WO2018139883A1 - Fused pyrimidine derivative as multi-target kinase inhibitor - Google Patents

Fused pyrimidine derivative as multi-target kinase inhibitor Download PDF

Info

Publication number
WO2018139883A1
WO2018139883A1 PCT/KR2018/001139 KR2018001139W WO2018139883A1 WO 2018139883 A1 WO2018139883 A1 WO 2018139883A1 KR 2018001139 W KR2018001139 W KR 2018001139W WO 2018139883 A1 WO2018139883 A1 WO 2018139883A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
amino
oxy
acrylamide
dihydrocyeno
Prior art date
Application number
PCT/KR2018/001139
Other languages
French (fr)
Korean (ko)
Inventor
이준
이영훈
박병선
유희원
Original Assignee
부광약품 주식회사
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 부광약품 주식회사 filed Critical 부광약품 주식회사
Publication of WO2018139883A1 publication Critical patent/WO2018139883A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to fusedpyrimidine derivatives useful as multiple target kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutical compositions for the prophylaxis or treatment of cancer or immune-related diseases comprising them in pharmacologically effective amounts.
  • Kinases are enzymes that catalyze the phosphorylation reaction that delivers the gamma position phosphate group of ATP (adenosine triphosphate) to specific substrates. Kinases are widely involved in biosignal transmission such as cell proliferation, survival, apoptosis, metabolism, and transcription. Until now, it is known that small molecule kinase inhibitors can be used to treat cancer, autoimmune diseases, metabolic diseases, etc., and some kinase inhibitors have been approved or developed as therapeutic agents. (Trends of Pharmacological Sciences 2014, 35, 604-620. Advances in kinase targeting: current clinical use and clinical trials)
  • BTK BMX kinases belonging to the TEC family belong to non-receptor tyrosine kinases, which play an important role in immune cell signaling. Therefore, it can be applied to the treatment of autoimmune diseases and cancer by effectively inhibiting these kinases.
  • JAK3 kinases belong to non-receptor tyrosine kinases and secrete cytokines involved in the immune response. Therefore, it can be applied to the treatment of autoimmune diseases by inhibiting JAK3 kinase. (Current Opinion in Investigational Drugs 2003, 4 (11), 1297-1303. JAK3 inhibition as a new concept for immune suppression)
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer or immune-related diseases comprising the fused pyrimidine derivatives, pharmaceutically acceptable salts or stereoisomers thereof as an active ingredient.
  • the present inventors have synthesized a fused pyrimidine derivative which is a multi-target kinase inhibitor capable of simultaneously inhibiting the BTK, BMX and JAK3 kinases described above, and completed the present invention by confirming this through a disease model animal test.
  • the present invention provides a compound of Formula 1 and pharmaceutically acceptable salts or stereoisomers thereof:
  • X is a direct bond, O, NH, C ( ⁇ O) or heterocycloalkyl
  • Y is alkoxyalkyl, heterocycloalkyl or heterocycloalkylalkyl
  • W is O or NH
  • Z is or Is
  • R 1 is hydrogen, alkoxy or halogen
  • R 2 is hydrogen or dialkylaminoalkyl.
  • alkyl when used alone or else in combination with additional terms (eg alkoxy), straight or branched, preferably saturated with 1 to 6 carbon atoms Radicals of the aliphatic hydrocarbon group.
  • halogen herein means a radical that is F, Cl, Br or I.
  • heterocycloalkyl refers to a 5-10 membered saturated monocyclic or bicyclic ring having 1 to 4 heteroatoms, preferably selected from the group consisting of N, O, S, Si and P. Meaning, specific examples include pyrrolidine, piperidine, tetrahydrofuran, 1,4-azasilinane, tetrahydropyran, morpholine (morpholine), piperazine, 1,4-azaphosphinane and 2,7-diazaspiro [3.5] nonane (2,7-diazaspiro [3.5] nonane) Including but not limited to.
  • the compounds according to the invention can have an asymmetric carbon center and an asymmetric axis or asymmetric plane, so that they can exist as stereoisomers such as E or Z isomers, R or S isomers, racemates, etc., all of these isomers and mixtures of It is included in a range.
  • X is a 5- to 10-membered heterocyclo having 1 to 3 heteroatoms selected from a direct bond, O, NH, C ( ⁇ O), or N, O and S. Alkyl.
  • Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl-C 1 -C 6 -alkyl, where heterocycloalkyl has 1 to 4 heteroatoms selected from N, O, S, Si, and P and is unsubstituted or C 1 -C 6 -alkyl, oxo, C 1 -C 6 -Alkylcarbonyl, aminocarbonyl, halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl Monocyclic or bicyclic compounds substituted with one or more substituents selected from the group.
  • Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5 to 10 membered heterocycloalkyl, or 5 or 6 membered heterocycloalkyl-C 1- C 6 -alkyl, wherein the heterocycloalkyl has 1 to 3 heteroatoms selected from N, O, S, Si and P and is unsubstituted or C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkylcarbonyl, aminocarbonyl, halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl Monocyclic or bicyclic compounds substituted with one to three substituents selected from the group consisting of:
  • R 1 is hydrogen, C 1 -C 6 -alkoxy or halogen
  • R 2 is hydrogen or di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkyl.
  • Representatives of the compounds of formula 1 according to the invention include the following:
  • the compound of formula 1 according to the present invention may be prepared by the method shown typically in the following scheme 1:
  • X, Y, W, R 1 and R 2 are as defined in Formula 1 above, and Z is OH or Cl.
  • the compounds of formula 1 according to the invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, in which case preferred salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid , Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfuric acid Salts derived from phonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, and the like.
  • preferred salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, ace
  • the compound of formula 1 according to the present invention a pharmaceutically acceptable salt or stereoisomer thereof effectively inhibits BTK, BMX and JAK3 kinases.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of cancer or immune-related diseases, including a compound of formula (1), a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient.
  • cancers include, but are not limited to, B-cell lymphoma, pancreatic cancer, prostate cancer, colon cancer, gastric cancer, and the like.
  • immune-related diseases include, but are not limited to, rheumatoid arthritis, Sjogren's syndrome, psoriasis, systemic lupus erythematosus, atopy, asthma, multiple sclerosis, and the like.
  • compositions of the present invention may be formulated according to conventional methods and may be administered in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or intramuscularly, intravenously or subcutaneously. It may be prepared in a parenteral dosage form such as
  • the carriers used are cellulose, calcium silicate, lactose, dextrose, corn starch, sucrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid Calcium, gelatin, talc, surfactant, emulsifier, suspending agent, diluent, etc. are mentioned.
  • the carrier may be, for example, water, saline solution, aqueous glucose solution, aqueous pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid. , Fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers and the like can be used.
  • a novel fused pyrimidine derivative capable of effectively inhibiting BTK, BMX and JAK3 kinases can be provided. Accordingly, the fused pyrimidine derivatives, pharmaceutically acceptable salts or stereoisomers thereof according to the present invention can be effectively used for the prevention or treatment of cancer or immune related diseases caused by activation of the kinase.
  • 1 is a graph showing the change in arthritis score according to oral administration of the compound of Example 3 in collagen-induced mouse arthritis (CIA, collagen-induced arthritis) model.
  • Step 2 3-((2-chloro-6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) aniline
  • the compound (146 g, 0.47 mol) prepared in step 1 was diluted with methanol (4 L), and then tin chloride (445.6 g, 2.35 mol) was added thereto, followed by heating to reflux for 2 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, ethyl acetate (2L) and distilled water (2L) were added to the resulting residue, and sodium carbonate was added to the mixture while stirring to neutralize. The resulting precipitate was filtered off with a filter filled with celite, and the filtrate was separated into water and an organic layer using a layer separation. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound (121). g, 92%).
  • Step 3 N -(3-((2-chloro-6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • step 2 The compound prepared in step 2 (120 g, 0.43 mol) and N, N -diisopropylethylamine (150 mL, 0.86 mol) were dissolved in tetrahydrofuran (2.4 L), followed by acryloyl chloride (52 mL, 0.65 mol) was added dropwise and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, water / methanol mixed solvent (4: 1, 1.2 L) was added to the resulting solid, stirred at room temperature for 1 hour, filtered and washed with distilled water. The resulting solid was triturated in ethyl acetate, filtered and dried to give the title compound (136 g, 95%).
  • Example 1-3 N -(3-((2-((4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 2-1 The compound (2.96 g, 14.17 mmol) prepared in Example 2-1 was dissolved in methanol (30 mL), and then a palladium catalyst (10% Pd / C, 0.3 g, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.54 g, 100%).
  • the separated organic layer was washed with an aqueous salt solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent.
  • the obtained solid was triturated in n -hexane / dichloromethane mixed solvent (1:10, 2L), filtered and dried to obtain the title compound (3.63 g, 93%).
  • Example 3-2 The compound (2 g, 5.85 mmol) prepared in Example 3-2 was dissolved in methanol (30 mL), cooled to 0 ° C., and added with a small amount of sodium borohydride (0.66 g, 17.54 mmol). The reaction mixture was raised to room temperature and stirred for 12 hours. At the end of the reaction, the reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The obtained residue (1.2 g) was used for the next step without purification.
  • Example 3-5 N -(3-((2-((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 4-2 The compound (0.44 g, 1.9 mmol) prepared in Example 4-2 was dissolved in methanol (10 mL), and then a palladium catalyst (10% Pd / C, 44 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.38 g, 98%).
  • Example 4-4 N -(3-((2-((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 5-1 After dissolving the compound (1 g, 4.5 mmol) prepared in Example 5-1 in methanol (10 mL), a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.87 g, 100%).
  • Example 6-1 After dissolving the compound (1 g, 4.5 mmol) prepared in Example 6-1 in methanol (10 mL), a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.87 g, 100%).
  • Example 6-3 (S) - N -(3-((2-((4-((1-methylpyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 7-2 N One -(One- Methylpiperidine -4-yl) benzene-1,4- Diamine Produce
  • Example 7-1 The compound (9.0 g, 38.09 mmol) prepared in Example 7-1 was dissolved in methanol (200 mL), and then a palladium catalyst (10% Pd / C, 0.9 g, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (6.6 g, 84%).
  • Example 7-3 N -(3-((2-((4-((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 8 N- (3-((2-((4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) phenyl) amino) -6,7 Preparation of -dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 8-1 After dissolving the compound (0.42 g, 1.43 mmol) prepared in Example 8-1 in methanol (5 mL), a palladium catalyst (10% Pd / C, 42 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.37 g, 97%).
  • a palladium catalyst (10% Pd / C, 42 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.37 g, 97%).
  • Example 8-3 N -(3-((2-((4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) phenyl) amino) -6,7-dihydrosaie Furnace [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 10-1 After dissolving the compound (15.0 g, 67.79 mmol) prepared in Example 10-1 in methanol (450 mL), a palladium catalyst (10% Pd / C, 1.5 g, 10 wt%) was added thereto and room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (11.0 g, 85%).
  • a palladium catalyst (10% Pd / C, 1.5 g, 10 wt%) was added thereto and room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (11.0 g, 85%).
  • Example 10-3 N -(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • 2-chloroethanesulfonyl chloride 500 mg, 3.07 mmol was dissolved in dichloromethane (5 mL) and then cooled to -78 ° C. Pyridine (1 mL, 12.28 mmol) was added dropwise under nitrogen gas, and then slowly raised to 0 ° C. and stirred for 1 hour.
  • Example 12-1 N -(3-((2-chloro-6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) amino) phenyl) acrylamide
  • 2,4-Dichlorothieno [3,2- d ] pyrimidine 500 mg, 3.7 mmol was dissolved in dimethyl formamide (5 mL), followed by N- (3-aminophenyl) acrylamide ( 766 mg, 3.08 mmol) and diisopropylethylamine (0.54 mL, 3.08 mmol) were added and stirred at 60 ° C. for 12 hours.
  • Example 12-2 N -(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) amino) phenyl) acrylamide
  • Example 13-1 The compound (1 g, 3.93 mmol) prepared in Example 13-1 was dissolved in methanol (20 mL), and then a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.85 g, 96%).
  • a palladium catalyst 10% Pd / C, 100 mg, 10 wt%
  • Example 13-3 N -(3-((2-((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7-dihydrocyeno [3 ,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 14-1 After dissolving the compound (3.0 g, 11.94 mmol) prepared in Example 14-1 in methanol (150 mL), a palladium catalyst (10% Pd / C, 300 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.5 g, 96%).
  • a palladium catalyst (10% Pd / C, 300 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.5 g, 96%).
  • Example 14-3 N -(3-((2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 15-1 The compound (9.0 g, 38.09 mmol) prepared in Example 15-1 was dissolved in methanol (200 mL), and then a palladium catalyst (10% Pd / C, 0.9 g, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (6.6 g, 84%).
  • Example 15-3 N -(3-((2-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 16-1 The compound (1 g, 5.07 mmol) prepared in Example 16-1 was dissolved in methanol (40 mL), and then a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto at room temperature under hydrogen gas. Stir for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (720 mg, 85%).
  • Example 16-3 N -(3-((2-((4- (2-methoxyethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 1- except that 4- (2-methoxyethoxy) aniline (1.2 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same process as in 3, the title compound (167 mg, 30%) was obtained.
  • Example 17-1 The compound (2.0 g, 8.5 mmol) prepared in Example 17-1 was dissolved in methanol (60 mL), and then a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.2 g, 69%).
  • a palladium catalyst 10% Pd / C, 200 mg, 10 wt%
  • Example 17-3 N -(3-((2-((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 18-1 The compound (2 g, 8.02 mmol) prepared in Example 18-1 was dissolved in methanol (60 mL), and then a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto at room temperature under hydrogen gas. Stir for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (400 mg, 23%).
  • a palladium catalyst 10% Pd / C, 200 mg, 10 wt%
  • Example 18-3 N -(3-((2-((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 19-1 After dissolving the compound (2 g, 8.02 mmol) prepared in Example 19-1 in methanol (60 mL), a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.2 g, 67%).
  • Example 19-3 N -(3-((2-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 20-1 The compound (2 g, 8.5 mmol) prepared in Example 20-1 was dissolved in methanol (60 mL), and then a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto at room temperature under hydrogen gas. Stir for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.1 g, 61%).
  • Example 21-2 N -(3-((2-((4- (2-acetyl-2,7-diazaspiro [3.5] nonane-7-yll) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 22-2 N -(3-((2-((4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 23-2 N -(3-((2-((4- (piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 24-2 N -(3-((2-((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 25-2 N -(3-((2-((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 26-2 N -(3-((2-((4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 27-2 N -(3-((2-((4- (2-morpholinoethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 1- except that 4- (2-morpholinoethoxy) aniline (1.35 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same procedure as in 3 was carried out to obtain the title compound (50 mg, 7%).
  • Example 28 N -(3-((2-((4- (4- (2- (dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 28-2 N -(3-((2-((4- (4- (2- (dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - d ] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
  • Example 29-2 N -(3-((2-((4- (4- Methylpiperazine -One- Carbonyl ) Phenyl) amino) -6,7- Dihydrocyeno [3,2- d ] Pyrimidine Preparation of -4-yl) oxy) phenyl) acrylamide
  • the inhibitory activity of the compounds against BTK, BMX, and JAK3 kinases was determined by measuring the inhibition of phosphorylation of the substrate using FRET, and was performed according to the Z'-LYTE assay method by Thermo Fisher Scientific.
  • the compound to be measured reacts with each kinase to control the FRET-peptide phosphorylation as a substrate, and FRET-peptide is not cleaved or cleaved depending on the phosphorylation.
  • IC 50 values that measure the emission of cleaved FRET-peptide (445 nm) and undivided FRET-peptide (520 nm) and calculate the emission ratio (445 nm / 520 nm) by 50% inhibition of activity Confirmed.
  • the IC 50 value ranges are indicated in Table 1 as follows: A (IC 50 ⁇ 100 nM), B (100 nM ⁇ IC 50 ⁇ 1,000 nM), C (IC 50 > 1,000 nM).
  • a collagen-induced arthritis (CIA) model was constructed to explore the efficacy of improving the arthritis of a test substance using a rheumatoid arthritis model through collagen injection.
  • CIA collagen-induced arthritis
  • bovine type 2 collagen was added to the base of the tail of 6-week-old male DBA / 1J mice.
  • Primary immunity was induced by intradermal injection into the site of about cm.
  • bovine type 2 collagen was mixed with IFA (Freund's incomplete adjuvant) and emulsified in the same manner as above, followed by intradermal injection into the tail to induce a second immune response.
  • Example 3 (10 mg / kg, QD), (3) Example 3 (30 mg / kg, QD), (4) dexamethasone (0.05 mg / kg, QD), (5) Example 3 (30 mg / kg, BID) was administered orally every day for two weeks, the general symptoms were observed every day during the administration period, the index score was measured twice a week to measure the results 1 is shown.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are: a compound of chemical formula 1; a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutical composition containing the same. The compound of chemical formula 1 or the pharmaceutically acceptable salt or stereoisomer thereof acts as a multi-target kinase inhibitor, thereby being usable in the prevention or treatment of cancers or immune-related diseases such as rheumatoid arthritis, Sjögren's syndrome, psoriasis, systemic lupus erythematosus, atopy, asthma and multiple sclerosis.

Description

다중 표적 키나아제 저해제로서 융합피리미딘 유도체Fusionpyrimidine Derivatives As Multiple Target Kinase Inhibitors
본 발명은 다중 표적 키나아제 저해제로서 유용한 융합피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체, 및 이를 약리학적 유효량으로 포함하는 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물에 관한 것이다.The present invention relates to fusedpyrimidine derivatives useful as multiple target kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutical compositions for the prophylaxis or treatment of cancer or immune-related diseases comprising them in pharmacologically effective amounts.
키나아제는 ATP(adenosine triphosphate)의 감마 위치 인산기를 특정 기질에 전달하는 인산화 반응을 촉매하는 효소이다. 키나아제는 세포증식, 생존, 세포사멸, 대사, 전사 등의 생체신호전달에 폭넓게 관여한다. 지금까지 저분자 키나아제 저해제를 이용하여 암, 자가면역질환, 대사성 질환 등을 치료할 수 있는 것으로 알려져 있으며, 일부 키나아제 저해제들이 치료제로 승인되었거나 개발 중이다. (Trends of Pharmacological Sciences 2014, 35, 604-620. Advances in kinase targeting: current clinical use and clinical trials)Kinases are enzymes that catalyze the phosphorylation reaction that delivers the gamma position phosphate group of ATP (adenosine triphosphate) to specific substrates. Kinases are widely involved in biosignal transmission such as cell proliferation, survival, apoptosis, metabolism, and transcription. Until now, it is known that small molecule kinase inhibitors can be used to treat cancer, autoimmune diseases, metabolic diseases, etc., and some kinase inhibitors have been approved or developed as therapeutic agents. (Trends of Pharmacological Sciences 2014, 35, 604-620. Advances in kinase targeting: current clinical use and clinical trials)
TEC family에 속하는 BTK, BMX 키나아제는 비-수용체 타이로신 키나아제에 속하며, 이들 키나아제는 면역세포 신호전달에 중요한 역할을 한다. 따라서, 이들 키나아제를 효과적으로 억제함으로써 자가면역질환 및 암의 치료에 적용할 수 있다. (Nature Reviews Immunology, 2005, 5, 284-295. TEC-FAMILY KINASES: REGULATORS OF T-HELPER-CELL DIFFERENTIATION)BTK, BMX kinases belonging to the TEC family belong to non-receptor tyrosine kinases, which play an important role in immune cell signaling. Therefore, it can be applied to the treatment of autoimmune diseases and cancer by effectively inhibiting these kinases. (Nature Reviews Immunology, 2005, 5, 284-295.TEC-FAMILY KINASES: REGULATORS OF T-HELPER-CELL DIFFERENTIATION)
JAK3 키나아제는 비-수용체 타이로신 키나아제에 속하며 면역반응에 관여하는 싸이토카인을 분비한다. 따라서, JAK3 키나아제를 저해함으로써 자가면역질환 치료에 적용할 수 있다. (Current Opinion in Investigational Drugs 2003, 4(11), 1297-1303. JAK3 inhibition as a new concept for immune suppression)JAK3 kinases belong to non-receptor tyrosine kinases and secrete cytokines involved in the immune response. Therefore, it can be applied to the treatment of autoimmune diseases by inhibiting JAK3 kinase. (Current Opinion in Investigational Drugs 2003, 4 (11), 1297-1303. JAK3 inhibition as a new concept for immune suppression)
면역 세포 신호전달은 서로가 상호 네트워크를 통해 이루어지기 때문에 특정 신호전달에 관여하는 키나아제만 억제할 경우 다른 경로를 통해 면역 세포 신호전달이 활성화될 수 있다. 따라서 면역 세포 신호 전달에 관여하는 여러 개의 키나아제를 동시에 억제할 경우 자가 면역 질환이나 암치료에 보다 효과적일 수 있다.Since immune cell signaling is achieved through a mutual network, the inhibition of only kinases involved in specific signaling can activate immune cell signaling through other pathways. Therefore, simultaneous inhibition of several kinases involved in immune cell signal transduction may be more effective in the treatment of autoimmune diseases or cancer.
이에 본 발명의 목적은 암 및 면역 관련 질환의 치료에 적용할 수 있는 다중 표적 키나아제 저해제로서 융합 피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 제공하는 것이다.It is therefore an object of the present invention to provide fused pyrimidine derivatives, pharmaceutically acceptable salts or stereoisomers thereof as multi-target kinase inhibitors applicable to the treatment of cancer and immune related diseases.
또한, 본 발명의 다른 목적은 상기 융합 피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 유효성분으로 포함하는 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer or immune-related diseases comprising the fused pyrimidine derivatives, pharmaceutically acceptable salts or stereoisomers thereof as an active ingredient.
본 발명자들은 상기 기술된 BTK, BMX 및 JAK3 키나아제를 동시에 억제할 수 있는 다중 표적 키나아제 저해제인 융합 피리미딘 유도체를 합성하였고, 이를 질환 모델 동물시험을 통해 확인함으로써 본 발명을 완성하였다.The present inventors have synthesized a fused pyrimidine derivative which is a multi-target kinase inhibitor capable of simultaneously inhibiting the BTK, BMX and JAK3 kinases described above, and completed the present invention by confirming this through a disease model animal test.
이하에서 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1의 화합물 및 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 제공한다:The present invention provides a compound of Formula 1 and pharmaceutically acceptable salts or stereoisomers thereof:
[화학식 1][Formula 1]
Figure PCTKR2018001139-appb-I000001
Figure PCTKR2018001139-appb-I000001
상기 식에서,Where
X는 직접결합, O, NH, C(=O) 또는 헤테로사이클로알킬이고; X is a direct bond, O, NH, C (═O) or heterocycloalkyl;
Y는 알콕시알킬, 헤테로사이클로알킬 또는 헤테로사이클로알킬알킬이며;Y is alkoxyalkyl, heterocycloalkyl or heterocycloalkylalkyl;
W는 O 또는 NH이고;W is O or NH;
Z는
Figure PCTKR2018001139-appb-I000002
또는
Figure PCTKR2018001139-appb-I000003
이며;Z is
Figure PCTKR2018001139-appb-I000002
or
Figure PCTKR2018001139-appb-I000003
Is;
R1은 수소, 알콕시 또는 할로겐이고;R 1 is hydrogen, alkoxy or halogen;
R2는 수소 또는 다이알킬아미노알킬이다.R 2 is hydrogen or dialkylaminoalkyl.
본원에서 용어 "알킬"은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 알콕시) 직쇄형 또는 측쇄형의 바람직하게는 1개 내지 6개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다.As used herein, the term "alkyl" when used alone or else in combination with additional terms (eg alkoxy), straight or branched, preferably saturated with 1 to 6 carbon atoms Radicals of the aliphatic hydrocarbon group.
본원에서 용어 "할로겐"은 F, Cl, Br 또는 I인 라디칼을 의미한다.The term "halogen" herein means a radical that is F, Cl, Br or I.
본원에서 용어 "헤테로사이클로알킬"은 바람직하게는 N, O, S, Si 및 P로 이루어진 그룹으로부터 선택되는 1 내지 4개의 헤테로원자를 갖는 5 내지 10원의 포화 모노사이클릭 또는 바이사이클릭 환을 의미하고, 구체적인 예로는 피롤리딘(pyrrolidine), 피페리딘(piperidine), 테트라하이드로퓨란(tetrahydrofuran), 1,4-아자실란(1,4-azasilinane), 테트라하이드로피란 (tetrahydropyran), 몰포린(morpholine), 피페라진(piperazine), 1,4-아자포스피난(1,4-azaphosphinane) 및 2,7-다이아자스파이로[3.5]노네인(2,7-diazaspiro[3.5]nonane)을 포함하나 이에 제한되는 것은 아니다.The term “heterocycloalkyl” herein refers to a 5-10 membered saturated monocyclic or bicyclic ring having 1 to 4 heteroatoms, preferably selected from the group consisting of N, O, S, Si and P. Meaning, specific examples include pyrrolidine, piperidine, tetrahydrofuran, 1,4-azasilinane, tetrahydropyran, morpholine (morpholine), piperazine, 1,4-azaphosphinane and 2,7-diazaspiro [3.5] nonane (2,7-diazaspiro [3.5] nonane) Including but not limited to.
본 발명에 따른 화합물들은 비대칭 탄소중심과 비대칭축 또는 비대칭평면을 가질 수 있으므로 E 또는 Z 이성질체, R 또는 S 이성질체, 라세미체 등의 입체이성질체로서 존재할 수 있으며, 이들 모든 이성질체 및 혼합물은 본 발명의 범위에 포함된다.The compounds according to the invention can have an asymmetric carbon center and an asymmetric axis or asymmetric plane, so that they can exist as stereoisomers such as E or Z isomers, R or S isomers, racemates, etc., all of these isomers and mixtures of It is included in a range.
본 발명의 일 측면에 따르면, 상기 화학식 1에서 X가 직접결합, O, NH, C(=O), 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로사이클로알킬이다.According to an aspect of the present invention, in Chemical Formula 1, X is a 5- to 10-membered heterocyclo having 1 to 3 heteroatoms selected from a direct bond, O, NH, C (═O), or N, O and S. Alkyl.
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 X가 직접결합, O, NH, C(=O), 또는 1 또는 2개의 N 원자를 갖는 5 또는 6원 헤테로사이클로알킬이다.According to another aspect of the invention, X in formula 1 is a direct bond, O, NH, C (= O), or a 5 or 6 membered heterocycloalkyl having 1 or 2 N atoms.
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 Y가 C1-C6-알콕시-C1-C6-알킬, 5 내지 10원 헤테로사이클로알킬 또는 5 내지 10원 헤테로사이클로알킬-C1-C6-알킬이고, 여기에서 헤테로사이클로알킬은 N, O, S, Si 및 P로부터 선택되는 1 내지 4개의 헤테로원자를 갖고, 비치환되거나 C1-C6-알킬, 옥소, C1-C6-알킬카보닐, 아미노카보닐, 할로겐, C1-C6-알콕시-C1-C6-알킬 및 다이(C1-C6-알킬)아미노-C1-C6-알킬카보닐로 이루어지는 그룹으로부터 선택되는 하나 이상의 치환기로 치환되는 모노사이클릭 또는 바이사이클릭 화합물이다.According to another aspect of the present invention, in formula 1, Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl-C 1 -C 6 -alkyl, where heterocycloalkyl has 1 to 4 heteroatoms selected from N, O, S, Si, and P and is unsubstituted or C 1 -C 6 -alkyl, oxo, C 1 -C 6 -Alkylcarbonyl, aminocarbonyl, halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl Monocyclic or bicyclic compounds substituted with one or more substituents selected from the group.
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 Y가 C1-C6-알콕시-C1-C6-알킬, 5 내지 10원 헤테로사이클로알킬, 또는 5 또는 6원 헤테로사이클로알킬-C1-C6-알킬이고, 여기에서 헤테로사이클로알킬은 N, O, S, Si 및 P로부터 선택되는 1 내지 3개의 헤테로원자를 갖고, 비치환되거나 C1-C6-알킬, 옥소, C1-C6-알킬카보닐, 아미노카보닐, 할로겐, C1-C6-알콕시-C1-C6-알킬 및 다이(C1-C6-알킬)아미노-C1-C6-알킬카보닐로 이루어지는 그룹으로부터 선택되는 1 내지 3개의 치환기로 치환되는 모노사이클릭 또는 바이사이클릭 화합물이다.According to another aspect of the present invention, in formula 1, Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5 to 10 membered heterocycloalkyl, or 5 or 6 membered heterocycloalkyl-C 1- C 6 -alkyl, wherein the heterocycloalkyl has 1 to 3 heteroatoms selected from N, O, S, Si and P and is unsubstituted or C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkylcarbonyl, aminocarbonyl, halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl Monocyclic or bicyclic compounds substituted with one to three substituents selected from the group consisting of:
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 R1은 수소, C1-C6-알콕시 또는 할로겐이고; R2는 수소 또는 다이(C1-C6-알킬)아미노-C1-C6-알킬이다.According to another aspect of the present invention, in formula 1 R 1 is hydrogen, C 1 -C 6 -alkoxy or halogen; R 2 is hydrogen or di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkyl.
본 발명에 따른 화학식 1의 화합물의 대표적인 것에는 다음의 것이 포함된다:Representatives of the compounds of formula 1 according to the invention include the following:
N-(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3, 2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
(R)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; (R) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
(S)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; (S) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyridine Midin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) phenyl) amino) -6,7-dihydrocysi Eno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((3-플루오로-4-몰포리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((3-fluoro-4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) Phenyl) acrylamide;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)에탄설폰아마이드; N- (3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) ethanesulfonamide;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)아크릴아마이드; N- (3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- One) amino) phenyl) acrylamide;
N-(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7-dihydrocyeno [ 3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyridine Midin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2-methoxyethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) acrylamide;
(S)-1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드; (S) -1- (4-((4- (3-acrylamidophenoxy) -6,7-dihydrocyeno [3,2- d ] pyrimidin-2-yl) amino) phenyl) Pyrrolidine-2-carboxamide;
N-(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2-acetyl-2,7-diazaspiro [3.5] nonane-7-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide ;
N-(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) Oxy) phenyl) acrylamide;
N-(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine -4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2-morpholinoethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
N-(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4- (2- (dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3, 2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]미리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-methylpiperazin-1-carbonyl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] myrimidine-4 -Yl) oxy) phenyl) acrylamide;
(E)-4-(다이메틸아미노)-N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드; 및 (E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) 5,6-dihydro-Im in the furnace [2,3- d ] pyrimidin-4-yl) oxy) phenyl) but-2-enamide; And
(E)-4-(다이메틸아미노)-N-(3-((2-((4-몰폴리노페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드. (E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- morpholinophenyl) amino) -5,6-dihydro furnace to Im [2,3- d] pyrimidin Midin-4-yl) oxy) phenyl) but-2-enamide.
본 발명에 따른 상기 화학식 1의 화합물은 하기 반응식 1의 대표적으로 도시된 방법에 의해 제조될 수 있다:The compound of formula 1 according to the present invention may be prepared by the method shown typically in the following scheme 1:
[반응식 1]Scheme 1
Figure PCTKR2018001139-appb-I000004
Figure PCTKR2018001139-appb-I000004
상기 반응식에서,In the above scheme,
X, Y, W, R1 및 R2는 상기 화학식 1에서 정의된 바와 같고, Z는 OH 또는 Cl이다.X, Y, W, R 1 and R 2 are as defined in Formula 1 above, and Z is OH or Cl.
상기 반응식 1에서, 화합물 8을 탄산칼륨 존재하에 N,N-다이메틸폼아마이드/아세톤 용매에서 화합물 7과 반응하여 중간체 6을 얻는다. 이어서, 팔라듐 촉매를 이용한 수소반응을 통하여 중간체 5를 얻는다. 그 다음으로, 중간체 5와 화합물 4의 축합반응을 통하여 중간체 3을 얻는다. 이어서, 트라이플루오로아세트산 존재하에 2-부탄올 용매에서 화합물 2와 반응하여 화학식 1의 화합물을 얻을 수 있다.In Scheme 1, compound 8 is reacted with compound 7 in a N , N -dimethylformamide / acetone solvent in the presence of potassium carbonate to obtain intermediate 6. Subsequently, intermediate 5 is obtained through hydrogen reaction using a palladium catalyst. Next, intermediate 3 is obtained through condensation reaction between intermediate 5 and compound 4. The compound of formula 1 can then be obtained by reacting with compound 2 in a 2-butanol solvent in the presence of trifluoroacetic acid.
본 발명에 따른 화학식 1의 화합물은 무기산 또는 유기산으로 유도된 약제학적으로 허용 가능한 염 형태로 사용될 수 있으며, 이 경우 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 에탄설폰산, 벤젠설폰산 또는 톨루엔설폰산 등으로부터 유도된 염을 들 수 있으나 이에 제한되는 것은 아니다.The compounds of formula 1 according to the invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, in which case preferred salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid , Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfuric acid Salts derived from phonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, and the like.
본 발명에 따른 화학식 1의 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체는 BTK, BMX 및 JAK3 키나아제를 효과적으로 억제한다.The compound of formula 1 according to the present invention, a pharmaceutically acceptable salt or stereoisomer thereof effectively inhibits BTK, BMX and JAK3 kinases.
이에, 본 발명은 유효성분으로서 화학식 1의 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 포함하는, 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물을 제공한다. 상기 암은 예를 들면, B-세포 림프종, 췌장암, 전립선암, 대장암, 위암 등이 있으나 이에 제한되지는 않는다. 상기 면역 관련 질환은 예를 들면, 류마티스 관절염, 쇼그렌 증후군, 건선, 전신 홍반 루푸스, 아토피, 천식, 다발성 경화증 등이 있으나 이에 제한되지는 않는다.Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer or immune-related diseases, including a compound of formula (1), a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient. Such cancers include, but are not limited to, B-cell lymphoma, pancreatic cancer, prostate cancer, colon cancer, gastric cancer, and the like. The immune-related diseases include, but are not limited to, rheumatoid arthritis, Sjogren's syndrome, psoriasis, systemic lupus erythematosus, atopy, asthma, multiple sclerosis, and the like.
구체적으로 본 발명의 약제학적 조성물은 통상적인 방법에 따라 제제화 될 수 있으며, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼, 마이크로에멀젼 등의 다양한 경구 투여 형태로, 또는 근육내, 정맥내 또는 피하투여와 같은 비경구 투여 형태로 제조될 수 있다.Specifically, the pharmaceutical compositions of the present invention may be formulated according to conventional methods and may be administered in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or intramuscularly, intravenously or subcutaneously. It may be prepared in a parenteral dosage form such as
본 발명의 약제학적 조성물이 경구 제형의 형태로 제조되는 경우, 사용되는 담체의 예로는 셀룰로오스, 규산칼슘, 락토스, 덱스트로스, 옥수수전분, 수크로스, 인산칼슘, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크, 계면활성제, 유화제, 현탁제, 희석제 등을 들 수 있다. 본 발명의 약제학적 조성물이 주사제의 형태로 제조되는 경우, 상기 담체로는, 예를 들면 물, 식염수, 포도당 수용액, 유사 당 수용액, 알코올, 글리콜, 에테르(예: 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세라이드, 계면활성제, 현탁제, 유화제 등을 사용할 수 있다.When the pharmaceutical composition of the present invention is prepared in the form of an oral dosage form, examples of the carriers used are cellulose, calcium silicate, lactose, dextrose, corn starch, sucrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid Calcium, gelatin, talc, surfactant, emulsifier, suspending agent, diluent, etc. are mentioned. When the pharmaceutical composition of the present invention is prepared in the form of injectables, the carrier may be, for example, water, saline solution, aqueous glucose solution, aqueous pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid. , Fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers and the like can be used.
본 발명에 따르면 BTK, BMX 및 JAK3 키나아제를 효과적으로 억제할 수 있는 신규한 융합 피리미딘 유도체가 제공될 수 있다. 따라서, 본 발명에 따른 융합 피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체는 상기 키나아제의 활성화에 의해 유발되는 암 또는 면역 관련 질환의 예방 또는 치료에 효과적으로 이용할 수 있다.According to the present invention a novel fused pyrimidine derivative capable of effectively inhibiting BTK, BMX and JAK3 kinases can be provided. Accordingly, the fused pyrimidine derivatives, pharmaceutically acceptable salts or stereoisomers thereof according to the present invention can be effectively used for the prevention or treatment of cancer or immune related diseases caused by activation of the kinase.
도 1은 콜라겐으로 유도한 마우스 관절염(CIA, collagen-induced arthritis) 모델에서 실시예 3의 화합물의 경구투여에 따른 관절염 스코어의 변화를 나타낸 그래프이다.1 is a graph showing the change in arthritis score according to oral administration of the compound of Example 3 in collagen-induced mouse arthritis (CIA, collagen-induced arthritis) model.
이하에서 본 발명을 실시예에 의해 상세히 설명한다. 다만 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.
제조예: Preparation Example: NN -(3-((2-클로로-6,7-다이하이드로싸이에노[3,2--(3-((2-chloro-6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
Figure PCTKR2018001139-appb-I000005
Figure PCTKR2018001139-appb-I000005
단계 1: 2-클로로-4-(3-나이트로페녹시)-6,7-다이하이드로싸이에노[3,2-Step 1: 2-Chloro-4- (3-nitrophenoxy) -6,7-dihydrocyeno [3,2- dd ]피리미딘의 제조] Preparation of Pyrimidine
Figure PCTKR2018001139-appb-I000006
Figure PCTKR2018001139-appb-I000006
2,4-다이클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘(100 g, 0.48 mol)과 3-나이트로페놀(67.2 g, 0.48 mol)을 아세톤/N,N-다이메틸폼아마이드 혼합 용매(3:1, 2L)에 용해시킨 후, 탄산칼륨 (133.5 g, 0.96 mol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척하였다. 얻어진 고체를 n-헥산/다이클로로메탄 혼합 용매(1:10, 2L)에 트리튜레이션(trituration)하여 여과하고 건조하여 표제화합물 (146 g, 98%)을 얻었다.2,4-dichloro-6,7-dihydrocyeno [3,2- d ] pyrimidine (100 g, 0.48 mol) and 3-nitrophenol (67.2 g, 0.48 mol) were acetone / N , After dissolving in N -dimethylformamide mixed solvent (3: 1, 2L), potassium carbonate (133.5 g, 0.96 mol) was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to produce a solid, which was filtered and washed with distilled water. The obtained solid was triturated in n -hexane / dichloromethane mixed solvent (1:10, 2L), filtered and dried to obtain the title compound (146 g, 98%).
1H NMR (400 MHz, DMSO-d 6) 8.20 - 8.18 (m, 2H), 7.79 - 7.78 (m, 2H), 3.57 - 3.52 (m, 2H), 3.44 - 3.39 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) 8.20-8.18 (m, 2H), 7.79-7.78 (m, 2H), 3.57-3.52 (m, 2H), 3.44-3.39 (m, 2H)
단계 2: 3-((2-클로로-6,7-다이하이드로싸이에노 [3,2-Step 2: 3-((2-chloro-6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)아닐린의 제조] Production of pyrimidin-4-yl) oxy) aniline
Figure PCTKR2018001139-appb-I000007
Figure PCTKR2018001139-appb-I000007
상기 단계 1에서 제조된 화합물(146 g, 0.47 mol)을 메탄올(4L)에 묽힌 후 염화제일주석(445.6 g, 2.35 mol)을 가하고 2시간 동안 가열 환류하였다. 반응이 종결되면 감압 증류로 용매를 제거한 후, 결과로 얻어진 잔사에 에틸 아세테이트(2L)와 증류수(2L)을 가하고 교반하면서 탄산 나트륨을 넣어 중화시켰다. 생성된 침전물을 셀라이트가 충진된 필터로 여과시켜 제거하고, 여액을 층분리를 이용하여 물과 유기층으로 분리시킨 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하여 표제화합물(121 g, 92%)을 얻었다.The compound (146 g, 0.47 mol) prepared in step 1 was diluted with methanol (4 L), and then tin chloride (445.6 g, 2.35 mol) was added thereto, followed by heating to reflux for 2 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, ethyl acetate (2L) and distilled water (2L) were added to the resulting residue, and sodium carbonate was added to the mixture while stirring to neutralize. The resulting precipitate was filtered off with a filter filled with celite, and the filtrate was separated into water and an organic layer using a layer separation. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound (121). g, 92%).
1H NMR (400 MHz, DMSO-d 6) δ 7.06 (t, 1H) 6.49 - 6.47 (m, 1H), 6.33 - 6.28 (m, 2H), 5.36 (s, 2H), 3.52 - 3.47 (m, 2H), 3.39 - 3.34 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.06 (t, 1H) 6.49-6.47 (m, 1H), 6.33-6.28 (m, 2H), 5.36 (s, 2H), 3.52-3.47 (m, 2H), 3.39-3.34 (m, 2H)
단계 3: Step 3: NN -(3-((2-클로로-6,7-다이하이드로싸이에노[3,2--(3-((2-chloro-6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
Figure PCTKR2018001139-appb-I000008
Figure PCTKR2018001139-appb-I000008
상기 단계 2에서 제조된 화합물(120 g, 0.43 mol)과 N,N-다이아이소프로필에틸아민(150 mL, 0.86 mol)을 테트라하이드로퓨란(2.4 L)에 용해시킨 후, 아크릴로일 클로라이드(52 mL, 0.65 mol)를 적가하고 상온에서 1시간 동안 교반하였다. 반응이 종결되면 감압 증류로 용매를 제거하고 결과로 얻어진 고체에 물/메탄올 혼합용매(4:1, 1.2 L)를 가하고 상온에서 1시간 동안 교반시킨 후, 여과하고 증류수로 세척하였다. 결과로 얻어진 고체를 에틸 아세테이트에 트리튜레이션(trituration)하여 여과하고 건조하여 표제화합물(136 g, 95%)을 얻었다.The compound prepared in step 2 (120 g, 0.43 mol) and N, N -diisopropylethylamine (150 mL, 0.86 mol) were dissolved in tetrahydrofuran (2.4 L), followed by acryloyl chloride (52 mL, 0.65 mol) was added dropwise and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, water / methanol mixed solvent (4: 1, 1.2 L) was added to the resulting solid, stirred at room temperature for 1 hour, filtered and washed with distilled water. The resulting solid was triturated in ethyl acetate, filtered and dried to give the title compound (136 g, 95%).
1H NMR (400 MHz, DMSO-d 6) δ 10.38 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H) 6.96 (d, 1H), 6.35 (dd, 1H), 6.29 (d, 1H), 5.80 - 5.77 (m, 1H), 3.52 (t, 2H), 3.39 (t, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.38 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H) 6.96 (d, 1H), 6.35 (dd , 1H), 6.29 (d, 1H), 5.80-5.77 (m, 1H), 3.52 (t, 2H), 3.39 (t, 2H)
실시예 1: Example 1: NN -(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 1-1: 1-(4-나이트로페닐)-4-(피롤리딘-1-일)피페리딘의 제조Example 1-1 Preparation of 1- (4-nitrophenyl) -4- (pyrrolidin-1-yl) piperidine
4-플루오로나이트로 벤젠(2 g, 14.17 mmol)과 4-(피롤리딘-1-일)피페리딘(2.4 g, 15.59 mmol)을 아세토나이트릴(20 mL)에 용해시킨 후, 트라이에틸아민(2.37 mL, 17.01 mmol)을 가하고 12시간 동안 가열 환류하였다. 반응이 종결되면 실온으로 냉각한 후, 생성된 고체를 여과하고 물로 세척하여 표제화합물(3.6 g, 92%)을 얻었다.4-fluoronitrobenzene (2 g, 14.17 mmol) and 4- (pyrrolidin-1-yl) piperidine (2.4 g, 15.59 mmol) were dissolved in acetonitrile (20 mL), followed by Ethylamine (2.37 mL, 17.01 mmol) was added and heated to reflux for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the resulting solid was filtered and washed with water to obtain the title compound (3.6 g, 92%).
실시예 1-2: 4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린의 제조Example 1-2 Preparation of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline
상기 실시예 1-1에서 제조된 화합물(3 g, 10.9 mmol)을 메탄올(30 mL)에 용해시킨 후, 팔라듐 촉매 (10% Pd/C, 0.3 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(2.3 g, 87%)을 얻었다.After dissolving the compound (3 g, 10.9 mmol) prepared in Example 1-1 in methanol (30 mL), a palladium catalyst (10% Pd / C, 0.3 g, 10 wt%) was added thereto and room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.3 g, 87%).
실시예 1-3: Example 1-3: NN -(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
상기 실시예 1-2에서 제조된 화합물(290 mg, 1.2 mmol)과 N-(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드(500 mg, 1.5 mmol)을 2-부탄올(15 mL)에 현탁시킨 후, 트라이플루오로아세트산(180 μL, 2 mmol)을 가하고 24시간 동안 가열 환류하였다. 반응혼합물을 다이클로로메탄에 묽힌 후, 염화 암모늄 수용액으로 2회 세척하고 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 9 : 1 (부피비))로 분리하여 표제화합물(23 mg, 3.5%)을 얻었다.Compound (290 mg, 1.2 mmol) prepared in Example 1-2 and N- (3-((2-chloro-6,7-dihydrocyeno [3,2- d ] pyrimidine-4- I) oxy) phenyl) acrylamide (500 mg, 1.5 mmol) was suspended in 2-butanol (15 mL), then trifluoroacetic acid (180 μL, 2 mmol) was added and heated to reflux for 24 hours. The reaction mixture was diluted with dichloromethane, washed twice with aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, separated by column chromatography (dichloromethane: methanol = 9: 1 (volume ratio)). Compound (23 mg, 3.5%) was obtained.
1H NMR (400 MHz, CD3OD) δ 7.71 (d, 1H), 7.48 - 7.47 (m, 1H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 (dd, 1H), 6.72 (d, 2H), 6.43 - 6.38 (m, 2H), 5.78 (dd, 1H), 4.91 (s, 1H), 3.60 (d, 2H), 3.40 (t, 2H), 3.35 - 3.27 (m, 4H) 3.12 - 3.06 (m, 1H), 2.65 (t, 2H), 2.18 (d, 2H), 2.06 (s, 4H), 1.82 - 1.73 (m, 2H) 1 H NMR (400 MHz, CD 3 OD) δ 7.71 (d, 1H), 7.48-7.47 (m, 1H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 (dd, 1H), 6.72 (d, 2H), 6.43-6.38 (m, 2H), 5.78 (dd, 1H), 4.91 (s, 1H), 3.60 (d, 2H), 3.40 (t, 2H), 3.35-3.27 (m, 4H ) 3.12-3.06 (m, 1H), 2.65 (t, 2H), 2.18 (d, 2H), 2.06 (s, 4H), 1.82-1.73 (m, 2H)
실시예 2: Example 2: NN -(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 2-1: 3-(4-나이트로페녹시)테트라하이드로퓨란의 제조Example 2-1 Preparation of 3- (4-nitrophenoxy) tetrahydrofuran
소듐 하이드라이드(60%, 0.65 g, 14.88 mmol)를 N,N-다이메틸폼아마이드(14 mL)에 넣고 0℃로 냉각한 후, 질소가스하에 3-하이드록시테트라하이드로퓨란(1.18 mL, 14.88 mmol)을 적가하고 30분간 교반시켰다. 4-플루오로나이트로 벤젠(2 g, 14.17 mmol)을 한번에 집어넣은 후, 상온으로 서서히 상승하여 4시간 동안 교반시킨 후, 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하였다. 얻어진 잔사(2.96 g)를 정제하지 않고 다음 단계에 사용하였다. Sodium hydride (60%, 0.65 g, 14.88 mmol) was added to N, N -dimethylformamide (14 mL), cooled to 0 ° C., and then 3-hydroxytetrahydrofuran (1.18 mL, 14.88) under nitrogen gas. mmol) was added dropwise and stirred for 30 minutes. Benzene (2 g, 14.17 mmol) in 4-fluoronitrate was added all at once, and then slowly raised to room temperature and stirred for 4 hours. After completion of the reaction by adding water to the reaction mixture, extraction was performed with ethyl acetate, followed by separation. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The obtained residue (2.96 g) was used for next step without purification.
실시예 2-2: 4-((테트라하이드로퓨란-3-일)옥시)아닐린의 제조Example 2-2 Preparation of 4-((tetrahydrofuran-3-yl) oxy) aniline
상기 실시예 2-1에서 제조된 화합물(2.96 g, 14.17 mmol)을 메탄올(30 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 0.3 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(2.54 g, 100%)을 얻었다.The compound (2.96 g, 14.17 mmol) prepared in Example 2-1 was dissolved in methanol (30 mL), and then a palladium catalyst (10% Pd / C, 0.3 g, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.54 g, 100%).
실시예 2-3: Example 2-3: NN -(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-((테트라하이드로퓨란-3-일)옥시)아닐린(1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(0.25 g, 45%)을 얻었다.Except for using 4-((tetrahydrofuran-3-yl) oxy) aniline (1.2 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline, The same process as in Example 1-3 was carried out to obtain the title compound (0.25 g, 45%).
1H NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.37 (s, 1H), 7.64 (t, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.29 (d, 2H), 6.93 (dd, 1H), 6.58 (d, 2H), 6.43 (dd, 1H), 6.25 (dd, 1H), 5.79 - 5.76 (m, 1H), 4.83 (d, 1H), 3.85 - 3.68 (m, 4H), 3.40 (t, 2H), 3.23 (t, 2H), 2.17 - 2.10 (m, 1H), 1.91 - 1.84 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.37 (s, 1H), 7.64 (t, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.29 ( d, 2H), 6.93 (dd, 1H), 6.58 (d, 2H), 6.43 (dd, 1H), 6.25 (dd, 1H), 5.79-5.76 (m, 1H), 4.83 (d, 1H), 3.85 -3.68 (m, 4H), 3.40 (t, 2H), 3.23 (t, 2H), 2.17-2.10 (m, 1H), 1.91-1.84 (m, 1H)
실시예 3: Example 3: NN -(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 3-1: 4-(4-나이트로페닐)피리딘의 제조Example 3-1 Preparation of 4- (4-nitrophenyl) pyridine
1-브로모-4-나이트로벤젠(3.94 g, 19.52 mmol)과 4-피리딘보로닉에시드(3 g, 24.41 mmol), 테트라키스(트라이페닐포스핀)팔라듐(0)(1.13 g, 0.98 mmol) 및 탄산칼륨(5.4 g, 39.04 mmol)을 1,4-다이옥세인/물 혼합용매(40 mL, 3:1)에 넣고, 질소가스로 15분 동안 용매에 통과시킨 후 12시간 동안 가열 환류하였다. 반응이 종결되면 반응 혼합물을 물에 녹인 후 에틸 아세테이트로 추출하였다. 분리된 유기층을 소금 수용액으로 씻어준 후, 무수 황산 마그네슘으로 건조시키고 감압 증류하여 용매를 제거하였다. 얻어진 고체를 n-헥산/다이클로로메탄 혼합 용매(1:10, 2L)에 트리튜레이션(trituration)하고 여과, 건조하여 표제화합물 (3.63 g, 93%)을 얻었다.1-bromo-4-nitrobenzene (3.94 g, 19.52 mmol) and 4-pyridineboronic acid (3 g, 24.41 mmol), tetrakis (triphenylphosphine) palladium (0) (1.13 g, 0.98 mmol) and potassium carbonate (5.4 g, 39.04 mmol) were added to a 1,4-dioxane / water mixed solvent (40 mL, 3: 1), passed through a solvent for 15 minutes with nitrogen gas, and heated to reflux for 12 hours. It was. At the end of the reaction, the reaction mixture was dissolved in water and extracted with ethyl acetate. The separated organic layer was washed with an aqueous salt solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained solid was triturated in n -hexane / dichloromethane mixed solvent (1:10, 2L), filtered and dried to obtain the title compound (3.63 g, 93%).
실시예 3-2: 1-메틸-4-(4-나이트로페닐)피리딘-1-윰 아이오다이드의 제조Example 3-2 Preparation of 1-methyl-4- (4-nitrophenyl) pyridine-1-'iodide
상기 실시예 3-1에서 제조된 화합물(2 g, 10 mmol)을 아세톤(20 mL)에 용해시킨 후, 아이오도메테인(3.1 mL, 50 mmol)을 가하고 상온에서 24시간 동안 교반시켰다. 반응이 종결되면, 생성된 고체를 여과하고 에틸 아세테이트로 세척하여 표제화합물(3.04 g, 89%)을 얻었다.After dissolving the compound (2 g, 10 mmol) prepared in Example 3-1 in acetone (20 mL), iodomethane (3.1 mL, 50 mmol) was added and stirred for 24 hours at room temperature. After the reaction was completed, the resulting solid was filtered and washed with ethyl acetate to give the title compound (3.04 g, 89%).
실시예 3-3: 1-메틸-4-(4-나이트로페닐)-1,2,3,6-테트라하이드로피리딘의 제조Example 3-3 Preparation of 1-methyl-4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine
상기 실시예 3-2에서 제조된 화합물(2 g, 5.85 mmol)을 메탄올(30 mL)에 용해시킨 후, 0℃로 냉각하고 소듐 보로하이드라이드(0.66 g, 17.54 mmol)를 소분하여 투입하였다. 반응혼합물을 상온으로 상승한 후 12시간 동안 교반하였다. 반응이 종결되면, 반응혼합물을 농축한 후, 물에 녹이고 에틸 아세테이트로 추출하였다. 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하였다. 얻어진 잔사(1.2 g)를 정제하지 않고 다음 단계에 사용하였다. The compound (2 g, 5.85 mmol) prepared in Example 3-2 was dissolved in methanol (30 mL), cooled to 0 ° C., and added with a small amount of sodium borohydride (0.66 g, 17.54 mmol). The reaction mixture was raised to room temperature and stirred for 12 hours. At the end of the reaction, the reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The obtained residue (1.2 g) was used for the next step without purification.
실시예 3-4: 4-(1-메틸피페리딘-4-일)아닐린의 제조Example 3-4 Preparation of 4- (1-methylpiperidin-4-yl) aniline
상기 실시예 3-3에서 제조된 화합물(630 mg, 2.89 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 63 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(490 mg, 90%)을 얻었다.After dissolving the compound (630 mg, 2.89 mmol) prepared in Example 3-3 in methanol (10 mL), a palladium catalyst (10% Pd / C, 63 mg, 10 wt%) was added thereto and room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (490 mg, 90%).
실시예 3-5: Example 3-5: NN -(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(1-메틸피페리딘-4-일)아닐린 (1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(135 mg, 23%)을 얻었다. Except for using 4- (1-methylpiperidin-4-yl) aniline (1.2 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline, The same process as in Example 1-3 was carried out to obtain the title compound (135 mg, 23%).
1H NMR (400 MHz, DMSO-d 6) δ 10.55 (s, 1H), 10.31 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.62 (d, 1H), 7.42 (t, 1H), 7.34 (d, 1H), 6.96 - 6.93 (m, 1H), 6.90 (d, 2H), 6.54 (dd, 1H), 6.26 (dd, 1H), 5.76 (dd, 1H), 3.46 - 3.40 (m, 4H), 3.25 (t, 2H), 3.06 - 2.97 (m, 2H), 2.75 (d, 3H), 2.65 - 2.60 (m, 1H), 1.94 - 1.88 (m, 4H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.55 (s, 1H), 10.31 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.62 (d, 1H), 7.42 ( t, 1H), 7.34 (d, 1H), 6.96-6.93 (m, 1H), 6.90 (d, 2H), 6.54 (dd, 1H), 6.26 (dd, 1H), 5.76 (dd, 1H), 3.46 -3.40 (m, 4H), 3.25 (t, 2H), 3.06-2.97 (m, 2H), 2.75 (d, 3H), 2.65-2.60 (m, 1H), 1.94-1.88 (m, 4H)
실시예 4: Example 4: NN -(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 4-1: 1-에틸-4-(4-나이트로페닐)피리딘-1-윰 아이오다이드의 제조Example 4-1 Preparation of 1-ethyl-4- (4-nitrophenyl) pyridine-1-'iodide
실시예 3-1에서 제조된 화합물(0.7 g, 3.5 mmol)을 아세톤(7 mL)에 용해시킨 후, 아이오도에테인(2.8 mL, 35 mmol)을 가하고 상온에서 24시간 동안 교반시켰다. 반응이 종결되면, 생성된 고체를 여과하고 에틸 아세테이트로 세척하여 표제화합물(0.86 g, 69%)을 얻었다.After dissolving the compound (0.7 g, 3.5 mmol) prepared in Example 3-1 in acetone (7 mL), iodoethane (2.8 mL, 35 mmol) was added and stirred at room temperature for 24 hours. After the reaction was completed, the resulting solid was filtered and washed with ethyl acetate to give the title compound (0.86 g, 69%).
실시예 4-2: 1-에틸-4-(4-나이트로페닐)-1,2,3,6-테트라하이드로피리딘의 제조Example 4-2 Preparation of 1-ethyl-4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine
상기 실시예 4-1에서 제조된 화합물(0.8 g, 2.25 mmol)을 메탄올(20 mL)에 용해시킨 후, 0℃로 냉각하고 소듐 보로하이드라이드(0.26 g, 6.74 mmol)를 소분하여 투입하였다. 반응혼합물을 상온으로 상승한 후 12시간 동안 교반하였다. 반응이 종결되면, 반응혼합물을 농축한 후, 물에 녹이고 에틸 아세테이트로 추출하였다. 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1 (부피비))로 분리하여 표제화합물(0.44 g, 84%)을 얻었다.The compound (0.8 g, 2.25 mmol) prepared in Example 4-1 was dissolved in methanol (20 mL), cooled to 0 ° C., and added with a small amount of sodium borohydride (0.26 g, 6.74 mmol). The reaction mixture was raised to room temperature and stirred for 12 hours. At the end of the reaction, the reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and separated by column chromatography (dichloromethane: methanol = 10: 1 (volume ratio)) to obtain the title compound (0.44 g, 84%).
실시예 4-3: 4-(1-에틸피페리딘-4-일)아닐린의 제조Example 4-3 Preparation of 4- (1-ethylpiperidin-4-yl) aniline
상기 실시예 4-2에서 제조된 화합물(0.44 g, 1.9 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 44 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.38 g, 98%)을 얻었다.The compound (0.44 g, 1.9 mmol) prepared in Example 4-2 was dissolved in methanol (10 mL), and then a palladium catalyst (10% Pd / C, 44 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.38 g, 98%).
실시예 4-4: Example 4-4: NN -(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(1-에틸피페리딘-4-일)아닐린 (1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(205 mg, 34%)을 얻었다.Except for using 4- (1-ethylpiperidin-4-yl) aniline (1.2 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline, The same process as in Example 1-3 was carried out to obtain the title compound (205 mg, 34%).
1H NMR (400 MHz, DMSO-d 6) δ 10.53 (s, 1H), 10.06 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.61 (d, 1H), 7.42 (t, 1H), 7.34 (d, 2H), 6.96 - 6.89 (m, 3H), 6.53 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 1H), 3.42 (t, 2H), 3.25 (t, 2H), 3.14 - 3.08 (m, 2H), 2.99 - 2.91 (m, 2H), 2.69 - 2.63 (m, 1H), 1.97 - 1.85 (m, 4H), 2.76 (t, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.53 (s, 1H), 10.06 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.61 (d, 1H), 7.42 ( t, 1H), 7.34 (d, 2H), 6.96-6.89 (m, 3H), 6.53 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 1H), 3.42 (t, 2H) , 3.25 (t, 2H), 3.14-3.08 (m, 2H), 2.99-2.91 (m, 2H), 2.69-2.63 (m, 1H), 1.97-1.85 (m, 4H), 2.76 (t, 3H)
실시예 5: Example 5: (R)(R) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 5-1: Example 5-1: (R)(R) -1-메틸-3-(4-나이트로페녹시)피롤리딘의 제조Preparation of -1-methyl-3- (4-nitrophenoxy) pyrrolidine
소듐 하이드라이드(60%, 0.4 g, 9.89 mmol)를 무수 테트라하이드로퓨란(10 mL)에 넣고 0℃로 냉각한 후, 질소가스 하에 (R)-1-메틸-3-피롤리딘올(0.5 g, 4.94 mmol)을 적가하고 60분간 교반시켰다. 반응 혼합물에 4-플루오로나이트로 벤젠(0.73 mL, 6.92 mmol)을 적가하고 상온으로 서서히 상승하여 12시간 동안 교반시킨 후, 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 95 : 5 (부피비))로 분리하여 표제화합물(1 g, 91%)을 얻었다.Sodium hydride (60%, 0.4 g, 9.89 mmol) was added to anhydrous tetrahydrofuran (10 mL) and cooled to 0 ° C., followed by ( R ) -1-methyl-3-pyrrolidinol (0.5 g) under nitrogen gas. , 4.94 mmol) was added dropwise and stirred for 60 minutes. 4-fluoronitrobenzene (0.73 mL, 6.92 mmol) was added dropwise to the reaction mixture, and the mixture was slowly raised to room temperature and stirred for 12 hours. After completion of the reaction by adding water to the reaction mixture, extraction with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then separated by column chromatography (dichloromethane: methanol = 95: 5 (volume ratio)) to obtain the title compound (1 g, 91%).
실시예 5-2: Example 5-2: (R)(R) -4-((1-메틸피롤리딘-3-일)옥시)아닐린의 제조Preparation of -4-((1-methylpyrrolidin-3-yl) oxy) aniline
상기 실시예 5-1에서 제조된 화합물(1 g, 4.5 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.87 g, 100%)을 얻었다.After dissolving the compound (1 g, 4.5 mmol) prepared in Example 5-1 in methanol (10 mL), a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.87 g, 100%).
실시예 5-3: Example 5-3: (R)(R) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (R)-4-((1-메틸피롤리딘 -3-일)옥시)아닐린(1.09 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(214 mg, 34%)을 얻었다. (R) -4-((1-methylpyrrolidin-3-yl) oxy) aniline (1.09 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for using the same process as in Example 1-3 to give the title compound (214 mg, 34%).
1H NMR (400 MHz, DMSO-d 6) δ 10.45 (s, 1H), 9.34 (s, 1H), 7.63 - 7.58 (m, 2H), 7.45 (t, 1H), 7.32 (d, 2H), 6.96 (dd, 1H), 6.65 (d, 2H), 6.45 (dd, 1H), 6.28 (dd, 1H), 5.81 (d, 1H), 5.00 (s, 1H), 3.85 - 3.70 (m, 7H), 3.41 (t, 2H), 3.24 (t, 2H), 2.88 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.45 (s, 1H), 9.34 (s, 1H), 7.63-7.58 (m, 2H), 7.45 (t, 1H), 7.32 (d, 2H), 6.96 (dd, 1H), 6.65 (d, 2H), 6.45 (dd, 1H), 6.28 (dd, 1H), 5.81 (d, 1H), 5.00 (s, 1H), 3.85-3.70 (m, 7H) , 3.41 (t, 2H), 3.24 (t, 2H), 2.88 (s, 3H)
실시예 6: Example 6: (S)(S) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 6-1: Example 6-1: (S)(S) -1-메틸-3-(4-나이트로페녹시)피롤리딘의 제조Preparation of -1-methyl-3- (4-nitrophenoxy) pyrrolidine
소듐 하이드라이드(60%, 0.4 g, 9.89 mmol)를 무수 테트라하이드로퓨란(10 mL)에 넣고 0℃로 냉각한 후, 질소가스 하에 (S)-(+)-1-메틸-3-피롤리딘올(0.5 g, 4.94 mmol)을 적가하고 60분간 교반시켰다. 반응 혼합물에 4-플루오로나이트로 벤젠(0.73 mL, 6.92 mmol)을 적가하고 상온으로 서서히 상승하여 12시간 동안 교반시킨 후, 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 95 : 5 (부피비))로 분리하여 표제화합물(1 g, 91%)을 얻었다.Sodium hydride (60%, 0.4 g, 9.89 mmol) was added to anhydrous tetrahydrofuran (10 mL) and cooled to 0 ° C., followed by (S) -(+)-1-methyl-3-pyrroli under nitrogen gas. Dinol (0.5 g, 4.94 mmol) was added dropwise and stirred for 60 minutes. 4-fluoronitrobenzene (0.73 mL, 6.92 mmol) was added dropwise to the reaction mixture, and the mixture was slowly raised to room temperature and stirred for 12 hours. After completion of the reaction by adding water to the reaction mixture, extraction with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then separated by column chromatography (dichloromethane: methanol = 95: 5 (volume ratio)) to obtain the title compound (1 g, 91%).
실시예 6-2: Example 6-2: (S)(S) -4-((1-메틸피롤리딘-3-일)옥시)아닐린의 제조Preparation of -4-((1-methylpyrrolidin-3-yl) oxy) aniline
상기 실시예 6-1에서 제조된 화합물(1 g, 4.5 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.87 g, 100%)을 얻었다.After dissolving the compound (1 g, 4.5 mmol) prepared in Example 6-1 in methanol (10 mL), a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.87 g, 100%).
실시예 6-3: Example 6-3: (S)(S) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (S)-4-((1-메틸피롤리딘-3-일)옥시)아닐린(1.04 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(0.17 g, 28%)을 얻었다. (S) -4-((1-methylpyrrolidin-3-yl) oxy) aniline (1.04 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for using, the same process as in Example 1-3 was carried out to obtain the title compound (0.17 g, 28%).
1H NMR (400 MHz, DMSO-d 6) δ 10.47 (s, 1H), 9.36 (s, 1H), 7.62 - 7.58 (m, 2H), 7.46 - 7.43 (m, 1H), 7.32 (d, 2H), 6.96 (d, 1H), 6.64 (d, 2H), 6.45 (dd, 1H), 6.28 (d, 1H), 5.80 (d, 1H), 4.98 (s, 1H), 3.86 - 3.64 (m, 6H), 3.52 (s, 1H), 3.41 (t, 2H), 3.23 (t, 2H), 2.85 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.47 (s, 1H), 9.36 (s, 1H), 7.62-7.58 (m, 2H), 7.46-7.43 (m, 1H), 7.32 (d, 2H ), 6.96 (d, 1H), 6.64 (d, 2H), 6.45 (dd, 1H), 6.28 (d, 1H), 5.80 (d, 1H), 4.98 (s, 1H), 3.86-3.64 (m, 6H), 3.52 (s, 1H), 3.41 (t, 2H), 3.23 (t, 2H), 2.85 (s, 3H)
실시예 7: Example 7: NN -(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 7-1: 1-메틸-Example 7-1: 1-methyl- NN -(4-나이트로페닐)피페리딘-4-아민의 제조Preparation of-(4-nitrophenyl) piperidin-4-amine
1-메틸피페리딘-4-아민(5.7 g, 49.49 mmol)과 4-플루오로 나이트로벤젠(5 mL, 47.13 mmol)을 다이메틸 설폭사이드(47 mL)에 용해시킨 후 탄산칼륨(1.98 g, 49.49 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(9.0 g, 81%)을 얻었다.Dissolve 1-methylpiperidin-4-amine (5.7 g, 49.49 mmol) and 4-fluoro nitrobenzene (5 mL, 47.13 mmol) in dimethyl sulfoxide (47 mL) and then add potassium carbonate (1.98 g , 49.49 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid. The mixture was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (9.0 g, 81%).
실시예Example 7-2:  7-2: NN 1One -(1--(One- 메틸피페리딘Methylpiperidine -4-일)벤젠-1,4--4-yl) benzene-1,4- 다이아민의Diamine 제조 Produce
상기 실시예 7-1에서 제조된 화합물(9.0 g, 38.09 mmol)을 메탄올(200 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 0.9 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(6.6 g, 84%)을 얻었다.The compound (9.0 g, 38.09 mmol) prepared in Example 7-1 was dissolved in methanol (200 mL), and then a palladium catalyst (10% Pd / C, 0.9 g, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (6.6 g, 84%).
실시예 7-3: Example 7-3: NN -(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 N 1-(1-메틸피페리딘-4-일)벤젠-1,4-다이아민(0.81 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(13 mg, 3.2%)을 얻었다.4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline instead of N 1 - (1- methylpiperidin-4-yl) benzene-1,4-diamine (0.81 mmol ), But the title compound (13 mg, 3.2%) was obtained in the same manner as the Example 1-3.
1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1H), 7.38 (t, 2H), 7.29 (s, 1H), 7.10 (d, 2H), 6.97 (d, 1H), 6.68 (s, 1H), 6.46 - 6.40 (m, 3H), 6.23 (dd, 1H), 5.78 (dd, 1H), 3.39 - 3.35 (m, 2H), 3.26 - 3.18 (m, 3H), 2.81 (d, 2H), 2.31 (s, 3H), 2.16 - 2.10 (m, 2H), 2.01 (d, 2H), 1.49 - 1.44 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, 1H), 7.38 (t, 2H), 7.29 (s, 1H), 7.10 (d, 2H), 6.97 (d, 1H), 6.68 (s, 1H), 6.46-6.40 (m, 3H), 6.23 (dd, 1H), 5.78 (dd, 1H), 3.39-3.35 (m, 2H), 3.26-3.18 (m, 3H), 2.81 (d, 2H) , 2.31 (s, 3H), 2.16-2.10 (m, 2H), 2.01 (d, 2H), 1.49-1.44 (m, 2H)
실시예 8: N -(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2- d ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조 Example 8: N- (3-((2-((4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) phenyl) amino) -6,7 Preparation of -dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 8-1: 4,4-다이메틸-1-(2-(4-나이트로페녹시)에틸)-1,4-아자실란의 제조Example 8-1 Preparation of 4,4-dimethyl-1- (2- (4-nitrophenoxy) ethyl) -1,4-azasilane
1-(2-브로모에톡시)-4-나이트로벤젠(0.5, 2.03 mmol)과 4,4-다이메틸-1,4-아자실란 염산염(0.37 g, 2.24 mmol)을 아세토나이트릴(5 mL)에 용해시킨 후, N,N-다이아이소프로필에틸아민(0.78 mL, 4.48 mmol)을 가하고 50℃에서 12시간 동안 교반하였다. 반응이 종결되면 실온으로 냉각한 후, 반응혼합물을 물에 녹이고 에틸 아세테이트로 추출하였다. 분리된 유기층을 염화나트륨 수용액으로 3회 세척하고 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1 (부피비))로 분리하여 표제화합물(424 mg, 71%)을 얻었다.1- (2-bromoethoxy) -4-nitrobenzene (0.5, 2.03 mmol) and 4,4-dimethyl-1,4-azasilane hydrochloride (0.37 g, 2.24 mmol) were acetonitrile (5 mL ), N, N -diisopropylethylamine (0.78 mL, 4.48 mmol) was added and stirred at 50 ° C. for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction mixture was dissolved in water and extracted with ethyl acetate. The separated organic layer was washed three times with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and separated by column chromatography (dichloromethane: methanol = 10: 1 (volume ratio)) to obtain the title compound (424 mg, 71%). )
실시예 8-2: 4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)아닐린의 제조Example 8-2 Preparation of 4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) aniline
상기 실시예 8-1에서 제조된 화합물(0.42 g, 1.43 mmol)을 메탄올(5 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 42 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.37 g, 97%)을 얻었다.After dissolving the compound (0.42 g, 1.43 mmol) prepared in Example 8-1 in methanol (5 mL), a palladium catalyst (10% Pd / C, 42 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.37 g, 97%).
실시예 8-3: Example 8-3: NN -(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) phenyl) amino) -6,7-dihydrosaie Furnace [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)아닐린(0.33 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(65 mg, 35%)을 얻었다.4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline ) The title compound (65 mg, 35%) was obtained in the same manner as the Example 1-3 except for using aniline (0.33 mmol).
1H NMR (400 MHz, DMSO-d 6) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.28 (d, 2H), 6.93 (dd, 1H), 6.60 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.78 - 5.75 (m 1H), 3.90 (s, 2H), 3.40 (t, 2H), 3.22 (t, 2H), 2.73 (s, 4H), 2.67 (s, 2H), 0.70 (s, 4H), 0.04 (s, 6H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.28 ( d, 2H), 6.93 (dd, 1H), 6.60 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.78-5.75 (m 1H), 3.90 (s, 2H), 3.40 ( t, 2H), 3.22 (t, 2H), 2.73 (s, 4H), 2.67 (s, 2H), 0.70 (s, 4H), 0.04 (s, 6H)
실시예 9: Example 9: NN -(3-((2-((3-플루오로-4-몰포리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((3-fluoro-4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 3-플루오로-4-몰포리노아닐린(1 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(0.1 g, 20%)을 얻었다. Examples 1-3, except that 3-fluoro-4-morpholinoaniline (1 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same procedure as in the title compound (0.1 g, 20%) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 10.33 (s, 1H), 9.58 (s, 1H), 7.67 (s, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.29 (d, 1H), 7.08 (d, 1H), 6.95 (dd, 1H), 6.74 (t, 1H), 6.42 (dd, 1H), 6.24 (dd, 1H), 5.76 (dd, 1H), 3.69 (t, 4H), 3.41 (t, 2H), 3.25 (t, 2H), 2.83 (t, 4H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.33 (s, 1H), 9.58 (s, 1H), 7.67 (s, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.29 ( d, 1H), 7.08 (d, 1H), 6.95 (dd, 1H), 6.74 (t, 1H), 6.42 (dd, 1H), 6.24 (dd, 1H), 5.76 (dd, 1H), 3.69 (t , 4H), 3.41 (t, 2H), 3.25 (t, 2H), 2.83 (t, 4H)
실시예 10: Example 10: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 10-1: 1-메틸-4-(4-나이트로페닐)피페라진의 제조Example 10-1 Preparation of 1-methyl-4- (4-nitrophenyl) piperazine
1-메틸피페라진(7.3 g, 72.68 mmol)과 4-플루오로 나이트로벤젠(10 g, 70.87 mmol)을 다이메틸 설폭사이드(15 mL)에 용해시킨 후 탄산칼륨(10.8 g, 77.85 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(15.2 g, 97%)을 얻었다.Dissolve 1-methylpiperazine (7.3 g, 72.68 mmol) and 4-fluoro nitrobenzene (10 g, 70.87 mmol) in dimethyl sulfoxide (15 mL), followed by potassium carbonate (10.8 g, 77.85 mmol). It was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to produce a solid, which was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (15.2 g, 97%).
실시예 10-2: 4-(4-메틸피페라진-1-일)아닐린의 제조Example 10-2 Preparation of 4- (4-methylpiperazin-1-yl) aniline
상기 실시예 10-1에서 제조된 화합물(15.0 g, 67.79 mmol)을 메탄올(450 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 1.5 g, 10 wt%)를 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(11.0 g, 85%)을 얻었다.After dissolving the compound (15.0 g, 67.79 mmol) prepared in Example 10-1 in methanol (450 mL), a palladium catalyst (10% Pd / C, 1.5 g, 10 wt%) was added thereto and room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (11.0 g, 85%).
실시예 10-3:Example 10-3: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-메틸피페라진-1-일)아닐린(0.78 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(80 mg, 21%)을 얻었다.Except that 4- (4-methylpiperazin-1-yl) aniline (0.78 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same procedure as in Example 1-3 was carried out to obtain the title compound (80 mg, 21%).
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 (t, 1H), 7.23 (d, 2H), 6.92 (m, 1H), 6.61 (d, 2H), 6.42 (m, 1H), 6.25 (m, 1H), 5.77 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.97 - 2.90 (m, 4H), 2.43 - 2.37 (m, 4H), 2.20 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.61-7.57 (m, 2H), 7.41 (t, 1H), 7.23 (d, 2H), 6.92 (m, 1H), 6.61 (d, 2H), 6.42 (m, 1H), 6.25 (m, 1H), 5.77 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.97- 2.90 (m, 4H), 2.43-2.37 (m, 4H), 2.20 (s, 3H)
실시예 11: Example 11: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)에탄설폰아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) ethanesulfonamide
2-클로로에탄설포닐 클로라이드(500 mg, 3.07 mmol)를 다이클로로메탄(5 mL)에 용해시킨 후, -78℃로 냉각하였다. 질소가스 하에 피리딘(1 mL, 12.28 mmol)을 적가한 후, 0℃로 서서히 상승시켜 1시간 동안 교반시켰다. 테트라하이드로퓨란(500 μL)에 용해시킨 4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-2-아민(50 mg, 0.15 mmol)을 반응 혼합물에 적가한 후, 실온으로 서서히 상승시켜 1시간 동안 교반하였다. 반응이 종결되면 반응혼합물을 물에 넣고 다이클로로메탄으로 추출하였다. 분리된 유기층을, 염화 암모늄 수용액으로 3회 세척한 후, 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(에틸 아세테이트 : 헥산 = 2 : 1 (부피비))로 분리하여 표제화합물(20 mg, 25%)을 얻었다.2-chloroethanesulfonyl chloride (500 mg, 3.07 mmol) was dissolved in dichloromethane (5 mL) and then cooled to -78 ° C. Pyridine (1 mL, 12.28 mmol) was added dropwise under nitrogen gas, and then slowly raised to 0 ° C. and stirred for 1 hour. In tetrahydrofuran (3-aminophenoxy) was dissolved in 4 (500 μL) - N - (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-furnace to thieno [3 , 2- d ] pyrimidin-2-amine (50 mg, 0.15 mmol) was added dropwise to the reaction mixture, which was then slowly raised to room temperature and stirred for 1 hour. After the reaction was completed, the reaction mixture was poured into water and extracted with dichloromethane. The separated organic layer was washed three times with an aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure, and separated by column chromatography (ethyl acetate: hexane = 2: 1 (volume ratio)) to obtain the title compound (20 mg). , 25%).
1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2H), 7.19 (t, 1H), 6.98 (s, 2H), 6.78 (d, 2H), 6.60 - 6.57 (m, 2H), 6.53 - 6.52 (m, 1H), 5.01 (s, 1H), 3.75 (s, 1H), 3.37 (t, 2H), 3.25 (t, 2H), 3.13 (s, 4H), 2.63 (s, 4H), 2.27 (s, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, 2H), 7.19 (t, 1H), 6.98 (s, 2H), 6.78 (d, 2H), 6.60-6.57 (m, 2H), 6.53- 6.52 (m, 1H), 5.01 (s, 1H), 3.75 (s, 1H), 3.37 (t, 2H), 3.25 (t, 2H), 3.13 (s, 4H), 2.63 (s, 4H), 2.27 (s, 3H)
실시예 12: Example 12: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)아미노)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) amino) phenyl) acrylamide
실시예 12-1: Example 12-1: NN -(3-((2-클로로-6,7-다이하이드로싸이에노[3,2--(3-((2-chloro-6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)아미노)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) amino) phenyl) acrylamide
2,4-다이클로로싸이에노[3,2-d]피리미딘(500 mg, 3.7 mmol)을 다이메틸 폼아마이드(5 mL)에 용해시킨 후, N-(3-아미노페닐)아크릴아마이드(766 mg, 3.08 mmol)와 다이아이소프로필에틸아민(0.54 mL, 3.08 mmol)을 가하고 60℃에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물을 다이클로로메탄에 묽힌 후, 염화 암모늄 수용액으로 2회 세척하고 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 에틸 아세테이트 = 5 : 1 (부피비))로 분리하여 표제화합물(542 mg, 53%)을 얻었다.2,4-Dichlorothieno [3,2- d ] pyrimidine (500 mg, 3.7 mmol) was dissolved in dimethyl formamide (5 mL), followed by N- (3-aminophenyl) acrylamide ( 766 mg, 3.08 mmol) and diisopropylethylamine (0.54 mL, 3.08 mmol) were added and stirred at 60 ° C. for 12 hours. At the end of the reaction, the reaction mixture was diluted with dichloromethane, washed twice with an aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure, followed by column chromatography (dichloromethane: ethyl acetate = 5: 1 (volume ratio). ) To give the title compound (542 mg, 53%).
실시예 12-2:Example 12-2: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)아미노)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) amino) phenyl) acrylamide
N-(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드 대신 N-(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)아크릴아마이드(1.37 mmol)를, 4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-메틸피페라진-1-일)아닐린(1.5 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(130 mg, 20%)을 얻었다. N- (3-((2-((2-chloro-6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide instead of N- (3-((2- Chloro-6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) amino) phenyl) acrylamide (1.37 mmol), 4- (4- (pyrrolidin-1-yl Except for using 4- (4-methylpiperazin-1-yl) aniline (1.5 mmol) instead of piperidin-1-yl) aniline, the same process as in Example 1-3 was performed. 130 mg, 20%).
1H NMR (400MHz, DMSO-d 6) δ 10.12 (s, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.48 (d, 2H), 7.42 (d, 1H), 7.30 - 7.20 (m, 2H), 6.71 (d, 2H), 6.45 (m, 1H), 6.25 (m, 1H), 5.74 (m, 1H), 3.30 (t, 2H), 3.10 (t, 2H), 3.00 - 2.93 (m, 4H), 2.46 - 2.39 (m, 4H), 2.20 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.12 (s, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.48 (d, 2H), 7.42 (d , 1H), 7.30-7.20 (m, 2H), 6.71 (d, 2H), 6.45 (m, 1H), 6.25 (m, 1H), 5.74 (m, 1H), 3.30 (t, 2H), 3.10 ( t, 2H), 3.00-2.93 (m, 4H), 2.46-2.39 (m, 4H), 2.20 (s, 3H)
실시예 13: Example 13: NN -(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7-dihydrocyeno [3 ,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 13-1: 4-메틸-1-(4-나이트로페닐)-1,4-아자포스피네인 4-옥사이드의 제조Example 13-1 Preparation of 4-methyl-1- (4-nitrophenyl) -1,4-azaphosphineine 4-oxide
4-메틸-1,4-아자포스피네인-4-옥사이드(3.5 g, 25.98 mmol)와 4-플루오로 나이트로벤젠(3.7 g, 25.98 mmol)을 다이메틸 설폭사이드(6 mL)에 용해시킨 후 탄산칼륨(4.0 g, 28.58 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(5.5 g, 84%)을 얻었다.4-Methyl-1,4-azaphosphinein-4-oxide (3.5 g, 25.98 mmol) and 4-fluoro nitrobenzene (3.7 g, 25.98 mmol) were dissolved in dimethyl sulfoxide (6 mL). Then potassium carbonate (4.0 g, 28.58 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (5.5 g, 84%).
실시예 13-2: 1-(4-아미노페닐)-4-메틸-1,4-아자포스피네인 4-옥사이드의 제조Example 13-2 Preparation of 1- (4-aminophenyl) -4-methyl-1,4-azaphosphineine 4-oxide
상기 실시예 13-1에서 제조된 화합물(1 g, 3.93 mmol)을 메탄올(20 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.85 g, 96%)을 얻었다.The compound (1 g, 3.93 mmol) prepared in Example 13-1 was dissolved in methanol (20 mL), and then a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.85 g, 96%).
실시예 13-3: Example 13-3: NN -(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7-dihydrocyeno [3 ,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(4-아미노페닐)-4-메틸-1,4-아자포스피네인 4-옥사이드(0.67 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물 (160 mg, 47%)을 얻었다. 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline instead of 1- (4-aminophenyl) -4-methyl-1,4-azaphosphineine 4-oxide (0.67 A title compound (160 mg, 47%) was obtained in the same manner as the Example 1-3, except that mmol) was used.
1H NMR (400MHz, DMSO-d 6) δ 10.36 (s, 1H), 9.26 (s, 1H), 7.62 - 7.55 (m, 2H), 7.40 (t, 1H), 7.24 (d, 2H), 6.91 (m, 1H), 6.63 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.76 (m, 1H), 3.77 - 3.60 (m, 2H), 3.40 (t, 2H), 3.38 - 3.26 (m, 2H), 3.21 (t, 2H), 1.80 - 1.61 (m, 4H), 1.48 (d, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.36 (s, 1H), 9.26 (s, 1H), 7.62-7.55 (m, 2H), 7.40 (t, 1H), 7.24 (d, 2H), 6.91 (m, 1H), 6.63 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.76 (m, 1H), 3.77-3.60 (m, 2H), 3.40 (t, 2H), 3.38-3.26 (m, 2H), 3.21 (t, 2H), 1.80-1.61 (m, 4H), 1.48 (d, 3H)
실시예 14: Example 14: NN -(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 14-1: 1-(3-메톡시-4-나이트로페닐)-4-메틸피페라진의 제조Example 14-1 Preparation of 1- (3-methoxy-4-nitrophenyl) -4-methylpiperazine
1-메틸피페라진(2 mL, 18.17 mmol)과 4-플루오로-2-메톡시-1-나이트로벤젠(3.1 g, 18.17 mmol)을 다이메틸 설폭사이드(4 mL)에 용해시킨 후 탄산칼륨(2.8 g, 19.99 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(3.9 g, 85%)을 얻었다.1-methylpiperazine (2 mL, 18.17 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (3.1 g, 18.17 mmol) were dissolved in dimethyl sulfoxide (4 mL) and then potassium carbonate (2.8 g, 19.99 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid. The mixture was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (3.9 g, 85%).
실시예 14-2: 2-메톡시-4-(4-메틸피페라진-1-일)아닐린의 제조Example 14-2 Preparation of 2-methoxy-4- (4-methylpiperazin-1-yl) aniline
상기 실시예 14-1에서 제조된 화합물(3.0 g, 11.94 mmol)을 메탄올(150 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 300 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(2.5 g, 96%)을 얻었다.After dissolving the compound (3.0 g, 11.94 mmol) prepared in Example 14-1 in methanol (150 mL), a palladium catalyst (10% Pd / C, 300 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.5 g, 96%).
실시예 14-3: Example 14-3: NN -(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 2-메톡시-4-(4-메틸피페라진-1-일)아닐린(0.9 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(158 mg, 34%)을 얻었다. Use of 2-methoxy-4- (4-methylpiperazin-1-yl) aniline (0.9 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for the same procedure as in Example 1-3, the title compound (158 mg, 34%) was obtained.
1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 7.69 (s, 1H), 7.61 - 7.54 (m, 2H), 7.42 - 7.35 (m, 2H), 6.91 (m, 1H), 6.53 (m, 1H), 6.45 (m, 1H), 6.25 (m, 1H), 6.14 (m, 1H), 5.78 (m, 1H), 3.75 (s, 3H), 3.38 (t, 2H), 3.19 (t, 2H), 3.04 - 2.98 (m, 4H), 2.47 - 2.39 (m, 4H), 2.21 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.33 (s, 1H), 7.69 (s, 1H), 7.61-7.54 (m, 2H), 7.42-7.35 (m, 2H), 6.91 (m, 1H) , 6.53 (m, 1H), 6.45 (m, 1H), 6.25 (m, 1H), 6.14 (m, 1H), 5.78 (m, 1H), 3.75 (s, 3H), 3.38 (t, 2H), 3.19 (t, 2H), 3.04-2.98 (m, 4H), 2.47-2.39 (m, 4H), 2.21 (s, 3H)
실시예 15: Example 15: NN -(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 15-1: 1-메틸-4-(4-나이트로페녹시)피페리딘의 제조Example 15-1 Preparation of 1-methyl-4- (4-nitrophenoxy) piperidine
소듐 하이드라이드(60%, 1.98 g, 49.49 mmol)를 N,N-다이메틸폼아마이드(47 mL)에 넣고 0℃로 냉각한 후, 질소가스 하에 1-메틸피페리딘-4-올(5.82 mL, 49.49 mmol)을 적가하고 60분간 교반시켰다. 반응 혼합물에 4-플루오로 나이트로벤젠(5 mL, 47.13 mmol)을 적가하고 상온으로 서서히 상승하여 12시간 동안 교반하였다. 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 95 : 5 (부피비))로 분리하여 표제화합물(9 g, 81%)을 얻었다.Sodium hydride (60%, 1.98 g, 49.49 mmol) was added to N, N -dimethylformamide (47 mL), cooled to 0 ° C., and then 1-methylpiperidin-4-ol (5.82) under nitrogen gas. mL, 49.49 mmol) was added dropwise and stirred for 60 minutes. 4-fluoro nitrobenzene (5 mL, 47.13 mmol) was added dropwise to the reaction mixture, which was slowly raised to room temperature and stirred for 12 hours. After completion of the reaction by adding water to the reaction mixture and extraction with ethyl acetate, the separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then purified by column chromatography (dichloromethane: methanol = 95: 5 (volume ratio)). Isolation gave the title compound (9 g, 81%).
실시예 15-2: 4-((1-메틸피페리딘-4-일)옥시)아닐린의 제조Example 15-2 Preparation of 4-((1-methylpiperidin-4-yl) oxy) aniline
상기 실시예 15-1에서 제조된 화합물(9.0 g, 38.09 mmol)을 메탄올(200 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 0.9 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(6.6 g, 84%)을 얻었다.The compound (9.0 g, 38.09 mmol) prepared in Example 15-1 was dissolved in methanol (200 mL), and then a palladium catalyst (10% Pd / C, 0.9 g, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (6.6 g, 84%).
실시예 15-3:Example 15-3: NN -(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-((1-메틸피페리딘-4-일)옥시)아닐린(1 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(126 mg, 25%)을 얻었다.Except using 4-((1-methylpiperidin-4-yl) oxy) aniline (1 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline In the same manner as in Example 1-3, the title compound (126 mg, 25%) was obtained.
1H NMR (400MHz, DMSO-d 6) δ 10.35 (s, 1H), 9.36 (s, 1H), 7.63 (m, 1H), 7.58 (m, 1H), 7.42 (t, 1H), 7.27 (d, 2H), 6.94 (m, 1H), 6.60 (d, 2H), 6.45 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 4.14 (m, 1H), 3.40 (t, 2H), 3.22 (t, 2H), 2.65 - 2.55 (m, 2H), 2.22 - 2.12 (m, 5H), 1.88 - 1.79 (m, 2H), 1.62 - 1.50 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.35 (s, 1H), 9.36 (s, 1H), 7.63 (m, 1H), 7.58 (m, 1H), 7.42 (t, 1H), 7.27 (d , 2H), 6.94 (m, 1H), 6.60 (d, 2H), 6.45 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 4.14 (m, 1H), 3.40 (t, 2H), 3.22 (t, 2H), 2.65-2.55 (m, 2H), 2.22-2.12 (m, 5H), 1.88-1.79 (m, 2H), 1.62-1.50 (m, 2H)
실시예 16: Example 16: NN -(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2-methoxyethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 16-1: 1-(2-메톡시에톡시)-4-나이트로벤젠의 제조Example 16-1 Preparation of 1- (2-methoxyethoxy) -4-nitrobenzene
2-메톡시에탄올(2 mL, 25.49 mmol)과 4-플루오로 나이트로벤젠(2.7 mL, 25.49 mmol)을 다이메틸 설폭사이드(4 mL)에 용해시킨 후 탄산칼륨(3.9 g, 28.04 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(2.7 g, 53%)을 얻었다.2-methoxyethanol (2 mL, 25.49 mmol) and 4-fluoro nitrobenzene (2.7 mL, 25.49 mmol) were dissolved in dimethyl sulfoxide (4 mL), followed by potassium carbonate (3.9 g, 28.04 mmol). It was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid. The mixture was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (2.7 g, 53%).
실시예 16-2: 4-(2-메톡시에톡시)아닐린의 제조Example 16-2: Preparation of 4- (2-methoxyethoxy) aniline
상기 실시예 16-1에서 제조된 화합물(1g, 5.07 mmol)을 메탄올(40 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(720 mg, 85%)을 얻었다.The compound (1 g, 5.07 mmol) prepared in Example 16-1 was dissolved in methanol (40 mL), and then a palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added thereto at room temperature under hydrogen gas. Stir for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (720 mg, 85%).
실시예 16-3:Example 16-3: NN -(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2-methoxyethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(2-메톡시에톡시)아닐린(1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(167 mg, 30%)을 얻었다. Example 1-, except that 4- (2-methoxyethoxy) aniline (1.2 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same process as in 3, the title compound (167 mg, 30%) was obtained.
1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.64 (m, 1H), 7.53 (m, 1H), 7.42 (t, 1H), 7.28 (d, 2H), 6.93 (m, 1H), 6.61 (d, 2H), 6.45 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.96 - 3.91 (m, 2H), 3.62 - 3.58 (m, 2H), 3.40 (t, 2H), 3.23 (t, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.64 (m, 1H), 7.53 (m, 1H), 7.42 (t, 1H), 7.28 (d , 2H), 6.93 (m, 1H), 6.61 (d, 2H), 6.45 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.96-3.91 (m, 2H), 3.62- 3.58 (m, 2H), 3.40 (t, 2H), 3.23 (t, 2H)
실시예 17: Example 17: NN -(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 17-1: 1-에틸-4-(4-나이트로페닐)피페라진의 제조Example 17-1 Preparation of 1-ethyl-4- (4-nitrophenyl) piperazine
1-에틸피페라진(5.0 mL, 31.17 mmol)과 4-플루오로 나이트로벤젠(3.3 mL, 31.17 mmol)을 다이메틸 설폭사이드(10 mL)에 용해시킨 후 탄산칼륨(4.7 g, 34.29 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(6.9 g, 94%)을 얻었다.1-ethylpiperazine (5.0 mL, 31.17 mmol) and 4-fluoro nitrobenzene (3.3 mL, 31.17 mmol) were dissolved in dimethyl sulfoxide (10 mL), followed by potassium carbonate (4.7 g, 34.29 mmol). It was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (6.9 g, 94%).
실시예 17-2: 4-(4-에틸피페라진-1-일)아닐린의 제조Example 17-2 Preparation of 4- (4-ethylpiperazin-1-yl) aniline
상기 실시예 17-1에서 제조된 화합물(2.0 g, 8.5 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.2 g, 69%)을 얻었다.The compound (2.0 g, 8.5 mmol) prepared in Example 17-1 was dissolved in methanol (60 mL), and then a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.2 g, 69%).
실시예 17-3:Example 17-3: NN -(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-에틸피페라진-1-일)아닐린(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(20 mg, 3%)을 얻었다.Except that 4- (4-ethylpiperazin-1-yl) aniline (1.25 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same procedure as in Example 1-3 was performed to obtain the title compound (20 mg, 3%).
1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 9.28 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 (m, 1H), 6.62 (d, 2H), 6.42 (m, 1H), 6.27 (m, 1H), 5.77 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 3.00 - 2.88 (m, 4H), 2.60 - 2.31 (m, 6H), 1.03 (t, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.33 (s, 1H), 9.28 (s, 1H), 7.61-7.57 (m, 2H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 (m, 1H), 6.62 (d, 2H), 6.42 (m, 1H), 6.27 (m, 1H), 5.77 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 3.00- 2.88 (m, 4H), 2.60-2.31 (m, 6H), 1.03 (t, 3H)
실시예 18: Example 18: NN -(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 18-1: 1-아이소프로필-4-(4-나이트로페닐)피페라진의 제조Example 18-1 Preparation of 1-isopropyl-4- (4-nitrophenyl) piperazine
1-아이소프로필피페라진(5.0 g, 39 mmol)과 4-플루오로 나이트로벤젠(4.1 mL, 38.61 mmol)을 다이메틸 설폭사이드(12 mL)에 용해시킨 후 탄산칼륨(5.9 g, 42.9 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(9.3 g, 95%)을 얻었다.Dissolve 1-isopropylpiperazine (5.0 g, 39 mmol) and 4-fluoro nitrobenzene (4.1 mL, 38.61 mmol) in dimethyl sulfoxide (12 mL) followed by potassium carbonate (5.9 g, 42.9 mmol) Was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid. The mixture was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (9.3 g, 95%).
실시예 18-2: 4-(4-아이소프로필피페라진-1-일)아닐린의 제조Example 18-2 Preparation of 4- (4-isopropylpiperazin-1-yl) aniline
상기 실시예 18-1에서 제조된 화합물(2g, 8.02 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(400 mg, 23%)을 얻었다.The compound (2 g, 8.02 mmol) prepared in Example 18-1 was dissolved in methanol (60 mL), and then a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto at room temperature under hydrogen gas. Stir for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (400 mg, 23%).
실시예 18-3:Example 18-3: NN -(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-아이소프로필피페라진-1-일)아닐린(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(20 mg, 3%)을 얻었다.Except for using 4- (4-isopropylpiperazin-1-yl) aniline (1.25 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline, The same process as in Example 1-3 was carried out to obtain the title compound (20 mg, 3%).
1H NMR (400MHz, DMSO-d 6) δ 10.35 (s, 1H), 9.27 (s, 1H), 7.62 - 7.59 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.92 (m, 1H), 6.61 (d, 2H), 6.44 (m, 1H), 6.28 (m, 1H), 5.78 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.98 - 2.88 (m, 4H), 2.65 (m, 1H), 2.60 - 2.52 (m, 4H), 1.00 (d, 6H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.35 (s, 1H), 9.27 (s, 1H), 7.62-7.59 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.92 (m, 1H), 6.61 (d, 2H), 6.44 (m, 1H), 6.28 (m, 1H), 5.78 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.98- 2.88 (m, 4H), 2.65 (m, 1H), 2.60-2.52 (m, 4H), 1.00 (d, 6H)
실시예 19: Example 19: NN -(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 19-1: 1-아세틸-4-(4-나이트로페닐)피페라진의 제조Example 19-1 Preparation of 1-acetyl-4- (4-nitrophenyl) piperazine
1-아세틸피페라진(5.0 g, 39.01 mmol)과 4-플루오로 나이트로벤젠(4.1 mL, 39.01 mmol)을 다이메틸 설폭사이드(10 mL)에 용해시킨 후 탄산칼륨(5.9 g, 42.91 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물 (8.7 g, 89%)을 얻었다.1-acetylpiperazine (5.0 g, 39.01 mmol) and 4-fluoro nitrobenzene (4.1 mL, 39.01 mmol) were dissolved in dimethyl sulfoxide (10 mL), followed by potassium carbonate (5.9 g, 42.91 mmol). It was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was filtered, washed with distilled water, and dried under reduced pressure to obtain the title compound (8.7 g, 89%).
실시예 19-2: 4-(4-아세틸피페라진-1-일)아닐린의 제조Example 19-2 Preparation of 4- (4-acetylpiperazin-1-yl) aniline
상기 실시예 19-1에서 제조된 화합물(2 g, 8.02 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.2 g, 67%)을 얻었다.After dissolving the compound (2 g, 8.02 mmol) prepared in Example 19-1 in methanol (60 mL), a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto, followed by room temperature under hydrogen gas. Stirred for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.2 g, 67%).
실시예 19-3:Example 19-3: NN -(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-아세틸피페라진-1-일)아닐린(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(110 mg, 17%)을 얻었다.Except that 4- (4-acetylpiperazin-1-yl) aniline (1.25 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same procedure as in Example 1-3 was performed to obtain the title compound (110 mg, 17%).
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.32 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.26 (d, 2H), 6.94 (m, 1H), 6.65 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.57 - 3.49 (m, 4H), 3.39 (t, 2H), 3.21 (t, 2H), 3.00 - 2.88 (m, 4H), 2.00 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.32 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.26 (d, 2H), 6.94 (m , 1H), 6.65 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.57-3.49 (m, 4H), 3.39 (t, 2H), 3.21 ( t, 2H), 3.00-2.88 (m, 4H), 2.00 (s, 3H)
실시예 20: Example 20: (S)(S) -1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2--1- (4-((4- (3-acrylamidophenoxy) -6,7-dihydrocyeno [3,2- dd ]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드의 제조] Production of pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide
실시예 20-1: Example 20-1: (S)(S) -1-(4-나이트로페닐)피롤리딘-2-카르복사마이드의 제조Preparation of -1- (4-nitrophenyl) pyrrolidine-2-carboxamide
(S)-피롤리딘-2-카르복사마이드(4 g, 35.04 mmol)와 4-플루오로 나이트로벤젠(3.7 mL, 34.7 mmol)을 다이메틸 설폭사이드(10 mL)에 용해시킨 후 탄산칼륨(5.3 g, 38.17 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물 (4.1 g, 50%)을 얻었다. (S) -Pyrrolidine-2-carboxamide (4 g, 35.04 mmol) and 4-fluoro nitrobenzene (3.7 mL, 34.7 mmol) were dissolved in dimethyl sulfoxide (10 mL), followed by potassium carbonate. (5.3 g, 38.17 mmol) was added and stirred at room temperature for 12 hours. Upon completion of the reaction, distilled water was added to the reaction mixture to form a solid, which was filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (4.1 g, 50%).
실시예 20-2: Example 20-2: (S)(S) -1-(4-아미노페닐)피롤리딘-2-카르복사마이드의 제조Preparation of -1- (4-aminophenyl) pyrrolidine-2-carboxamide
상기 실시예 20-1에서 제조된 화합물(2g, 8.5 mmol)를 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.1 g, 61%)을 얻었다.The compound (2 g, 8.5 mmol) prepared in Example 20-1 was dissolved in methanol (60 mL), and then a palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added thereto at room temperature under hydrogen gas. Stir for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.1 g, 61%).
실시예 20-3: Example 20-3: (S)(S) -1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2--1- (4-((4- (3-acrylamidophenoxy) -6,7-dihydrocyeno [3,2- dd ]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드의 제조] Production of pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (S)-1-(4-아미노페닐)피롤리딘-2-카르복사마이드(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(20 mg, 3%)을 얻었다. (S) -1- (4-aminophenyl) pyrrolidine-2-carboxamide (1.25 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for the use, the same procedure as in Example 1-3 was carried out to obtain the title compound (20 mg, 3%).
1H NMR (400MHz, DMSO-d 6) δ 10.31 (s, 1H), 9.11 (s, 1H), 7.63 (s, 1H), 7.52 (m, 1H), 7.39 (t, 1H), 7.29 - 7.19 (m, 3H), 7.00 - 6.90 (m, 2H), 6.44 (m, 1H), 6.30 - 6.18 (m, 3H), 5.77 (m, 1H), 3.72 (m, 1H), 3.47 (m, 1H), 3.38 (t, 2H), 3.20 (t, 2H), 3.06 (m, 1H), 2.15 (m, 1H), 2.00 - 1.86 (m, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.31 (s, 1H), 9.11 (s, 1H), 7.63 (s, 1H), 7.52 (m, 1H), 7.39 (t, 1H), 7.29-7.19 (m, 3H), 7.00-6.90 (m, 2H), 6.44 (m, 1H), 6.30-6.18 (m, 3H), 5.77 (m, 1H), 3.72 (m, 1H), 3.47 (m, 1H ), 3.38 (t, 2H), 3.20 (t, 2H), 3.06 (m, 1H), 2.15 (m, 1H), 2.00-1.86 (m, 3H)
실시예 21: Example 21: NN -(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2-acetyl-2,7-diazaspiro [3.5] nonane-7-yl) phenyl) amino) -6,7-dihydrocyeno [ 3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 21-1: 1-(7-(4-아미노페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온의 제조Example 21-1 Preparation of 1- (7- (4-aminophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온(150 mg, 0.52 mmol), 아연(170 mg, 2.59 mmol) 및 염화 암모늄 (140 mg, 2.59 mmol)을 테트라하이드로퓨란(10 mL)과 메탄올(10 mL)에 현탁시킨 후 상온에서 24 시간 동안 교반하였다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 아연 및 염화 암모늄을 제거하고, 여액을 감압 증류하여 표제화합물(48 mg, 36%)을 얻었다.1- (7- (4-nitrophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone (150 mg, 0.52 mmol), zinc (170 mg, 2.59 mmol) and Ammonium chloride (140 mg, 2.59 mmol) was suspended in tetrahydrofuran (10 mL) and methanol (10 mL) and stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture was filtered through a filter filled with celite to remove zinc and ammonium chloride, and the filtrate was distilled under reduced pressure to obtain the title compound (48 mg, 36%).
실시예 21-2: Example 21-2: NN -(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일l)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2-acetyl-2,7-diazaspiro [3.5] nonane-7-yll) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(7-(4-아미노페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온(36 mg, 0.14 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(11 mg, 14%)을 얻었다.1- (7- (4-aminophenyl) -2,7-diazaspiro [3.5] nonane- instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for using 2-yl) ethanone (36 mg, 0.14 mmol), the title compound (11 mg, 14%) was obtained in the same manner as the Example 1-3.
1H-NMR (400 MHz, CDCl3) δ 7.66 (m, 1H), 7.40 (t, 1H), 7.20 (d, 2H), 6.99 (dd, 1H), 6.78 (s, 1H), 6.73 (d, 2H), 6.44 (dd, 1H), 6.23 (dd, 1H), 5.79 (dd, 1H), 3.83 (s, 2H), 3.73 (s, 2H), 3.38 (t, 2H), 3.26 (t, 2H), 2.99 (t, 3H), 1.89 (s, 3H) 1 H-NMR (400 MHz, CDCl 3 ) δ 7.66 (m, 1H), 7.40 (t, 1H), 7.20 (d, 2H), 6.99 (dd, 1H), 6.78 (s, 1H), 6.73 (d , 2H), 6.44 (dd, 1H), 6.23 (dd, 1H), 5.79 (dd, 1H), 3.83 (s, 2H), 3.73 (s, 2H), 3.38 (t, 2H), 3.26 (t, 2H), 2.99 (t, 3H), 1.89 (s, 3H)
실시예 22: Example 22: NN -(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 22-1: 4-몰폴리노아닐린의 제조Example 22-1: Preparation of 4-morpholinoaniline
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 4-(4-나이트로페닐)몰폴린(1.8 g, 8.65 mmol)을 사용한 것을 제외하고는, 실시예 21-1과 동일한 공정을 수행하여 표제화합물(0.8 g, 51%)을 얻었다.4- (4-nitrophenyl) morpholine (1.8 g, 8.65 instead of 1- (7- (4-nitrophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone A title compound (0.8 g, 51%) was obtained in the same manner as the Example 21-1, except that mmol) was used.
실시예 22-2: Example 22-2: NN -(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-몰폴리노아닐린(320 mg, 1.8 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(300 mg, 35%)을 얻었다.Examples 1-3, except that 4-morpholinoaniline (320 mg, 1.8 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same process was followed to obtain the title compound (300 mg, 35%).
1H-NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (ddd, 1H), 6.63 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 3.73 - 3.67 (m, 4H), 3.44 - 3.36 (m, 2H), 3.22 (t, 2H), 2.95 - 2.88 (m, 4H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62-7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H) , 6.93 (ddd, 1H), 6.63 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 2H), 3.73-3.67 (m, 4H), 3.44-3.36 (m, 2H), 3.22 (t, 2H), 2.95-2.88 (m, 4H)
실시예 23: Example 23: NN -(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 23-1: 4-(피페리딘-1-일)아닐린의 제조Example 23-1 Preparation of 4- (piperidin-1-yl) aniline
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 1-(4-나이트로페닐)피페리딘(2.8 g, 13.58 mmol)을 사용한 것을 제외하고는, 실시예 21-1과 동일한 공정을 수행하여 표제화합물(2.1 g, 86%)을 얻었다.1- (4-nitrophenyl) piperidine (2.8 g, instead of 1- (7- (4-nitrophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone 13.58 mmol) was used in the same manner as Example 21-1 to obtain the title compound (2.1 g, 86%).
실시예 23-2: Example 23-2: NN -(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(피페리딘-1-일)아닐린(317 mg, 1.8 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(380 mg, 45%)을 얻었다.Except for using 4- (piperidin-1-yl) aniline (317 mg, 1.8 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline, The same process as in Example 1-3 was performed to obtain the title compound (380 mg, 45%).
1H-NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.27 (s, 1H), 7.61 (m, 2H), 7.42 (t, 1H), 7.23 (d, 2H), 6.92 (ddd, 1H), 6.61 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 3.44 - 3.36 (m, 2H), 3.21 (t, 2H), 2.96 - 2.89 (m, 4H), 1.62 - 1.54 (m, 4H), 1.51 - 1.43 (m, 2H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.27 (s, 1H), 7.61 (m, 2H), 7.42 (t, 1H), 7.23 (d, 2H), 6.92 (ddd, 1H), 6.61 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 2H), 3.44-3.36 (m, 2H), 3.21 (t, 2H ), 2.96-2.89 (m, 4H), 1.62-1.54 (m, 4H), 1.51-1.43 (m, 2H)
실시예 24: Example 24: NN -(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 24-1: 4-(4,4-다이플루오로피페리딘-1-일)아닐린의 제조Example 24-1 Preparation of 4- (4,4-difluoropiperidin-1-yl) aniline
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 4,4-다이플루오로-1-(4-나이트로페닐)피페리딘 (600 mg, 2.48 mmol)을 사용한 것을 제외하고, 실시예 21-1과 동일한 공정을 수행하여 표제화합물 (347 mg, 66%)을 얻었다.4,4-difluoro-1- (4-nitrophenyl) instead of 1- (7- (4-nitrophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone ) The title compound (347 mg, 66%) was obtained in the same manner as Example 21-1, except that piperidine (600 mg, 2.48 mmol) was used.
실시예 24-2: Example 24-2: NN -(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4,4-다이플루오로피페리딘-1-일)아닐린(347 mg, 1.63 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(97 mg, 11%)을 얻었다.4- (4,4-difluoropiperidin-1-yl) aniline (347 mg, 1.63 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for using, the same process as in Example 1-3 was carried out to obtain the title compound (97 mg, 11%).
1H-NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.33 (s, 1H), 7.60 (m, 2H), 7.42 (t, 1H), 7.27 (d, 2H), 6.93 (dd, 1H), 6.68 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 1H), 3.44 - 3.36 (m, 2H), 3.22 (t, 2H), 3.16 - 3.10 (m, 4H), 2.08 - 1.95 (m, 4H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.33 (s, 1H), 7.60 (m, 2H), 7.42 (t, 1H), 7.27 (d, 2H), 6.93 (dd, 1H), 6.68 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 1H), 3.44-3.36 (m, 2H), 3.22 (t, 2H ), 3.16-3.10 (m, 4H), 2.08-1.95 (m, 4H)
실시예 25: Example 25: NN -(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 25-1: 1-(4-(4-아미노페녹시)피페리딘-1-일)에탄온의 제조Example 25-1 Preparation of 1- (4- (4-aminophenoxy) piperidin-1-yl) ethanone
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 1-(4-(4-나이트로페녹시)피페리딘-1-일)에탄온(1.5 g, 5.8 mmol)을 사용한 것을 제외하고, 실시예 21-1과 동일한 공정을 수행하여 표제화합물(0.8 g, 59%)을 얻었다.1- (4- (4-nitrophenoxy) piperidine instead of 1- (7- (4-nitrophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone -1-yl) ethanone (1.5 g, 5.8 mmol) was used in the same manner as Example 21-1, to obtain the title compound (0.8 g, 59%).
실시예 25-2: Example 25-2: NN -(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(4-(4-아미노페녹시)피페리딘-1-일)에탄온(600 mg, 2.56 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(330 mg, 24%)을 얻었다.1- (4- (4-aminophenoxy) piperidin-1-yl) ethanone (600 mg, instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline 2.56 mmol) was used in the same manner as Example 1-3 to obtain the title compound (330 mg, 24%).
1H-NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.36 (s, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.42 (t, 1H), 7.29 (d, 2H), 6.94 (dd, 1H), 6.65 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 4.38 (m, 1H), 3.79 (m, 1H), 3.63 (m, 1H), 3.44 - 3.29 (m, 4H), 3.23 (t, 2H), 1.91 - 1.75 (m, 2H), 1.59 - 1.36 (m, 2H) 1 H-NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.36 (s, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.42 (t, 1H), 7.29 (d, 2H), 6.94 (dd, 1H), 6.65 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 2H), 4.38 (m, 1H), 3.79 (m, 1H), 3.63 (m, 1H), 3.44-3.29 (m, 4H), 3.23 (t, 2H), 1.91-1.75 (m, 2H), 1.59-1.36 (m, 2H)
실시예26: Example 26: NN -(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 26-1: 4-(4-(2-메톡시에틸)피페라진-1-일)아닐린의 제조Example 26-1 Preparation of 4- (4- (2-methoxyethyl) piperazin-1-yl) aniline
1-(2-메톡시에틸)-4-(4-나이트로페닐)피페라진(4.3g, 16.02 mmol)를 메탄올(120 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 430 mg, 10 wt%)를 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(3.7 g, 97%)을 얻었다.Dissolve 1- (2-methoxyethyl) -4- (4-nitrophenyl) piperazine (4.3 g, 16.02 mmol) in methanol (120 mL), then palladium catalyst (10% Pd / C, 430 mg) , 10 wt%) was added and stirred at room temperature under hydrogen gas for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (3.7 g, 97%).
실시예 26-2: Example 26-2: NN -(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-(2-메톡시에틸)피페라진-1-일)아닐린(2.13 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물 (130 mg, 11%)을 얻었다. 4- (4- (2-methoxyethyl) piperazin-1-yl) aniline (2.13 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for the same procedure as in Example 1-3, the title compound (130 mg, 11%) was obtained.
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.63 - 7.55 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.93 (m, 1H), 6.61 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.46 (t, 2H), 3.39 (t, 2H), 3.25 (s, 3H), 3.21 (t, 2H), 2.97 - 2.90 (m, 4H), 2.54 - 2.48 (m, 6H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.63-7.55 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.93 (m, 1H), 6.61 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.46 (t, 2H), 3.39 (t, 2H), 3.25 ( s, 3H), 3.21 (t, 2H), 2.97-2.90 (m, 4H), 2.54-2.48 (m, 6H)
실시예 27: Example 27: NN -(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2-morpholinoethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 27-1: 4-(2-몰포리노에톡시)아닐린의 제조Example 27-1 Preparation of 4- (2-morpholinoethoxy) aniline
4-(2-(4-나이트로페녹시)에틸)몰폴린(3 g, 11.89 mmol)를 메탄올 (80 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 300 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물 (2.24 g, 85%)을 얻었다.4- (2- (4-nitrophenoxy) ethyl) morpholine (3 g, 11.89 mmol) was dissolved in methanol (80 mL) and then palladium catalyst (10% Pd / C, 300 mg, 10 wt% ) Was added and stirred at room temperature under hydrogen gas for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.24 g, 85%).
실시예 27-2: Example 27-2: NN -(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (2-morpholinoethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(2-몰포리노에톡시)아닐린(1.35 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(50 mg, 7%)을 얻었다Example 1- except that 4- (2-morpholinoethoxy) aniline (1.35 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline The same procedure as in 3 was carried out to obtain the title compound (50 mg, 7%).
1H NMR (400MHz, CDCl3) δ 8.08 (s, 1H), 7.55- 7 .39 (m, 2H), 7.30 (t, 1H), 7.17 (d, 2H), 7.11 (s, 1H), 6.92 (d, 1H), 6.65 (d, 2H), 6.39 (m, 1H), 6.23 (m, 1H), 5.70 (d, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.97 - 2.90 (m, 4H), 2.43 - 2.37 (m, 4H), 2.20 (s, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.55- 7.39 (m, 2H), 7.30 (t, 1H), 7.17 (d, 2H), 7.11 (s, 1H), 6.92 (d, 1H), 6.65 (d, 2H), 6.39 (m, 1H), 6.23 (m, 1H), 5.70 (d, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.97- 2.90 (m, 4H), 2.43-2.37 (m, 4H), 2.20 (s, 3H)
실시예 28: Example 28: NN -(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4- (2- (dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 28-1: 1-(4-(4-아미노페닐)피페라진-1-일)-2-(다이메틸아미노)에타논의 제조Example 28-1 Preparation of 1- (4- (4-aminophenyl) piperazin-1-yl) -2- (dimethylamino) ethanone
2-(다이메틸아미노)-1-(4-(4-나이트로페닐)피페라진-1-일)에타논(2 g, 6.84 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.6 g, 89%)을 얻었다.2- (dimethylamino) -1- (4- (4-nitrophenyl) piperazin-1-yl) ethanone (2 g, 6.84 mmol) was dissolved in methanol (60 mL), followed by palladium catalyst ( 10% Pd / C, 200 mg, 10 wt%) was added and stirred at room temperature under hydrogen gas for 12 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.6 g, 89%).
실시예 28-2: Example 28-2: NN -(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4- (2- (dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2 - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(4-(4-아미노페닐)피페라진-1-일)-2-(다이메틸아미노)에타논(1.91 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(150 mg, 14%)을 얻었다.1- (4- (4-aminophenyl) piperazin-1-yl) -2- (dimethylamino) instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for using ethanone (1.91 mmol), the same process as in Example 1-3 was performed to obtain the title compound (150 mg, 14%).
1H NMR (400MHz, DMSO-d 6) δ 10.38 (s, 1H), 9.33 (s, 1H), 7.64 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (m, 1H), 6.65 (d, 2H), 6.44 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.67 - 3.60 (m, 2H), 3.59 - 3.52 (m, 2H), 3.40 (t, 2H), 3.22 (t, 2H), 3.16 (s, 2H), 2.99 - 2.86 (m, 4H), 2.22 (s, 6H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.38 (s, 1H), 9.33 (s, 1H), 7.64-7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (m, 1H), 6.65 (d, 2H), 6.44 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.67-3.60 (m, 2H), 3.59-3.52 (m, 2H ), 3.40 (t, 2H), 3.22 (t, 2H), 3.16 (s, 2H), 2.99-2.86 (m, 4H), 2.22 (s, 6H)
실시예 29: Example 29: NN -(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2--(3-((2-((4- (4-methylpiperazin-1-carbonyl) phenyl) amino) -6,7-dihydrocyeno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Production of pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 29-1: (4-아미노페닐)(4-메틸피페라진-1-일)메타논의 제조Example 29-1: Preparation of (4-aminophenyl) (4-methylpiperazin-1-yl) methanone
(4-메틸피페라진-1-일)(4-나이트로페닐)메타논(5.3 g, 21.14 mmol), 아연(7.1 g, 108.67 mmol) 및 염화 암모늄(5.8 g, 108.67 mmol)을 테트라하이드로퓨란(100 mL)과 메탄올(60 mL)에 현탁시킨 후 상온에서 24 시간 동안 교반하였다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 아연 및 염화 암모늄을 제거하고, 여액을 감압 증류하여 표제화합물(4.6 g, 99%)을 얻었다.(4-methylpiperazin-1-yl) (4-nitrophenyl) methanone (5.3 g, 21.14 mmol), zinc (7.1 g, 108.67 mmol) and ammonium chloride (5.8 g, 108.67 mmol) were added to tetrahydrofuran (100 mL) and methanol (60 mL) and then stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was filtered through a filter filled with celite to remove zinc and ammonium chloride, and the filtrate was distilled under reduced pressure to obtain the title compound (4.6 g, 99%).
실시예Example 29-2:  29-2: NN -(3-((2-((4-(4--(3-((2-((4- (4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )페닐)아미노)-6,7-) Phenyl) amino) -6,7- 다이하이드로싸이에노[3,2-Dihydrocyeno [3,2- dd ]피리미딘] Pyrimidine -4-일)옥시)페닐)아크릴아마이드의 제조Preparation of -4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (4-아미노페닐)(4-메틸피페라진-1-일)메타논(1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(77 mg, 12%)을 얻었다.(4-aminophenyl) (4-methylpiperazin-1-yl) methanone (1.2 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline Except for the same procedure as in Example 1-3, the title compound (77 mg, 12%) was obtained.
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.78 (s, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.47 -7.39 (m, 3H), 7.05 (d, 2H), 6.96 (m, 1H), 6.42 (m, 1H), 6.24 (m, 1H), 5.76 (m, 1H), 3.51 - 3.33 (br, 4H), 3.43 (t, 2H), 3.28 (t, 2H), 2.97 - 2.90 (m, 4H), 2.31 - 2.22 (br, 4H), 2.19 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.78 (s, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.47 -7.39 (m, 3H), 7.05 (d, 2H), 6.96 (m, 1H), 6.42 (m, 1H), 6.24 (m, 1H), 5.76 (m, 1H), 3.51-3.33 (br, 4H), 3.43 (t, 2H), 3.28 (t, 2H), 2.97-2.90 (m, 4H), 2.31-2.22 (br, 4H), 2.19 (s, 3H)
실시예 30: Example 30: (E)(E) -4-(다이메틸아미노)--4- (dimethylamino)- NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,6-다이하이드로싸이에노[2,3--(3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -5,6-dihydrocyeno [2,3- dd ]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드의 제조] Preparation of pyrimidin-4-yl) oxy) phenyl) but-2-enamide
4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-2-아민(400 mg, 0.92 mmol)을 N,N-다이메틸폼아마이드(3 mL)에 용해시키고 (E)-4-(다이메틸아미노)뷰트-2-엔산 염산염(244 mg, 1.47 mmol), N-(3-다이메틸아미노프로필)-N'-에틸카보다이이미드 염산염(282 mg, 1.47 mmol)과 피리딘(0.3 mL, 3.68 mmol)을 가하여 상온에서 3 시간 동안 교반하였다. 반응이 완결되면 반응혼합물을 에틸 아세테이트로 묽히고 포화염수로 세척하였다. 유기층을 무수황산나트륨으로 건조한 후, 감압 여과 및 감압 증류하였다. 얻어진 잔사를 컬럼 크로마토그래피(다이클로로메탄 : 에틸 아세테이트 : 메탄올 = 3 : 3 : 1 (부피비))로 분리하여 표제화합물(226 mg, 45%)을 얻었다.4- (3-aminophenoxy) - N - (4- (4-methylpiperazin-1-yl) phenyl) -5,6-dihydro furnace to Im [2,3- d] pyrimidin-2 Amine (400 mg, 0.92 mmol) was dissolved in N , N -dimethylformamide (3 mL) and (E) -4- (dimethylamino) but-2-enoic acid hydrochloride (244 mg, 1.47 mmol), N -stirred-ethylcarbodiimide hydrochloride (282 mg, 1.47 mmol) and 3 h at room temperature was added pyridine (0.3 mL, 3.68 mmol) - (3- dimethylaminopropyl) - N '. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: ethyl acetate: methanol = 3: 3: 1 (volume ratio)) to obtain the title compound (226 mg, 45%).
1H NMR (400MHz, δ 10.20 (s, 1H), 9.24 (s, 1H), 7.58 - 7.49 (m, 2H), 7.36 (t, 1H), 7.19 (d, 2H), 6.86 (ddd, 1H), 6.69 (dt, 1H), 6.57 (d, 2H), 6.22 (dt, 1H), 3.35 (t, 2H), 3.17 (t, 2H), 3.00 (dd, 2H), 2.94 - 2.86 (m, 4H), 2.39 - 2.34 (m, 4H), 2.16 (s, 3H). 1 H NMR (400 MHz, δ 10.20 (s, 1H), 9.24 (s, 1H), 7.58-7.49 (m, 2H), 7.36 (t, 1H), 7.19 (d, 2H), 6.86 (ddd, 1H) , 6.69 (dt, 1H), 6.57 (d, 2H), 6.22 (dt, 1H), 3.35 (t, 2H), 3.17 (t, 2H), 3.00 (dd, 2H), 2.94-2.86 (m, 4H ), 2.39-2.34 (m, 4H), 2.16 (s, 3H).
실시예 31: Example 31: (E)(E) -4-(다이메틸아미노)--4- (dimethylamino)- NN -(3-((2-((4-몰폴리노페닐)아미노)-5,6-다이하이드로싸이에노[2,3--(3-((2-((4-morpholinophenyl) amino) -5,6-dihydrocyeno [2,3- dd ]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드의 제조] Preparation of pyrimidin-4-yl) oxy) phenyl) but-2-enamide
4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-2-아민 대신 4-(3-아미노페녹시)-N-(4-몰폴리노페닐)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-2-아민(150 mg, 0.36 mmol)을 사용한 것을 제외하고, 실시예 30과 동일한 공정을 수행하여 표제화합물(70 mg, 37%)을 얻었다.4- (3-aminophenoxy) - N - (4- (4-methylpiperazin-1-yl) phenyl) -5,6-dihydro furnace to Im [2,3- d] pyrimidin-2 amine instead of 4- (3-aminophenoxy) - N - (4-morpholinophenyl) -5,6-dihydro furnace to Im [2,3- d] pyrimidin-2-amine (150 mg, 0.36 mmol) was used, and the title compound was obtained in the same manner as Example 30 (70 mg, 37%).
1H NMR (400MHz, δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (ddd, 1H), 6.63 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 3.73 - 3.67 (m, 4H), 3.44 - 3.36 (m, 2H), 3.22 (t, 2H), 2.95 - 2.88 (m, 4H). 1 H NMR (400 MHz, δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62-7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (ddd, 1H) , 6.63 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 2H), 3.73-3.67 (m, 4H), 3.44-3.36 (m, 2H), 3.22 (t, 2H), 2.95-2.88 (m, 4H).
Figure PCTKR2018001139-appb-I000009
Figure PCTKR2018001139-appb-I000009
Figure PCTKR2018001139-appb-I000010
Figure PCTKR2018001139-appb-I000010
Figure PCTKR2018001139-appb-I000011
Figure PCTKR2018001139-appb-I000011
Figure PCTKR2018001139-appb-I000012
Figure PCTKR2018001139-appb-I000012
Figure PCTKR2018001139-appb-I000013
Figure PCTKR2018001139-appb-I000013
Figure PCTKR2018001139-appb-I000014
Figure PCTKR2018001139-appb-I000014
Figure PCTKR2018001139-appb-I000015
Figure PCTKR2018001139-appb-I000015
Figure PCTKR2018001139-appb-I000016
Figure PCTKR2018001139-appb-I000016
Figure PCTKR2018001139-appb-I000017
Figure PCTKR2018001139-appb-I000017
Figure PCTKR2018001139-appb-I000018
Figure PCTKR2018001139-appb-I000018
Figure PCTKR2018001139-appb-I000019
Figure PCTKR2018001139-appb-I000019
실험예 1: 키나아제 활성 시험Experimental Example 1: Kinase Activity Test
화합물의　BTK, BMX, JAK3 키나아제에 대한 활성억제율은　FRET을 이용한 기질(substrate)의 인산화작용 억제율을 측정함으로서 결정하였고, Thermo Fisher Scientific사에 의뢰하여　Z'-LYTE assay　시험법에 따라 진행되었다.The inhibitory activity of the compounds against BTK, BMX, and JAK3 kinases was determined by measuring the inhibition of phosphorylation of the substrate using FRET, and was performed according to the Z'-LYTE assay method by Thermo Fisher Scientific.
측정하고자 하는 화합물은 각　키나아제를 반응하여　기질인　FRET-peptide　인산화 반응이 조절되고,　인산화 유무에 따라　FRET-peptide가 분열되거나 분열되지 않는다.　분열된　FRET-peptide(445 nm)와 분열되지 않은　FRET-peptide(520 nm)의 각각의　emission을 측정하고, emission ratio(445 nm/520 nm)를 계산하여 활성을　50%　억제하는　IC50 values를 확인하였다. IC50 값 범위는 표 1에 다음과 같이 표기하였다: A (IC50<100 nM), B (100 nM<IC50<1,000 nM), C (IC50>1,000 nM).The compound to be measured reacts with each kinase to control the FRET-peptide phosphorylation as a substrate, and FRET-peptide is not cleaved or cleaved depending on the phosphorylation. IC 50 values that measure the emission of cleaved FRET-peptide (445 nm) and undivided FRET-peptide (520 nm) and calculate the emission ratio (445 nm / 520 nm) by 50% inhibition of activity Confirmed. The IC 50 value ranges are indicated in Table 1 as follows: A (IC 50 <100 nM), B (100 nM <IC 50 <1,000 nM), C (IC 50 > 1,000 nM).
[표 1] BTK, BMX 및 JAK3 키나아제 저해 활성 (IC50)TABLE 1 BTK, BMX and JAK3 Kinase Inhibitory Activity (IC 50 )
Figure PCTKR2018001139-appb-I000020
Figure PCTKR2018001139-appb-I000020
상기 표 1에서 볼 수 있듯이, 본 발명의 화합물들이 BTK, BMX 및 JAK3 키나아제를 매우 우수한 활성으로 억제함을 확인할 수 있었다.As shown in Table 1, it was confirmed that the compounds of the present invention inhibit the BTK, BMX and JAK3 kinase with very good activity.
실험예 2: CIA(collagen-induced arthritis) 마우스 모델 시험Experimental Example 2: CIA (collagen-induced arthritis) mouse model test
콜라겐 주입을 통한 류마티스 관절염모델을 이용하여 시험물질의 관절염 개선효능을 탐색하고자 콜라겐-유도 관절염(collagen-induced arthritis, CIA) 모델을 제작하였다. 2 mg/ml의 소의 2형 콜라겐(collagen)과 4 mg/ml의 CFA(Freund's complete adjuvant)를 혼합하여 에멀젼화(emulsion)한 후, 이 용액을 6주령 수컷 DBA/1J 마우스의 꼬리 기저에서 2 cm 가량 되는 부위에 피내 주사하여 1차 면역을 유도하였다. 1차 면역 후 21일째에 소의 2형 콜라겐을 IFA(Freund's incomplete adjuvant)와 혼합하여 상기와 동일한 방법으로 에멀젼화 한 후, 꼬리 부위에 피내 주사하여 2차 면역(boosting) 반응을 유도하였으며, 2차 면역 반응 유도 10일 후 clinical score의 평균값(score index)을 기준으로 6 마리씩 5 그룹으로 군분리 하였다. 각 군은 (1) 질환 유도군 (2) 실시예 3 (10 mg/kg, QD), (3) 실시예 3 (30 mg/kg, QD), (4) 덱사메타손(dexamethasone) (0.05mg/kg, QD), (5) 실시예 3 (30 mg/kg, BID)의 조건으로 2주간 매일 경구 투여하였고, 투여기간 동안 매일 일반증상을 관찰하였으며, 주 2회씩 index score를 측정하여 그 결과를 도 1에 나타내었다.A collagen-induced arthritis (CIA) model was constructed to explore the efficacy of improving the arthritis of a test substance using a rheumatoid arthritis model through collagen injection. After emulsion of 2 mg / ml bovine type 2 collagen and 4 mg / ml Freund's complete adjuvant (CFA), the solution was added to the base of the tail of 6-week-old male DBA / 1J mice. Primary immunity was induced by intradermal injection into the site of about cm. On day 21 after the first immunization, bovine type 2 collagen was mixed with IFA (Freund's incomplete adjuvant) and emulsified in the same manner as above, followed by intradermal injection into the tail to induce a second immune response. Ten days after the induction of the immune response, the animals were divided into 5 groups of 6 animals based on the score of the clinical score. Each group was (1) disease induction group (2) Example 3 (10 mg / kg, QD), (3) Example 3 (30 mg / kg, QD), (4) dexamethasone (0.05 mg / kg, QD), (5) Example 3 (30 mg / kg, BID) was administered orally every day for two weeks, the general symptoms were observed every day during the administration period, the index score was measured twice a week to measure the results 1 is shown.

Claims (10)

  1. 하기 화학식 1의 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체:A compound of Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2018001139-appb-I000021
    Figure PCTKR2018001139-appb-I000021
    상기 식에서,Where
    X는 직접결합, O, NH, C(=O) 또는 헤테로사이클로알킬이고;X is a direct bond, O, NH, C (═O) or heterocycloalkyl;
    Y는 알콕시알킬, 헤테로사이클로알킬 또는 헤테로사이클로알킬알킬이며;Y is alkoxyalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    W는 O 또는 NH이고;W is O or NH;
    Z는
    Figure PCTKR2018001139-appb-I000022
    또는
    Figure PCTKR2018001139-appb-I000023
    이며;    Z is
    Figure PCTKR2018001139-appb-I000022
    or
    Figure PCTKR2018001139-appb-I000023
    Is;
    R1은 수소, 알콕시 또는 할로겐이고;R 1 is hydrogen, alkoxy or halogen;
    R2는 수소 또는 다이알킬아미노알킬이다.R 2 is hydrogen or dialkylaminoalkyl.
  2. 제1항에 있어서, X가 직접결합, O, NH, C(=O), 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로사이클로알킬인 것을 특징으로 하는 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체.The method of claim 1, wherein X is a 5- to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from direct bonds, O, NH, C (= O), or N, O and S Compounds, pharmaceutically acceptable salts or stereoisomers thereof.
  3. 제2항에 있어서, X가 직접결합, O, NH, C(=O), 또는 1 또는 2개의 N 원자를 갖는 5 또는 6원 헤테로사이클로알킬인 것을 특징으로 하는 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체.3. A compound according to claim 2, wherein X is a direct bond, O, NH, C (═O), or a 5 or 6 membered heterocycloalkyl having 1 or 2 N atoms, pharmaceutically acceptable Salts or stereoisomers.
  4. 제1항에 있어서, Y가 C1-C6-알콕시-C1-C6-알킬, 5 내지 10원 헤테로사이클로알킬 또는 5 내지 10원 헤테로사이클로알킬-C1-C6-알킬이고, 여기에서 헤테로사이클로알킬은 N, O, S, Si 및 P로부터 선택되는 1 내지 4개의 헤테로원자를 갖고, 비치환되거나 C1-C6-알킬, 옥소, C1-C6-알킬카보닐, 아미노카보닐, 할로겐, C1-C6-알콕시-C1-C6-알킬 및 다이(C1-C6-알킬)아미노-C1-C6-알킬카보닐로 이루어지는 그룹으로부터 선택되는 하나 이상의 치환기로 치환되는 모노사이클릭 또는 바이사이클릭 화합물인 것을 특징으로 하는 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체.The compound of claim 1, wherein Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl-C 1 -C 6 -alkyl, wherein Heterocycloalkyl at has 1 to 4 heteroatoms selected from N, O, S, Si and P and is unsubstituted or C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkylcarbonyl, amino At least one selected from the group consisting of carbonyl, halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl A compound, a pharmaceutically acceptable salt or stereoisomer thereof, which is a monocyclic or bicyclic compound substituted with a substituent.
  5. 제4항에 있어서, Y가 C1-C6-알콕시-C1-C6-알킬, 5 내지 10원 헤테로사이클로알킬, 또는 5 또는 6원 헤테로사이클로알킬-C1-C6-알킬이고, 여기에서 헤테로사이클로알킬은 N, O, S, Si 및 P로부터 선택되는 1 내지 3개의 헤테로원자를 갖고, 비치환되거나 C1-C6-알킬, 옥소, C1-C6-알킬카보닐, 아미노카보닐, 할로겐, C1-C6-알콕시-C1-C6-알킬 및 다이(C1-C6-알킬)아미노-C1-C6-알킬카보닐로 이루어지는 그룹으로부터 선택되는 1 내지 3개의 치환기로 치환되는 모노사이클릭 또는 바이사이클릭 화합물인 것을 특징으로 하는 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체.The compound of claim 4, wherein Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5 to 10 membered heterocycloalkyl, or 5 or 6 membered heterocycloalkyl-C 1 -C 6 -alkyl, Wherein heterocycloalkyl has 1 to 3 heteroatoms selected from N, O, S, Si and P and is unsubstituted or C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkylcarbonyl, 1 selected from the group consisting of aminocarbonyl, halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl A compound, a pharmaceutically acceptable salt or stereoisomer thereof, which is a monocyclic or bicyclic compound substituted with from 3 to 3 substituents.
  6. 제1항에 있어서, R1은 수소, C1-C6-알콕시 또는 할로겐이고; R2는 수소 또는 다이(C1-C6-알킬)아미노-C1-C6-알킬인 것을 특징으로 하는 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체.The compound of claim 1, wherein R 1 is hydrogen, C 1 -C 6 -alkoxy or halogen; R 2 is hydrogen or di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkyl, a pharmaceutically acceptable salt or stereoisomer thereof.
  7. 제1항에 있어서, 다음의 화합물들로 이루어진 그룹으로부터 선택되는 것을 특징으로 하는 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체:The compound according to claim 1, wherein the compound is selected from the group consisting of the following compounds, pharmaceutically acceptable salts or stereoisomers thereof:
    N-(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3, 2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
    (R)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; (R) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    (S)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; (S) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyridine Midin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2- (4,4-dimethyl-1,4-azasilane-1-yl) ethoxy) phenyl) amino) -6,7-dihydrocysi Eno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((3-플루오로-4-몰포리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((3-fluoro-4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) Phenyl) acrylamide;
    N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)에탄설폰아마이드; N- (3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) ethanesulfonamide;
    N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)아크릴아마이드; N- (3-((2-((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- One) amino) phenyl) acrylamide;
    N-(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7-dihydrocyeno [ 3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyridine Midin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2-methoxyethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
    N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4 -Yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine-4- Yl) oxy) phenyl) acrylamide;
    (S)-1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드; (S) -1- (4-((4- (3-acrylamidophenoxy) -6,7-dihydrocyeno [3,2- d ] pyrimidin-2-yl) amino) phenyl) Pyrrolidine-2-carboxamide;
    N-(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2-acetyl-2,7-diazaspiro [3.5] nonane-7-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4-morpholinophenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide ;
    N-(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (piperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) Oxy) phenyl) acrylamide;
    N-(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidine -4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (2-morpholinoethoxy) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
    N-(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4- (2- (dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydrocyeno [3, 2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
    N-(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]미리미딘-4-일)옥시)페닐)아크릴아마이드; N- (3-((2-((4- (4-methylpiperazin-1-carbonyl) phenyl) amino) -6,7-dihydrocyeno [3,2- d ] myrimidine-4 -Yl) oxy) phenyl) acrylamide;
    (E)-4-(다이메틸아미노)-N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드; 및 (E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) 5,6-dihydro-Im in the furnace [2,3- d ] pyrimidin-4-yl) oxy) phenyl) but-2-enamide; And
    (E)-4-(다이메틸아미노)-N-(3-((2-((4-몰폴리노페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드. (E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- morpholinophenyl) amino) -5,6-dihydro furnace to Im [2,3- d] pyrimidin Midin-4-yl) oxy) phenyl) but-2-enamide.
  8. 유효성분으로서 치료학적 유효량의 제1항에 따른 화학식 1의 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체, 및 약제학적으로 허용되는 담체를 포함하는, 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물.A pharmaceutical agent for the prophylaxis or treatment of cancer or immune-related diseases, comprising as an active ingredient a therapeutically effective amount of a compound of formula 1 according to claim 1, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier Pharmaceutical composition.
  9. 제8항에 있어서, 상기 암이 B-세포 림프종, 췌장암, 전립선암, 대장암 및 위암으로 이루어진 그룹으로부터 선택되는 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 8, wherein the cancer is selected from the group consisting of B-cell lymphoma, pancreatic cancer, prostate cancer, colon cancer and gastric cancer.
  10. 제8항에 있어서, 상기 면역 관련 질환이 류마티스 관절염, 쇼그렌 증후군, 건선, 전신 홍반 루푸스, 아토피, 천식 및 다발성 경화증으로 이루어진 그룹으로부터 선택되는 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 8, wherein the immune related disease is selected from the group consisting of rheumatoid arthritis, Sjogren's syndrome, psoriasis, systemic lupus erythematosus, atopy, asthma and multiple sclerosis.
PCT/KR2018/001139 2017-01-26 2018-01-25 Fused pyrimidine derivative as multi-target kinase inhibitor WO2018139883A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20170012916 2017-01-26
KR10-2017-0012916 2017-01-26

Publications (1)

Publication Number Publication Date
WO2018139883A1 true WO2018139883A1 (en) 2018-08-02

Family

ID=62979602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/001139 WO2018139883A1 (en) 2017-01-26 2018-01-25 Fused pyrimidine derivative as multi-target kinase inhibitor

Country Status (2)

Country Link
KR (1) KR20180088318A (en)
WO (1) WO2018139883A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111732597A (en) * 2020-06-20 2020-10-02 江西科技师范大学 Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220099825A (en) * 2021-01-07 2022-07-14 주식회사 온코빅스 Compounds for inhibiting Bruton's tyrosine kinase and medical uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129053A2 (en) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Egfr inhibitors and methods of treating disorders
WO2011079231A1 (en) * 2009-12-23 2011-06-30 Gatekeeper Pharmaceutical, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith
KR20110139653A (en) * 2010-06-23 2011-12-29 한미홀딩스 주식회사 Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
KR20150001967A (en) * 2013-06-28 2015-01-07 한국과학기술연구원 Inhibitory activity of thieno[3,2-d]pyrimidine derivatives on T315I-Bcr-Abl point mutation
KR20150113195A (en) * 2013-03-05 2015-10-07 에프. 호프만-라 로슈 아게 Inhibitors of bruton's tyrosine kinase
KR20160037929A (en) * 2013-07-11 2016-04-06 에이시아 바이오사이언시스 인코포레이티드. Heterocyclic compounds and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129053A2 (en) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Egfr inhibitors and methods of treating disorders
WO2011079231A1 (en) * 2009-12-23 2011-06-30 Gatekeeper Pharmaceutical, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith
KR20110139653A (en) * 2010-06-23 2011-12-29 한미홀딩스 주식회사 Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
KR20150113195A (en) * 2013-03-05 2015-10-07 에프. 호프만-라 로슈 아게 Inhibitors of bruton's tyrosine kinase
KR20150001967A (en) * 2013-06-28 2015-01-07 한국과학기술연구원 Inhibitory activity of thieno[3,2-d]pyrimidine derivatives on T315I-Bcr-Abl point mutation
KR20160037929A (en) * 2013-07-11 2016-04-06 에이시아 바이오사이언시스 인코포레이티드. Heterocyclic compounds and uses thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111732597A (en) * 2020-06-20 2020-10-02 江西科技师范大学 Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy
CN111732597B (en) * 2020-06-20 2022-11-01 江西科技师范大学 Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy

Also Published As

Publication number Publication date
KR20180088318A (en) 2018-08-03

Similar Documents

Publication Publication Date Title
WO2019190259A1 (en) Novel sulfonamide derivative having inhibitory effect on epidermal growth factor receptor mutation
WO2017026718A1 (en) Novel 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine compound, which is ret kinase inhibitor
WO2021080359A1 (en) Bicyclic compound and use thereof
WO2017142325A1 (en) Novel 2,3,5-substituted thiophene compound as protein kinase inhibitor
WO2012115478A2 (en) Diaminopyrimidine derivatives and processes for the preparation thereof
AU2012221925A1 (en) Diaminopyrimidine derivatives and processes for the preparation thereof
WO2014109530A1 (en) 2-(phenylethynyl)thieno[3,4-b]pyrazine derivative and pharmaceutical composition comprising same for preventing or treating cancer
WO2022010150A1 (en) Novel tnf activity inhibitor compound, and pharmaceutically acceptable salt thereof
WO2016032209A2 (en) Substituted n-(pyrrolidine-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine as janus kinase inhibitor
WO2022139304A1 (en) Novel quinazoline derivative compound as sos1 inhibitor, and use thereof
AU2017256488B2 (en) Quinazoline derivative or its salt and pharmaceutical composition comprising the same
WO2019074241A1 (en) Inhibitor against interaction between pd-1 and pd-l1, comprising phenylacetylene derivative
WO2020242204A1 (en) Jak inhibitor compound and pharmaceutical composition containing same
WO2018139883A1 (en) Fused pyrimidine derivative as multi-target kinase inhibitor
WO2017034245A1 (en) Janus kinase 1 selective inhibitor and pharmaceutical use thereof
AU2020360000A1 (en) N-(1H-imidazol-2-yl)benzamide compound and pharmaceutical composition comprising the same as active ingredient
WO2021096112A1 (en) Pyrrolopyrimidine, pyrrolopyridine and indazole compound derivative, and therapeutic pharmaceutical composition containing same
WO2017131425A1 (en) Novel imidazole derivative having jnk inhibitory activity 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
WO2021040422A1 (en) Novel pyrimido[4,5-d]pyrimidine-2-one derivative having protein kinase inhibitory activity
WO2019198940A1 (en) Excellent kinase inhibitory activity-exhibiting pyrimidine derivative having various substituents
WO2021182914A1 (en) Novel cdk7 inhibitory compound or pharmaceutically acceptable salt thereof
WO2019235894A1 (en) Composition for preventing or treating solid cancer comprising compound inhibiting binding of aimp2-dx2 and k-ras and novel compound inhibiting binding of aimp2-dx2 and k-ras
WO2023096304A1 (en) Isoxazole derivative or pharmaceutically acceptable salt thereof and use thereof
WO2021080346A1 (en) Novel pyridinyltriazine derivative having protein kinase inhibitory activity, and pharmaceutical composition for preventing, ameliorating, or treating cancer comprising same

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: 18744374

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18744374

Country of ref document: EP

Kind code of ref document: A1