WO2009126003A9 - Nouveaux dérivés de pyridine à substitution pyrazole et benzoxazole ou leurs sels pharmaceutiquement acceptables, leur procédé de préparation, et composition pharmaceutique contenant ces dérivés/sels en tant que principes actifs pour prévenir et traiter des troubles impliquant une prolifération cellulaire aberrante - Google Patents

Nouveaux dérivés de pyridine à substitution pyrazole et benzoxazole ou leurs sels pharmaceutiquement acceptables, leur procédé de préparation, et composition pharmaceutique contenant ces dérivés/sels en tant que principes actifs pour prévenir et traiter des troubles impliquant une prolifération cellulaire aberrante Download PDF

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WO2009126003A9
WO2009126003A9 PCT/KR2009/001866 KR2009001866W WO2009126003A9 WO 2009126003 A9 WO2009126003 A9 WO 2009126003A9 KR 2009001866 W KR2009001866 W KR 2009001866W WO 2009126003 A9 WO2009126003 A9 WO 2009126003A9
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Prior art keywords
pyrazol
pyridin
formula
piperidin
amine
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PCT/KR2009/001866
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English (en)
Korean (ko)
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WO2009126003A2 (fr
WO2009126003A3 (fr
Inventor
고종성
이종국
조성윤
한선영
이정옥
류재욱
박경찬
한동초
하재두
박성규
정희정
권병목
유경호
심태보
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한국화학연구원
한국생명공학연구원
한국과학기술연구원
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Publication of WO2009126003A2 publication Critical patent/WO2009126003A2/fr
Publication of WO2009126003A9 publication Critical patent/WO2009126003A9/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the present invention relates to novel pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions for preventing and treating aberrant cell growth diseases containing the same as an active ingredient.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • the protein kinases play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation, and thus the activity of protein kinases affects almost all aspects of cell life.
  • Protein kinases can be classified into tyrosine kinases (TK) and serine-threonine kinases (STK).
  • TK tyrosine kinases
  • STK serine-threonine kinases
  • tyrosine kinases are cell surface proteins that, when bound to growth factor ligands, convert the growth factor receptors into active form and interact with proteins on the inner surface of the cell membrane, causing phosphorylation on tyrosine residues of these receptors and other proteins.
  • growth factor receptors are cell surface proteins that, when bound to growth factor ligands, convert the growth factor receptors into active form and interact with proteins on the inner surface of the cell membrane, causing phosphorylation on tyrosine residues of these receptors and other proteins.
  • complexes with various cytoplasmic signaling molecules are formed inside cells, resulting in numerous cellular reactions such as cell growth, differentiation and proliferation, and expression of metabolic effects on extracellular microenvironments (Schleessinger and Ullrich, Neuron. 1992 9, 303-391).
  • RTK receptor tyrosine kinase
  • Subtype receptor tyrosine kinases such as those previously termed 19 or more "HER RTKs" are known, and such HER RTKs include epidermal growth factor receptors (EGFR), HER2, HER3, HER4 and the like.
  • the receptor tyrosine kinase consists of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic domain capable of phosphorylating tyrosine residues on proteins.
  • the receptor tyrosine kinase subfamily also consists of insulin receptor (IR), insulin like growth I receptor (IGF-1R) and insulin receptor related receptor (IRR).
  • IR and IGF-IR interact with insulin, IGF-I and IGF-II, resulting in heterologous doses of two ⁇ subunits and two completely extracellular glycosylated ⁇ subunits that cross the cell membrane and contain a kinase domain Forms a heterotetramer.
  • the receptor tyrosine kinase subfamily includes PDGFR ⁇ , PDGFR ⁇ , CSFIR, c-Kit and c-Fms, which are termed platelet induced growth factor receptors (PDGFR).
  • PDGFR platelet induced growth factor receptors
  • the receptor consists of a glycosylated extracellular domain consisting of a variable immunoglobulin-like loop and an intracellular domain. Due to its similarity to the PDGFR subfamily, fetal liver kinase (Flk) receptor subfamily belonging to the PDGFR group is known.
  • the Flk subfamily is a kinase insert domain-receptor fetal liver kinase-1 (KDR / Flk-1), Flk-1R, Flk-1, Fms-like tyrosine kinase 1 or 3 (Flt-1 or Flt-3) and the like. Is done.
  • MET As a family of tyrosine kinase growth factor receptors, MET is named c-Met and is believed to play a role in primary tumor growth and metastasis as human hepatocyte growth factor receptor tyrosine kinase (hHGFR) (Plowman et al., DN & P, 1994, 7, 6, 334-339).
  • hHGFR human hepatocyte growth factor receptor tyrosine kinase
  • nonreceptor tyrosine kinases In addition to receptor tyrosine kinases, there is a specific family of complete intracellular TKs called nonreceptor tyrosine kinases or cellular tyrosine kinases (CTKs).
  • CTKs cellular tyrosine kinases
  • the non-receptor tyrosine kinase contains no extracellular and transmembrane domains and consists of the Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak and Ack subfamily.
  • Src subfamily includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1 (Aurora-B), AUR2 (Aurora-A), AUR3 (Aurora-C), Yrk, etc. (Bolen, Oncogene. 1993, 8, 2025-2031).
  • Pathogenic diseases associated with receptor tyrosine kinases and non-receptor tyrosine kinases include psoriasis, cirrhosis, diabetes, angiogenesis, recurrent stenosis, ophthalmic diseases, rheumatoid arthritis, autoimmune diseases, atherosclerosis, kidney disorders and the like.
  • receptor tyrosine kinases such as Bcr-Abl, EGFR, and VEGFR have been studied as a good anticancer target, and anticancer agents such as Gleevec and Iresa have been developed and marketed.
  • HGFR Hepatocyte Growth Factor Receptor
  • HGF / SF hepatocyte growth factor / scatter factor
  • c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69).
  • c-MET and its ligand, HGF are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively.
  • HGF / SF is an angiogenesis factor and c-MET signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.
  • c-Met and its ligand, HGF are co-expressed at increased levels in various human cancers.
  • receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.
  • c-Met and / or HGF / SF are associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.)
  • Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast.
  • c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-1043).
  • HGF / SF binds to the extracellular domain of c-Met to activate c-Met, and activation of c-Met is tyrosine phosphorylation and downstream via Gab1 and Grb2-mediated PI3-kinase and Ras / MAPK activation, respectively. Signaling to induce cell motility and proliferation.
  • c-Met has been shown to interact with other proteins leading to receptor activation, transformation and invasion, and c-Met also has an extracellular matrix (ECM) such as ⁇ 6 ⁇ 4 integrin (laminin) that forms focal adhesion.
  • ECM extracellular matrix
  • laminin ⁇ 6 ⁇ 4 integrin
  • the inventors of the present invention while studying the development of protein kinase inhibitors, pyridine derivatives substituted with pyrazole and benzoxazole having excellent inhibitory activity against protein kinase, c-Met, useful for the treatment of abnormal cell growth, Inhibits protein kinases such as Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc., and therefore can be usefully used for the prevention and treatment of abnormal cell growth diseases. It was found and completed the present invention.
  • Another object of the present invention is to provide a method for preparing novel pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing and treating aberrant cell growth disease, which contains a novel pyrazole and benzoxazole substituted pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a novel pyrazole and benzoxazole-substituted pyridine derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical for preventing and treating aberrant cell growth disease containing the same as an active ingredient. To provide a composition.
  • the pyridine derivatives or pharmaceutically acceptable salts thereof substituted with the novel pyrazoles and benzoxazoles according to the present invention exhibit excellent inhibitory activity against protein kinases, which are useful for the treatment of aberrant cell growth diseases, for example It has excellent inhibitory effect on c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc., and thus can be usefully used for the prevention and treatment of abnormal cell growth diseases. .
  • Figure 1 is a schematic diagram showing the active c-Met and luciferase (Luciferase) expression vector according to the present invention.
  • the present invention provides a pyridine derivative or a pharmaceutically acceptable salt thereof substituted with pyrazole and benzoxazole represented by the following formula (1).
  • R 1 is hydrogen or NHR 4 , wherein R 4 is hydrogen, C 1 -C 4 straight or branched chain alkyl or benzyl;
  • R 2 is hydrogen, halogen, C 1 -C 4 straight or branched chain alkyl, -NHR 5 , -NR 6 R 7 , OR 5 , -CN, -NHC (O) R 6 , -SO 2 R 6 , -OS (O) any one selected from 2 R 6 , pyrrolidine, piperidine and morpholine, substituted in positions 5 or 6 of the benzoxazole ring or in positions 5 and 6 of the benzoxazole ring C 6 -C 12 aryl, wherein R 5 is hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 4 straight or branched chain alkynyl, C 1 -C 4 straight chain or branched chain alkenyl, aryl of C 6 a C 6 -C 12 aryl substituted with halogen or tri-methyl substituted with a C 6 -C 12 aryl, halogen, -C 12, wherein R 6 is a C
  • R 3 is hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-piperidine;
  • A is carbon or nitrogen.
  • R 1 is hydrogen or —NHR 4 , wherein R 4 is hydrogen, methyl or benzyl;
  • R 2 is hydrogen, fluorine, chlorine, methyl, -CN, -NHR 5 , -NR 6 R 7 , OR 5 , -CN, -NHC (O) R 6 , -SO 2 R 6 , -OS (O) 2 R 6 , pyrrolidine, piperidine and morpholine, either substituted at position 5 or 6 of the benzoxazole ring or conjugated at positions 5 and 6 of the benzoxazole ring Benzene, where R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, phenyl, 4-fluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl or 3,5- Ditrifluoromethyl, R 6 is methyl or ethyl, R 7 is methyl or phenyl;
  • R 3 is hydrogen, methyl or 4-piperidine
  • A is carbon or nitrogen.
  • the pyridine derivatives substituted with pyrazole and benzoxazole represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid moiety formed by a pharmaceutically acceptable free acid. Salting is useful.
  • the expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient and that any side effects due to the salt do not degrade the beneficial efficacy of the base compound of formula 1, or Means inorganic addition salts.
  • These salts may include inorganic acids and organic acids as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine as organic acids.
  • Acids gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galluxuronic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, methanesulfonic acid, ethanesulfonic acid, 4 Toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid and the like can be used.
  • These salts also include alkali metal salts (sodium salts, potassium salts, and the like), alkaline earth metal salts (calcium salts, magnesium salts, and the like) and the like.
  • acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, edisylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, cit
  • pyridine derivatives substituted with pyrazole and benzoxazole represented by Formula 1 of the present invention include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods. do.
  • the addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
  • a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • the present invention provides a method for preparing a pyridine derivative or a pharmaceutically acceptable salt thereof substituted with pyrazole and benzoxazole represented by the formula (1).
  • the compound of Formula 1 according to the present invention may be prepared by the method as shown in Schemes 1-6.
  • Step 1 Preparing a compound of Chemical Formula 3 by bromination of a compound of Chemical Formula 2 as a starting material
  • Step 5 Preparing a compound of Chemical Formula 8 by performing a substitution reaction between the compound of Chemical Formula 7 and an amine compound (R 4 NH 2 ) prepared in Step 4 (Step 5);
  • Step 6 Preparing a compound of Formula 10 by performing a Suzuki coupling reaction between the compound of Formula 8 and the compound of Formula 9 prepared in Step 5 (Step 6); And
  • It may be prepared by a manufacturing method comprising the step (step 7) of preparing a compound of Formula 1a by the deprotection reaction of the compound of Formula 10 prepared in step 6.
  • R 2 , R 4 and A are as defined in formula 1, R 4 ′ is hydrogen or R 4 , n is an integer of 1-3, formula 1a is a derivative of formula 1 or a pharmaceutically acceptable salt thereof , NBS: N-bromosuccinimide, NaOBr: sodium hypobromide PPTS: paratoluenesulfonic acid-pyridine salt, Pd (dppf) Cl 2 : 1,1′-bis (diphenylphosphino) ferrocenedichloro palladium, Pd (Ph 3 P) 2 Cl 2 : bistriphenylphosphinedichloropalladium, TFA: trifluoroacetic acid, Boc: tert-butoxycarbonyl)
  • Deprotection of the compound of Chemical Formula 12 prepared in Step 1 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1b (Step 2).
  • R 4 , R 6 and R 7 are as defined in Formula 1, R 8 is -NHR 4 or -NR 6 R 7 , n is an integer of 1-3, Formula 1b is a derivative of Formula 1 or a pharmaceutical thereof Is an acceptable salt)
  • Deprotection of the compound of Chemical Formula 13 prepared in Step 1 may be prepared by a preparation method comprising the step of preparing a compound of Chemical Formula 1d (Step 4).
  • R 5 and R 6 are as defined in Formula 1, X is halogen, n is an integer of 1-3, R 9 is -R 5 or -SO 2 R 6 , Formula 1c and 1d are derivatives of Formula 1 Or a pharmaceutically acceptable salt thereof)
  • Step 2 It may be prepared by a manufacturing method comprising the step (step 2) of preparing a compound of Formula 1e by deprotection reaction of the compound of Formula 16 prepared in Step 1.
  • R 2 , R 3 , R 4 and A are as defined in formula 1, R 4 ′ is hydrogen or R 4 , n is an integer of 1-3, formula 1e is a derivative of formula 1 or a pharmaceutically acceptable thereof Possible salts, A is carbon or nitrogen)
  • Step 1 Preparing a compound of Chemical Formula 18 by chlorination of a compound of Chemical Formula 17 as a starting material
  • Step 2 Preparing a compound of Formula 19 by performing a substitution reaction of the compound of Formula 18 and the compound of Formula 5 prepared in Step 1 (step 2);
  • step 3 Preparing a compound of formula 20 by cyclization of the compound of formula 19 prepared in step 2 (step 3);
  • Step 4 Preparing a compound of Formula 21 by performing a Suzuki coupling reaction between the compound of Formula 20 and the compound of Formula 9 prepared in Step 3 (Step 4); And
  • Deprotection of the compound of Chemical Formula 21 prepared in Step 4 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1f (Step 5).
  • R 2 and A are as defined in Formula 1, n is an integer of 1-3 and Formula 1f is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof)
  • the compound of Formula 22 and the compound of Formula 15 may be prepared by a preparation method comprising the step of preparing a compound of Formula 1g by performing a Suzuki coupling reaction.
  • R 2 , R 3 and A are as defined in Formula 1, where Formula 1g is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof)
  • the present invention also provides a pharmaceutical composition for the prevention and treatment of aberrant cell growth diseases containing a pyridine derivative substituted with pyrazole and benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • the abnormal cell growth disease is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrium Cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, Bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, and the like are preferred.
  • CNS central nervous system
  • the abnormal cell growth disease is preferably psoriasis, benign prostatic hypertrophy or retinopathy.
  • the abnormal cell growth disease is preferably a benign proliferative disease
  • the benign proliferative disease is preferably fibroadenoma, sclerotic gland disease, papilloma and the like.
  • Pyridine derivatives substituted with pyrazole and benzoxazole represented by Formula 1 or pharmaceutically acceptable salts, solvates and hydrates thereof are c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, protein kinases such as b-Raf and Aurora-A can be inhibited.
  • c-Met is a hepatocyte growth factor (HGF / SF) receptor that is being studied as an anticancer agent, and many anticancer agents targeting it have been reported (JG Christensen, J. Burrows et al., Cancer Letters, 2005). , 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).
  • HGF / SF hepatocyte growth factor
  • c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69).
  • c-MET and its ligand, HGF are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively.
  • HGF / SF is an angiogenesis factor and c-MET signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.
  • c-Met and its ligand, HGF are co-expressed at increased levels in various human cancers.
  • receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.
  • c-Met has been observed in various human cancers with gene amplification, mutations and rearrangements. Classes with germline mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues.
  • c-Met and / or HGF / SF are associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.)
  • Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast.
  • c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-043).
  • the derivative of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof showed the result that the IC 50 had a c-Met kinase inhibitory activity of 20 ⁇ M or less in the c-Met kinase activity experiment.
  • the derivative of Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof has GI 50 having a cancer cell proliferation inhibitory activity of 100 ⁇ M or less against HT-29, A549 and SK-MEL-28 in cancer cell proliferation experiments. The results are shown.
  • the pharmaceutical composition containing pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutical salts thereof according to the present invention as an active ingredient can be usefully used to treat various cancers described above derived from the expression of c-Met. have.
  • the compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.
  • Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.
  • Et means ethyl
  • Me means methyl
  • t -Bu means tert-butyl
  • Boc means tert-butoxycarbonyl
  • EtOAc means ethyl acetate
  • NEt 3 or “Et 3 N” means triethylamine
  • Et 2 O means diethyl ether
  • MeOH means methanol
  • DMSO means dimethylsulfoxide
  • CDCl 3 means deuterated chloroform
  • CH 2 Cl 2 means methylene chloride (carbon dichloride)
  • DF means dimethyl formamide
  • SOCl 2 means thionylchloride
  • MsCl means methanesulfonylchloride
  • PPTS means paratoluenesulfonic acid-pyridine salt
  • TFA means trifluoro Acetic acid
  • X-Phos means 2-dicyclohexyl
  • the target compound (5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid) was prepared by the method described in the reference. Obtained by reference (AD Cale, Jr., TW Gero et. Al. J. Med. Chem. 1989, 32, 2178-2199; US Pat. No. 5,034,531).
  • Step 3 Preparation of 5-bromo-2-chloro-N- (5-chloro-2-hydroxyphenyl) nicotinamide
  • 5-bromo-2-chloronicotinoyl chloride (22.7 g, 89.1 mmol) was immersed in a methylene chloride solution containing 2-amino-4-chlorophenol (14.5 g) and triethylamine (12.8 mL). was slowly added at 0 ° C. The temperature of the reaction was raised to room temperature and stirred for 2 hours under nitrogen atmosphere. The reaction was poured into water, stirred for 30 minutes, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The mixed organic layer was dried using anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Step 4 Preparation of 2- (5-bromo-2-chloropyridin-3-yl) -5-chlorobenz [d] oxazole
  • Step 5 Preparation of 5-bromo-N-tert-butyl-3- (5-chlorobenz [d] oxazol-2-yl) pyridin-2-amine
  • Step 6 tert-butyl 4- (4- (6- (tert-butylamino) -5- (5-chlorobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyra Preparation of zol-1-yl) piperidine-1-carboxylate
  • Step 7 3- (5-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Of ditrifluoroacetic acid salts of
  • Target compound (3- (benz [d] oxazol-2yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Ditrifluoroacetic acid salt) was obtained (38.8 mg, 65%).
  • Step 1 tert-butyl-4- (4- (6- (tert-butylamino) -5- (5- (propylamino) benz [d] oxazol-2-yl) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate
  • Step 2 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-propylbenz [d] oxazole Preparation of tritrifluoroacetic acid salt of -5-amine
  • Example 14 Except that dimethylamine was used instead of propylamine used in Example 14, the same procedure as in Step 1 and Step 2 of Example 14 was carried out to obtain the target compound as a solid (2- (2-amino-5- (1- (P Tridinfluoroyl) -1H-pyrazol-4-yl) pyridin-3-yl) -N, N-dimethylbenz [d] oxazol-5-amine) 92 mg, 76%).
  • a solid target compound (5- (1- (piperidin-4-yl) was prepared by the same method as Step 1 and Step 2 of Example 14, except that pyrrolidin was used instead of the propylamine used in Example 14.
  • pyrrolidin was used instead of the propylamine used in Example 14.
  • -1H-pyrazol-4-yl) -3- (tritriacetic acid salt of 5- (pyrrolidin-1-yl) benz [d] oxazol-2-yl) pyridin-2-amine) was obtained (4 mg, 59%).
  • a solid target compound (3- (5- (piperidin-1-yl) was prepared by the same method as Step 1 and Step 2 of Example 14, except that piperidine was used instead of propylamine.
  • Benz [d] oxazol-2yl) -5- (trifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) Obtained (14 mg, 49%).
  • Example 14 Except for using morpholine instead of propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (3- (5-morpholinobenz [d] oxazole -2-yl) -5- (trifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained (10 mg, 62 %).
  • Example 14 Except for using aniline in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (2- (2-amino-5- (1- (piperi) Ditrifluoroacetic acid salt of di-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-phenylbenz [d] oxazol-5-amine) (7 mg, 76%).
  • Example 14 Except for using N-methylaniline in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to give the target compound (2- (2-amino-5- (1- Tritrifluoroacetic acid salt of (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methyl-N-phenylbenz [d] oxazol-5-amine ) (61 mg, 47%).
  • Example 14 Except for using acetamide in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (N- (2- (2-amino-5- (1 Ditriacetic acid salt of-(piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-yl) acetamide) 13 mg, 90%).
  • the target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) as a solid was obtained.
  • Tripyridine-3-yl) -N-isopropylbenz [d] oxazol-6-amine tritrifluoroacetic acid salt was obtained (8 mg, 99%).
  • the target compound (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (6- Tritrifluoroacetic acid salt of (pyrrolidin-1-yl) benz [d] oxazol-2-yl) pyridin-2-amine) (15 mg, 23%).
  • Steps 1 to 6 of Example 1 except that 2-amino-5-chlorophenol and piperidine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14.
  • the target compound (3- (6- (piperidin-1-yl) benz [d] oxazol-2yl) -5- (1- Tritrifluoroacetic acid salt of (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained (16 mg, 30%).
  • the target compound (3- (6-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4) as a solid was carried out in the same manner as in Step 1 and Step 2 of Example 14.
  • Triylfluoroacetic acid salt of -yl) -1H-pyrazol-4-yl) pyridin-2-amine) (33 mg, 52%).
  • the desired compound as a solid was prepared in the same manner as in Steps 1 and 2 of 14 (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 3-triyl) -trifluoroacetic acid salt of N-phenylbenz [d] oxazol-6-amine) was obtained (46 mg, 65%).
  • Steps 1 to 6 of Example 1 except that 2-amino-5-chlorophenol and N-methylaniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 And the desired compound as a solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-4- in the same manner as in Step 1 and Step 2 of Example 14).
  • pyridin-3-yl) -trimethylacetic acid salt of N-methyl-N-phenylbenz [d] oxazol-6-amine was obtained (40 mg, 41%).
  • Steps 1 to 1 of Example 1 except that 2-amino-5-chlorophenol and 4-fluoroaniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 6 and the same procedure as in Step 1 and Step 2 of Example 14 to give the target compound of the solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-4 -Yl) pyridin-3-yl) -N- (4-fluorophenyl) benz [d] oxazol-6-amine) tritrifluoroacetic acid salt) (26 mg, 50%).
  • Example 14 The steps of Example 1, except that 2-amino-5-chlorophenol and 2,6-difluoroaniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. 1 to 6 and the same procedure as in Step 1 and Step 2 of Example 14 to give a solid target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyra) Zol-4-yl) pyridin-3-yl) -N- (2,6-difluorophenyl) benz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (18 mg, 23 %).
  • Example 14 The steps of Example 1, except that 2-amino-5-chlorophenol and 3,5-difluoroaniline were used in place of the 2-amino-4-chlorophenol used in Example 1 and the propylamine used in Example 14 1 to 6 and the same procedure as in Step 1 and Step 2 of Example 14 to give a solid target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyra) Zol-4-yl) pyridin-3-yl) -N- (3,5-difluorophenyl) benz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (56 mg, 73 %).
  • Example 2 except that 2-amino-5-chlorophenol and 2,4-dimethoxyphenylmethylamine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. Performing the same procedure as in Step 1 to Step 6 and Step 1 and Step 2 of Example 14 to give the target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-) as a solid Pyrazol-4-yl) pyridin-3-yl) -benz [d] oxazol-6-amine) tritrifluoroacetic acid salt) (8 mg, 95%).
  • Step 3 3- (5-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2- Preparation of Itrifluoroacetic Acid Salts of Amine
  • the target compound (3- (5-methoxybenz [d] oxazole-) was prepared by the same method as in Step 1 to Step 3 of Example 38, except that methyl iodine was used instead of ethyl iodine used in Example 38.
  • 2-yl) -5- (1-trifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained (15 mg, 81% ).
  • the desired compound (3- (6-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-) as a solid was carried out in the same manner as in the steps 1 to 3 of Example 38.
  • Steps 1 through 6 of Example 1 except that 2-amino-5-chlorophenol and methanesulfonylchloride were used instead of 2-amino-4-chlorophenol used in Example 1 and ethyl iodine used in Example 38 And the desired compound as a solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-4- in the same manner as in steps 1 to 3 of Example 38). 1) pyridin-3-yl) benz [ d ] ditrifluoroacetic acid salt of oxazol-6-yl methanesulfonate) was obtained (19 mg, 87%).
  • Step 4 was carried out in the same manner as in Step 1 of Example 38, and then Step 4 was performed.
  • Example 44 the same as in Example 1 Step 1 to Step 6 and Example 43, except that 2-amino-5-chlorophenol was used instead of the 2-amino-4-chlorophenol used in Example 1
  • the desired compound as a solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] Ditrifluoroacetic acid salt of oxazole-6-ol) (20 mg, 78%).
  • Step 1 Preparation of 3- (benz [d] oxazol-2yl) -N-tert-butyl-5- (1methyl-1H-pyrazol-4-yl) pyridin-2-amine
  • Step 2 Preparation of 3- (benz [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine
  • a solid target compound (3- (benz [d] oxazol-2yl) was prepared in the same manner as in Step 1 and Step 2 of Example 45, except that methylamine was used instead of t-butylamine used in Example 45. ) -N-methyl-5- (1methyl-1H-pyrazol-4-yl) pyridin-2-amine) was obtained (6 mg, 38%).
  • Example 45 The concentrate was subjected to tube chromatography in steps 1 to 5 of Example 1 and step 2 of Example 45, except that 2-amino-5-chlorophenol was used instead of 2-amino-4-chlorophenol used in Example 1.
  • a solid target compound (3- (6-chlorobenz [d] oxa) was prepared in the same manner as in Step 1 and Step 2 of Example 45, except that the solidification was performed using ethyl ether instead of the purification by chromatography.
  • DELFIA Dissociation Enhanced Lanthanide Fluoro Immuno Assay
  • TRF time-resolved fluorescence
  • Example 1 4, 5, 7, 9-45, and 47-50 (10 mL) were added to a Grainer 96-well V-type bottom plate, followed by addition of tyrosine kinase buffer (20 ⁇ L) mixed with c-Met enzyme. Enzyme and Example 1, 4, 5, 7, 9-45 and 47-50 mixtures were incubated for 15 minutes by mixing. ATP solution (10 ⁇ L) was added thereto, followed by kinase reaction at room temperature for 30 minutes, and then 50 mM ethylenediaminetetraacetic acid solution (EDTA, 40 ⁇ L) was added to stop the reaction. The reactions were transferred to streptavidin-coated plates, incubated under shaking and washed three times with PBS-T buffer (PBS 0.05% Tween20) after 2 hours.
  • PBS-T buffer PBS 0.05% Tween20
  • Europium-containing anti-phosphotyrosine antibody was diluted 1: 2,500, added 100 ml per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% Tween20).
  • Enhancement solution (100 mL) was added and shaken for 5 minutes, then read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument.
  • the IC 50 of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 that performed the experiments were determined in two data sets and obtained using Prism (version 5.01, GraphPad) software.
  • the IC 50 of this compound which reduces c-Met kinase enzyme activity by 50% is shown in Table 2 below.
  • the IC 50 of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 were determined to be 20 ⁇ M or less, from which pyrazole and benzoxazole substituted pyridine according to the invention It can be seen that the derivative or pharmaceutically acceptable salt thereof has an excellent inhibitory effect on c-Met kinase.
  • Cell culture medium RPMI 1640 medium, fetal bovine serum (FBS) and trypsin were purchased from Gibco (Grand Island, NY), and sodium hydrogen carbonate, amphotericin B and gentogenycin were used as sig-chemical products.
  • reagents such as SRB (sulforhodamine) B, trisma base, and trichloroacetic acid (TCA), which are reagents used in cytotoxicity measurement experiments, were purchased from Sigma Chemical.
  • T-25 culture vessels used for cell culture, 96-well plates, and disposable supernatants used for other cell cultures were manufactured by Lincoln Park (NJ).
  • the drug used in the experiment was diluted as an experimental medium to the desired concentration in the test, and the final dimethyl sulfoxide concentration was adjusted to 0.5% or less.
  • the cancer cell lines used in the experiment were all human-derived cancer cell lines, including A549, a non-small cell lung cancer cell line, SK-MEL-28, a skin cancer cell line, and HT-29, a colon cancer cell line.
  • the culture medium was incubated in 37 ° C and 5% carbon dioxide incubator using RPMI 1640 medium to which 5% FBS (fetal bovine serum) was added, and maintained once every 3 to 4 days.
  • FBS fetal bovine serum
  • A549 dispenses 5 ⁇ 10 3 cells, SKMEL-28 and HT-29 dispense 1 ⁇ 10 4 cells, After culturing for 24 hours to allow the cells to adhere to the bottom surface, the culture solution was removed, and the culture solution containing the compounds of Examples 1, 4, 5, 7, 9 to 45, and 47 to 50 was added thereto and cultured for 72 hours. It was. After incubation with the compound was terminated, cytotoxicity was measured using SRB, a protein staining reagent.
  • each well was treated with cold TCA solution, and then treated at 4 ° C. for 1 hour.
  • the cells were fixed by standing for a while.
  • a dye solution in which 0.4% SRB was dissolved in 1% acetic acid solution was added and left at room temperature for 30 minutes to stain cells.
  • Extra SRB that did not bind to cells was removed by washing with 1% acetic acid solution, and SRB was eluted by adding 10 mM Trisma buffer (unbuffered) at pH 10.3-10.5 to the stained cells.
  • the absorbance of each well was measured in a wavelength range of 520 nm using a microplate reader.
  • GI 50 of the compound that inhibits cancer cell (HT-29, A549 and SK-MEL-28) proliferation by 50% is shown in Table 3 below.
  • the GI 50 for cancer cells (HT-29, A549 and SK-MEL-28) of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 were all measured to be 100 ⁇ M or less. From this, it can be seen that the pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention have an excellent effect of inhibiting abnormal cell proliferation such as cancer cells.
  • Ba / F3 cells are IL-3 dependent pro-B cell lines that can only proliferate when interleukin-3 (IL-3) is in the media, but IL- when the transformation is caused by tyrosine kinases. 3 Independent proliferation is possible.
  • IL-3 interleukin-3
  • a vector expressing the activated c-Met was prepared and a Ba / F3 c-Met cell line capable of independent growth of IL-3 by c-Met activity was prepared.
  • FIG. 1 To produce a Ba / F3_c-Met cell line capable of IL-3 independent growth, a vector capable of expressing c-Met that is always active was constructed ( FIG. 1 ).
  • the pcDNA3.0 vector was selected as the parent vector and the neo r gene region, which is unnecessary, was removed using SmaI / BstBI restriction enzymes to reduce the overall size of the vector to be produced.
  • Luciferase was used as a marker for measuring cell proliferation, and an internal ribosome entry site (IRS) was used to always express luciferase with c-Met kinase in cells.
  • IRES is composed of stratagene (Stratagene; pShuttle-IRES-hrGFP) using forward primer (5'-CTCATCTCAGAAGAGGATCTGAATTAGCAATTCCTCGACGACTGC-3 ') and reverse primer (5'- TTTT TCTAGA AGTGGCCATTATCATCGTG-3').
  • the IRES 2 nd forward primer (5'- TTTT CTCGAG GAACAAAAACTCATCTCAGAAGAGGATCTG-3 ') containing the myc epitope sequence to attach the myc epitope to the carbon end of the kinase by performing a 2 nd PCR as the one IRES reverse transcription to obtain a plastic armor IRES sequence.
  • An IRES-Puro r -Luc (pcDNA-Luc) vector was constructed.
  • the N- of the Tel gene containing the myristoylation sequence (myr) of Src at the N-terminus first.
  • the terminal domain was obtained by PCR and then cloned into the pShuttle-IRES-hrGFP-1 vector, followed by fusion of myr-Tel at the N-terminus of the c-Met kinase domain and determination of myc antigen at the C-terminus.
  • P-Shuttle-myrTel-Met vector was prepared by adding c-Met kinase domain obtained by PCR to attach a group. Primers used in the present invention are shown below.
  • Reverse transcription primer (5'-AAGCAGTCTACAGTCTGCTATTCTCCC-3 ')
  • Reverse transcription primer (5'- TTTT ACTAGT AAGCAGTCTACAGTCTGCTA-3 ')
  • Reverse transcription primer (5'- TTTT GTCGAC TCACATGGACATAGTGCTCC-3 ')
  • Inhibition activity assay for c-Met kinase was performed on the Ba / F3 c-Met cell line prepared as described above.
  • the IC 50 of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 were all It was measured to be 20 ⁇ M or less, from which it can be seen that the pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention have an excellent inhibitory effect on c-Met kinase.
  • the airtight cloth was filled to prepare a powder.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • the solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

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Abstract

L'invention concerne de nouveaux dérivés de pyridine à substitution pyrazole et benzoxazole ou leurs sels pharmaceutiquement acceptables, leur procédé de préparation, et une composition pharmaceutique contenant ces dérivés en tant que principes actifs pour prévenir et traiter des troubles impliquant une prolifération cellulaire aberrante. L'invention permet d'obtenir d'excellents effets pour inhiber une grande variété de protéines kinases, par exemple: c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A et analogues, l'invention s'avère ainsi utile pour traiter des troubles impliquant une prolifération cellulaire aberrante, et peut être avantageusement utilisée pour prévenir et pour traiter des troubles impliquant une prolifération cellulaire aberrante.
PCT/KR2009/001866 2008-04-10 2009-04-10 Nouveaux dérivés de pyridine à substitution pyrazole et benzoxazole ou leurs sels pharmaceutiquement acceptables, leur procédé de préparation, et composition pharmaceutique contenant ces dérivés/sels en tant que principes actifs pour prévenir et traiter des troubles impliquant une prolifération cellulaire aberrante WO2009126003A2 (fr)

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DE102009033208A1 (de) 2009-07-15 2011-01-20 Merck Patent Gmbh Aminopyridinderivate
KR101598664B1 (ko) 2013-09-04 2016-03-02 씨제이헬스케어 주식회사 피롤로피리다진 유도체를 포함하는 단백질 키나제 억제제
US9359336B2 (en) 2014-10-09 2016-06-07 Allergan, Inc. Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
WO2018111049A1 (fr) * 2016-12-15 2018-06-21 한국생명공학연구원 Composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à dyrk, comprenant un composé à base de pyridine comme principe actif
KR102279347B1 (ko) * 2016-12-15 2021-07-21 한국생명공학연구원 피리딘계 화합물을 유효성분으로 함유하는 dyrk 관련 질환의 예방 또는 치료용 약학적 조성물
KR102200032B1 (ko) * 2019-03-13 2021-01-08 전남대학교산학협력단 호흡기 질환의 예방 또는 치료용 조성물
KR20220136542A (ko) 2021-03-30 2022-10-11 현대모비스 주식회사 차량 제어 시스템 및 방법
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US7348325B2 (en) 2005-11-30 2008-03-25 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
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