀴놀린-5-일)페닐)우레아;(15) 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (3-methyl-4- (1-nitroisoquinoline- 5-yl) phenyl) urea;
    (16) 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)우레아;(16) 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoro Rhomethyl) phenyl) urea;
    (17) 1-(4-(1-아미노이소퀴놀린-5-일)-3-메틸페닐)-3-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)우레아;(17) 1- (4- (1-aminoisoquinolin-5-yl) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoro Rhomethyl) phenyl) urea;
    (18) N-(4-이소퀴놀린-5-일)페닐)-3-(4-메틸-1H-이미다졸-1-일)-5 -(트리플루오로메틸)벤즈아미드;(18) N- (4-isoquinolin-5-yl) phenyl) -3- (4-methyl-1H-imidazol-1-yl) -5-(trifluoromethyl) benzamide;
    (19) N-(4-(이소퀴놀린-5-일)페닐)-3-모르폴리노-5-(트리플루오로메틸)벤즈아미드;(19) N- (4- (isoquinolin-5-yl) phenyl) -3-morpholino-5- (trifluoromethyl) benzamide;
    (20) N-(4-(이소퀴놀린-5-일)페닐)-4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)벤즈아미드;(20) N- (4- (isoquinolin-5-yl) phenyl) -4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) benzamide;
    (21) N-(4-(이소퀴놀린-5-일)페닐)-4-모르폴리노-3-(트리플루오로메틸)벤즈아미드;(21) N- (4- (isoquinolin-5-yl) phenyl) -4-morpholino-3- (trifluoromethyl) benzamide;
    (22) 3-(4-히드록시피페리딘-1-일)-N-(4-(이소퀴놀린-5-일)페닐)- 5-(트리플루오로메틸)벤즈아미드;(22) 3- (4-hydroxypiperidin-1-yl) -N- (4- (isoquinolin-5-yl) phenyl) -5 (trifluoromethyl) benzamide;
    (23) N-(4-(이소퀴놀린-5-일)페닐)-3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤즈아미드;(23) N- (4- (isoquinolin-5-yl) phenyl) -3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) benzamide;
    (24) 1-(4-(이소퀴놀린-5-일)페닐)-3-(4-(4-메틸피페라진-1-일)-3-(트리플루오로메틸)페닐)우레아;(24) 1- (4- (isoquinolin-5-yl) phenyl) -3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) urea;
    (25) 1-(4-(2,4-디메틸-1H-이미다졸-1-일)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아;(25) 1- (4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl Urea;
    (26) 1-(4-((4-에틸피페라진-1-일)메틸)-3-(트리플루오로메틸)페닐)-3-(4-(이소퀴놀린-5-일)페닐)우레아; 및(26) 1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (isoquinolin-5-yl) phenyl) urea ; And
    (27) 1-(4-(이소퀴놀린-5-일)페닐)-3-(3-(메틸티오)페닐)우레아로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염.(27) 5- (4-aminophenyl)-, which is selected from the group consisting of 1- (4- (isoquinolin-5-yl) phenyl) -3- (3- (methylthio) phenyl) urea. Isoquinoline derivatives or pharmaceutically acceptable salts thereof.
  6. 하기 반응식 1에 표시되는 바와 같이, As shown in Scheme 1 below,
    출발물질인 화학식 2의 화합물을 용매에 용해시킨 후, 팔라듐촉매하에서 화학식 3의 화합물 및 탄산칼륨을 첨가하여 가열 환류시킴으로써 화학식 4의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of formula 4 by dissolving a compound of formula 2, which is a starting material, in a solvent, and then refluxing by adding a compound of formula 3 and potassium carbonate under a palladium catalyst (step 1); And
    상기 단계 1에서 제조된 화학식 4의 화합물을 커플링 시약 및 염기와 함께 용매에 용해시킨 후, 화학식 5의 화합물과 반응시켜 화학식 1a의 화합물을 제조하는 단계; 상기 단계 1에서 제조된 화학식 4의 화합물과 화학식 6의 아민화합물을 용매에 용해시킨 후, 화학식 5의 화합물과 반응시켜 화학식 1a의 화합물을 제조하는 단계; 및 상기 단계 1에서 제조된 화학식 4의 화합물을 용매 하에서 화학식 7의 화합물과 반응시켜 화학식 1a의 화합물을 제조하는 단계로 이루어지는 군으로부터 선택되는 어느 하나의 화학식 1a의 화합물을 제조하는 단계(단계 2)를 포함하는 5-(4-아미노페닐)-이소퀴놀린 유도체의 제조방법:Preparing a compound of Formula 1a by dissolving the compound of Formula 4 prepared in Step 1 in a solvent together with a coupling reagent and a base, and then reacting with the compound of Formula 5; Preparing a compound of formula 1a by dissolving the compound of formula 4 and the amine compound of formula 6 prepared in step 1 in a solvent and then reacting with the compound of formula 5; And preparing a compound of Formula 1a selected from the group consisting of reacting the compound of Formula 4 prepared in Step 1 with a compound of Formula 7 in a solvent (Step 2). Method for preparing 5- (4-aminophenyl) -isoquinoline derivative comprising:
    [반응식 1]Scheme 1
    Figure PCTKR2009005326-appb-I000048
    .
    Figure PCTKR2009005326-appb-I000048
    .
    (상기 식에서, R2 및 R3는 상기 화학식 1에서 정의한 바와 같으며, 화학식 1a는 화학식 1에 포함된다.)(Wherein R 2 and R 3 are as defined in Formula 1 above, and Formula 1a is included in Formula 1).
  7. 하기 반응식 2에 표시되는 바와 같이, As shown in Scheme 2 below,
    화학식 2의 화합물을 반응시켜 니트로가 도입된 화학식 8의 화합물을 제조하는 단계(단계 1');Reacting the compound of Formula 2 to prepare a compound of Formula 8 into which nitro is introduced (step 1 ′);
    상기 단계 1'에서 제조된 화학식 8의 화합물을 용매하에서 화학식 9의 화합물과 반응시켜 화학식 10의 화합물을 제조하는 단계(단계 2');Preparing a compound of formula 10 by reacting the compound of formula 8 prepared in step 1 ′ with a compound of formula 9 in a solvent (step 2 ′);
    상기 단계 2'에서 제조된 화학식 10의 화합물과 화학식 11의 아민 화합물을 용매에 용해시킨 후, p-니트로클로로포메이트(12)를 첨가하여 실온에서 반응시켜 화학식 13의 화합물을 제조하는 단계(단계 3'); 및Preparing a compound of Chemical Formula 13 by dissolving the compound of Chemical Formula 10 and the amine compound of Chemical Formula 11 prepared in Step 2 'in a solvent, and then reacting at room temperature by adding p-nitrochloroformate (12) (step 3 '); And
    상기 단계 3'에서 제조된 화학식 13의 화합물을 팔라듐 촉매 수소 조건하에서 환원반응시켜 화학식 1b의 화합물을 제조하는 단계(단계 4')를 포함하는 5-(4-아미노페닐)-이소퀴놀린 유도체의 제조방법:Preparation of the 5- (4-aminophenyl) -isoquinoline derivative comprising the step of reducing the compound of formula 13 prepared in step 3 'under palladium catalytic hydrogen conditions to produce the compound of formula 1b (step 4') Way:
    [반응식 2]Scheme 2
    Figure PCTKR2009005326-appb-I000049
    .
    Figure PCTKR2009005326-appb-I000049
    .
    (상기 식에서, R2 및 R5는 상기 화학식 1에서 정의한 바와 같으며, 화학식 1b는 화학식 1에 포함된다.)(Wherein R 2 and R 5 are as defined in Formula 1 above, and Formula 1b is included in Formula 1).
  8. 하기 반응식 3에 표시되는 바와 같이, As shown in Scheme 3 below,
    화학식 3의 화합물의 아미노기에 보호기를 도입한 화학식 14의 화합물을 제조하는 단계(단계 1");Preparing a compound of formula 14 having a protecting group introduced into an amino group of a compound of formula 3 (step 1 ″);
    상기 단계 1"에서 제조된 화학식 14의 화합물을 화학식 2의 화합물과 반응시켜 화학식 15의 화합물을 제조하는 단계(단계 2");Preparing a compound of Formula 15 by reacting the compound of Formula 14 prepared in Step 1 ″ with the compound of Formula 2 (Step 2 ″);
    상기 단계 2"에서 제조된 화학식 15의 화합물에 산화제를 이용하여 화학식 16의 화합물을 제조하는 단계(단계 3"); Preparing a compound of Chemical Formula 16 using an oxidant to the compound of Chemical Formula 15 prepared in Step 2 ″ (Step 3 ″);
    상기 단계 3"에서 제조된 화학식 16의 화합물의 아미노기 보호기를 제거하고 시아노기를 도입한 화학식 17의 화합물을 제조하는 단계(단계 4");Removing the amino group protecting group of the compound of Formula 16 prepared in step 3 ″ and preparing a compound of formula 17 incorporating a cyano group (step 4 ″);
    상기 단계 4"에서 제조된 화학식 17의 화합물에 이소시아네이트 화합물(18)을 반응시켜 화학식 19의 화합물을 제조하는 단계(단계 5"); 및Preparing a compound of formula 19 by reacting an isocyanate compound 18 with the compound of formula 17 prepared in step 4 ″ (step 5 ″); And
    상기 단계 5"에서 제조된 화학식 19의 화합물을 염기와 반응시켜 아미드기를 도입한 화학식 1c의 화합물을 제조하는 단계(단계 6")를 포함하는 5-(4-아미노페닐)-이소퀴놀린 유도체의 제조방법:Preparation of a 5- (4-aminophenyl) -isoquinoline derivative comprising the step of preparing a compound of formula 1c having a amide group introduced therein by reacting a compound of formula 19 prepared in step 5 "with a base (step 6") Way:
    [반응식 3]Scheme 3
    Figure PCTKR2009005326-appb-I000050
    .
    Figure PCTKR2009005326-appb-I000050
    .
    (상기 식에서, R2 및 R5는 상기 화학식 1에서 정의한 바와 같으며, 화학식 1c는 화학식 1에 포함된다.)(Wherein R 2 and R 5 are as defined in Formula 1 above, and Formula 1c is included in Formula 1).
  9. 제1항의 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 Raf 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating a disease caused by the overactivity of Raf kinase containing the 5- (4-aminophenyl) -isoquinoline derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  10. 제9항에 있어서, 상기 Raf 키나제의 과활성에 의해 유발되는 질환은 암 또는 흑색종인 것을 특징으로 하는 조성물.10. The composition of claim 9, wherein the disease caused by the overactivity of Raf kinase is cancer or melanoma.
  11. 제10항에 있어서, 상기 암은 갑상선암, 대장암 또는 난소암인 것을 특징으로 하는 조성물.The composition of claim 10, wherein the cancer is thyroid cancer, colon cancer or ovarian cancer.
PCT/KR2009/005326 2008-09-18 2009-09-18 Novel 5-(4-aminophenyl)-isoquinoline derivative, pharmaceutically acceptable salt thereof, production method for same, and composition containing same as active ingredient for prophylaxis and treatment of medical condition induced by raf kinase hyperactivity WO2010032986A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020080091405A KR20100032496A (en) 2008-09-18 2008-09-18 Novel 5-(4-aminophenyl)-isoquinoline derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for prevention or treatment of diseases induced by overactivation of raf kinase containing the same as an active ingredient
KR10-2008-0091405 2008-09-18

Publications (2)

Publication Number Publication Date
WO2010032986A2 true WO2010032986A2 (en) 2010-03-25
WO2010032986A3 WO2010032986A3 (en) 2010-08-19

Family

ID=42040023

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2009/005326 WO2010032986A2 (en) 2008-09-18 2009-09-18 Novel 5-(4-aminophenyl)-isoquinoline derivative, pharmaceutically acceptable salt thereof, production method for same, and composition containing same as active ingredient for prophylaxis and treatment of medical condition induced by raf kinase hyperactivity

Country Status (2)

Country Link
KR (1) KR20100032496A (en)
WO (1) WO2010032986A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
WO2018146253A1 (en) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway
WO2019133810A1 (en) 2017-12-28 2019-07-04 Tract Pharmaceuticals, Inc. Stem cell culture systems for columnar epithelial stem cells, and uses related thereto

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102337870B1 (en) * 2020-02-03 2021-12-10 순천대학교 산학협력단 Substituted diarylurea compound for inducing apoptosis and composition for anticancer comprising the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114679A1 (en) * 2001-09-12 2003-06-19 Mceachern Ernest J. Synthesis of enantiomerically pure amino-substituted fused bicyclic rings
WO2005049574A1 (en) * 2003-11-20 2005-06-02 Warner-Lambert Company Llc Androgen receptor modulators
WO2005049576A1 (en) * 2003-11-19 2005-06-02 Glaxo Group Limited Substitute isoquinolines useful in the treatment of diseases such as cancer and atherosclerosis
KR20070009530A (en) * 2003-09-24 2007-01-18 노파르티스 아게 1,4-disubstituted isoquinoline derivatives as raf-kinase inhibitors useful for the treatment of proliferative diseases
US20070037796A1 (en) * 2003-11-25 2007-02-15 Barda David A 7-Phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (proteinkinase b)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114679A1 (en) * 2001-09-12 2003-06-19 Mceachern Ernest J. Synthesis of enantiomerically pure amino-substituted fused bicyclic rings
KR20070009530A (en) * 2003-09-24 2007-01-18 노파르티스 아게 1,4-disubstituted isoquinoline derivatives as raf-kinase inhibitors useful for the treatment of proliferative diseases
WO2005049576A1 (en) * 2003-11-19 2005-06-02 Glaxo Group Limited Substitute isoquinolines useful in the treatment of diseases such as cancer and atherosclerosis
WO2005049574A1 (en) * 2003-11-20 2005-06-02 Warner-Lambert Company Llc Androgen receptor modulators
US20070037796A1 (en) * 2003-11-25 2007-02-15 Barda David A 7-Phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (proteinkinase b)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
WO2018146253A1 (en) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway
WO2019133810A1 (en) 2017-12-28 2019-07-04 Tract Pharmaceuticals, Inc. Stem cell culture systems for columnar epithelial stem cells, and uses related thereto

Also Published As

Publication number Publication date
WO2010032986A3 (en) 2010-08-19
KR20100032496A (en) 2010-03-26

Similar Documents

Publication Publication Date Title
WO2010064875A2 (en) Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient
WO2017204445A2 (en) Pharmaceutical composition inducing decomposition of alk protein, and pharmaceutical composition for cancer prevention or treatment containing same as active component
WO2019190259A1 (en) Novel sulfonamide derivative having inhibitory effect on epidermal growth factor receptor mutation
WO2016032120A1 (en) Novel amino-phenyl-sulfonyl-acetate derivative and use thereof
WO2017142325A1 (en) Novel 2,3,5-substituted thiophene compound as protein kinase inhibitor
WO2018139903A1 (en) Pyrimidine compound and pharmaceutical use thereof
WO2014109530A1 (en) 2-(phenylethynyl)thieno[3,4-b]pyrazine derivative and pharmaceutical composition comprising same for preventing or treating cancer
WO2019231271A1 (en) Heterocyclic derivatives and use thereof
WO2010032986A2 (en) Novel 5-(4-aminophenyl)-isoquinoline derivative, pharmaceutically acceptable salt thereof, production method for same, and composition containing same as active ingredient for prophylaxis and treatment of medical condition induced by raf kinase hyperactivity
WO2018021826A1 (en) Novel pyrimidine-2,4-diamine derivative and pharmaceutical composition for prevention or treatment of cancer containing same as active ingredient
WO2011122815A2 (en) Novel quinoxaline derivatives
WO2016006975A2 (en) Novel imidazotriazinone or imidazopyrazinone derivatives, and use thereof
WO2018056621A1 (en) Novel imidazolyl pyrimidine derivative, method for preparing same, and pharmaceutical composition comprising same as active ingredient for prevention or treatment of cancer
WO2011049274A1 (en) Imidazole derivatives and compositions for treating melanoma
WO2017131425A1 (en) Novel imidazole derivative having jnk inhibitory activity and use thereof
WO2020013531A1 (en) N-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-5-phenyl-4,5-dihydro-1h-pyrazole-1-carboxamide derivative, and pharmaceutical composition containing same as active ingredient for treating kinase-related diseases
WO2018139883A1 (en) Fused pyrimidine derivative as multi-target kinase inhibitor
WO2021137665A1 (en) 1, 2, 3-triazole derivative compound as hsp90 inhibitor, and use thereof
WO2021040422A1 (en) Novel pyrimido[4,5-d]pyrimidine-2-one derivative having protein kinase inhibitory activity
WO2017164705A1 (en) Novel pyridine derivative, method for preparing same, and pharmaceutical composition for preventing or treating fgfr-related disease containing same as active component
WO2021112626A1 (en) Novel indirubin derivative and use thereof
WO2018021762A1 (en) Novel compound, preparation method therefor, and pharmaceutical composition containing same
EP3166945A2 (en) Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof
WO2019098785A1 (en) 7-amino-1h-indole-5-carboxamide derivative and use thereof
WO2022119090A1 (en) Biphenyl pyrrolidine and biphenyl dihydroimidazole derivatives for inhibiting activity of 5-ht7 serotonin receptor, and pharmaceutical composition comprising same as active ingredient

Legal Events

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

Ref document number: 09814802

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09814802

Country of ref document: EP

Kind code of ref document: A2