WO2018139883A1 - Dérivé de pyrimidine condensé à titre d'inhibiteur de kinase multi-cible - Google Patents

Dérivé de pyrimidine condensé à titre d'inhibiteur de kinase multi-cible Download PDF

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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
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phenyl
amino
oxy
acrylamide
dihydrocyeno
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Korean (ko)
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이준
이영훈
박병선
유희원
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부광약품 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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.

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Abstract

L'invention concerne : un composé de formule chimique 1 ; un sel ou stéréoisomère de celui-ci pharmaceutiquement acceptable ; et une composition pharmaceutique le contenant. Le composé de formule chimique 1 ou le sel ou stéréoisomère de celui-ci pharmaceutiquement acceptable agit à titre d'inhibiteur de kinase multi-cible, et peut par conséquent être utilisé dans la prévention ou le traitement des cancers ou des maladies liées au système immunitaire telles que la polyarthrite rhumatoïde, le syndrome de Sjögren, le psoriasis, le lupus érythémateux disséminé, l'atopie, l'asthme et la sclérose en plaques.
PCT/KR2018/001139 2017-01-26 2018-01-25 Dérivé de pyrimidine condensé à titre d'inhibiteur de kinase multi-cible WO2018139883A1 (fr)

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CN111732597A (zh) * 2020-06-20 2020-10-02 江西科技师范大学 含4-酰胺苯氧基的2-氨基嘧啶杂环类化合物的制备及应用

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KR20220099825A (ko) * 2021-01-07 2022-07-14 주식회사 온코빅스 브루톤 타이로신 키나제 억제용 화합물 및 이들의 의약 용도

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WO2011079231A1 (fr) * 2009-12-23 2011-06-30 Gatekeeper Pharmaceutical, Inc. Composés qui modulent l'activité egfr et des procédés pour traiter ou prévenir des affections avec ceux-ci
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KR20150001967A (ko) * 2013-06-28 2015-01-07 한국과학기술연구원 티에노[3,2-ｄ]피리미딘 유도체의 Ｔ315Ｉ-Ｂｃｒ-Ａｂｌ 점돌연변이종의 저해 활성
KR20150113195A (ko) * 2013-03-05 2015-10-07 에프. 호프만-라 로슈 아게 브루톤 티로신 키나아제의 억제제
KR20160037929A (ko) * 2013-07-11 2016-04-06 에이시아 바이오사이언시스 인코포레이티드. 키나아제 억제제로써의 피리미딘 유도체

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WO2010129053A2 (fr) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Inhibiteurs d'egfr et procédés de traitement de troubles
WO2011079231A1 (fr) * 2009-12-23 2011-06-30 Gatekeeper Pharmaceutical, Inc. Composés qui modulent l'activité egfr et des procédés pour traiter ou prévenir des affections avec ceux-ci
KR20110139653A (ko) * 2010-06-23 2011-12-29 한미홀딩스 주식회사 타이로신 카이네이즈 활성 억제 효과를 갖는 신규 융합 피리미딘 유도체
KR20150113195A (ko) * 2013-03-05 2015-10-07 에프. 호프만-라 로슈 아게 브루톤 티로신 키나아제의 억제제
KR20150001967A (ko) * 2013-06-28 2015-01-07 한국과학기술연구원 티에노[3,2-ｄ]피리미딘 유도체의 Ｔ315Ｉ-Ｂｃｒ-Ａｂｌ 점돌연변이종의 저해 활성
KR20160037929A (ko) * 2013-07-11 2016-04-06 에이시아 바이오사이언시스 인코포레이티드. 키나아제 억제제로써의 피리미딘 유도체

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111732597A (zh) * 2020-06-20 2020-10-02 江西科技师范大学 含4-酰胺苯氧基的2-氨基嘧啶杂环类化合物的制备及应用
CN111732597B (zh) * 2020-06-20 2022-11-01 江西科技师范大学 含4-酰胺苯氧基的2-氨基嘧啶杂环类化合物的制备及应用

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