WO2013133556A1 - Novel triazolo pyridazine derivative and use therefor - Google Patents

Novel triazolo pyridazine derivative and use therefor Download PDF

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WO2013133556A1
WO2013133556A1 PCT/KR2013/001443 KR2013001443W WO2013133556A1 WO 2013133556 A1 WO2013133556 A1 WO 2013133556A1 KR 2013001443 W KR2013001443 W KR 2013001443W WO 2013133556 A1 WO2013133556 A1 WO 2013133556A1
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Prior art keywords
triazolo
methyl
pyrido
dihydro
cancer
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PCT/KR2013/001443
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French (fr)
Korean (ko)
Inventor
정희정
김형래
하재두
이정옥
조성윤
최상운
이종국
박지훈
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한국화학연구원
주식회사 한독약품
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Publication of WO2013133556A1 publication Critical patent/WO2013133556A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel triazolo pyridazine derivative having tyrosine kinase inhibitory activity and a pharmaceutical composition comprising the same as an active ingredient.
  • Ligands of hepatocyte growth factor receptor (c-MET or HGFR) tyrosine kinase (RTK) may be HGF or scatter factor [L. Naldini, ⁇ . ⁇ . Weidner, ⁇ . Vigna, G. Gaud i no, A. Bar del 1 i, C. Ponzetto, G.. Michalopoulos, Eur. Mo I. Biol. Org. J.
  • Hepatocyte growth factor binds to c-Met with strong binding and is automatically phosphorylated to specific intracellular tyrosine kinases. When activated, cell growth, survival, angiogenic wound healing, tissue regeneration, dispersion and cell motility Control various cell functions, including invasion and morphogenesis.
  • c-Met and HGF are expressed in many tissues, but their expression normally occurs in tissues consisting primarily of epithelial and mesenchymal cells, and is required for normal mammalian development, and in cell migration, cell proliferation and survival, differentiation and tissue arrangement.
  • HGF / SF is also an angiogenesis factor, and c-Met signaling in epithelial cells can induce many of the cell proliferation, motility, and invasiveness necessary for angiogenesis.
  • c-Met receptors have been shown to be expressed in many human cancers. C-Met gene amplification, mutations and rearrangements have also been observed in various human cancers.
  • c-Met and its ligand, HGF have also been reported to be overexpressed in various human cancers, such as brain tumors, lung cancers, gastric cancers, pancreatic cancers, colon cancers, ovarian cancers, renal cell cancers and prostate cancers (Oncology Reports, 5: 1013). (1998)). Classes with mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues. In addition, overexpression of c-Met or HGF has been found to correlate with poor prognosis and disease outcomes in many major human cancers including lung, liver, stomach and breast, and c-Met is also associated with pancreatic cancer (RM Thomas, K Toney, C).
  • hepatocyte growth factor receptor c—Met or HGFR
  • RTK tyrosine kinase
  • the present inventors earnestly researched to develop a composition for efficiently preventing or treating various hyper proliferative disorders caused by abnormal tyrosine kinase activity by identifying compounds having inhibitory activity against tyrosine kinase. .
  • a novel triazole pyridazine derivative of Formula 1 which is not known until now, binds to hepatocyte growth factor (HGF) to activate phosphorylation, thereby triggering cell proliferation, migration, invasion and formation of neovascularization.
  • HGF hepatocyte growth factor
  • the present invention has been completed by discovering that c—met kinase significantly inhibits the activity of c. ⁇ Accordingly, it is an object of the present invention to provide novel triazolo pyridazine derivatives or pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the novel triazole pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of hyperproliferative disorders comprising the novel triazole pyridazine derivatives, pharmaceutically acceptable salts or solvates thereof as an active ingredient.
  • Another object of the present invention comprises the step of administering to the subject a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient, c- To provide a method for inhibiting Met tyrosine kinase activity.
  • Another object of the present invention comprising administering to the subject a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient, hyperproliferative disease (hyper To provide a method for preventing or treating proliferative disorders.
  • Another object of the present invention is to provide the use of a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient for inhibiting fet tyrosine kinase activity. have.
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient for preventing or treating hyper proliferative disorder.
  • the present invention provides a triazolo pyridazine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • A is a 5- or 10-membered aryl or hetero aryl ring;
  • Ri to R 5 are each independently hydrogen or dC 5 alkyl;
  • 3 ⁇ 4 is hydrogen, hydroxy, cyano, halogen, dC 4 alcohol, heterocycloalkyl of a pentagonal -hexagonal ring, CrC 5 alkyl unsubstituted or substituted with a heterocycloalkyl of a pentagonal -hexacycle, unsubstituted -Cs alkoxy substituted with heterocycloalkyl of the pentagonal -hexagonal ring, dC 5 alkyl ester, amine unsubstituted or substituted with d-Cs alkyl,-(:( ) ) ⁇ 7 3 ⁇ 4 (1?
  • R 7 and R 8 are each independently hydrogen or C ⁇ C 5 alkyl, R 7 is a post 5 and 3 ⁇ 4 each -6 heterocycloalkyl of each ring is connected to) amide represented by a; n is an integer of 0-5.
  • the present inventors made diligent research efforts to develop a composition for effectively preventing or treating various hyper proliferative disorders caused by abnormal tyrosine kinase activity by discovering compounds having inhibitory activity against tyrosine kinase.
  • the novel triazolo pyridazine derivative of the above-mentioned formula (1) which has not been known so far, was found to significantly inhibit the activity of c-Met kinase.
  • the compound of formula 1 of the present invention binds to hepatocyte growth factor (HGF) to activate phosphorylation of c-Met kinase that triggers cell proliferation, migration, invasion and neovascularization Significantly inhibit activity. Therefore, the compounds of the present invention can be usefully used to treat or prevent various aproliferative diseases mediated by cell proliferation and excessive angiogenesis.
  • HGF hepatocyte growth factor
  • aryl refers to a substituted or unsubstituted monocyclic or polycyclic carbon ring which is wholly or partially unsaturated and has aromatic (& 1 " 01 ⁇ (; ⁇ ).
  • heteroaryl refers to a heterocyclic aromatic group containing oxygen, sulfur or nitrogen in the ring as a heteroatom.
  • the heteroatom is nitrogen or oxygen.
  • the number of heteroatoms is 1-4, preferably 1-2.
  • heteroaryl aryl is preferably monoaryl or biaryl.
  • alkyl refers to a straight or branched saturated hydrocarbon group, and includes, for example, methyl, ethyl, propyl, isobutyl pentyl or nuclear chambers and the like.
  • d-Cs alkyl means an alkyl group having an alkyl unit having 1 to 5 carbon atoms, and when dC 5 alkyl is substituted, carbon atoms of the substituent are not included.
  • d-Csalkyl at 3 ⁇ 4-position is preferably Ci-C 3 alkyl, more preferably Ci-C 2 alkyl.
  • gen refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.
  • heterocycloalkyl as used herein means a saturated carbon ring containing oxygen, sulfur or nitrogen in the ring as a heteroatom.
  • the heteroatom is nitrogen or oxygen.
  • Heterocycloalkyl of a 5-6 hexacyclic ring means that the sum of the numbers of carbon and heteroatoms constituting the ring is 5-6.
  • alkoxy refers to a radical formed by the removal of hydrogen from an alcohol, and does not include the carbon number of the substituent when dC 3 alkoxy is substituted.
  • d—c 5 alkyl ester means an ester having a dC 5 alkoxy group bonded to an acyl group (—c (o) —).
  • the triazolo pyridazine derivatives of the present invention are selected from the group consisting of compounds represented by the formulas 2 to 5, 14 to 16, 18, 20, 22 and 26.
  • the eleven compounds listed above have very low IC 50 values of ⁇ . ⁇ or less in c-Met kinase inhibitory activity. Thus, they can be used as very effective therapeutic compositions for various dysplastic diseases.
  • Triazolo pyridazine derivatives of the present invention may be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as salts.
  • Inorganic acids and organic acids can be used as the free acid.
  • the pharmaceutically acceptable salts of the triazolopyridazine derivatives of the present invention are hydrochlorides, bromates, sulfates, phosphates, citrate acetates, trifluoroacetates, lactates, tartarates, maleates, fumarates, Gluconate, methanesulfonate, glyconate, succinate, 4-luluenesulfonate, gluturonate ' embonate, glutamate, or aspartate, but may be selected from the group consisting of, but not limited to All salts formed using various inorganic and organic acids commonly used in the art are included.
  • triazolo pyridazine derivatives of the present invention may also exist in the form of solvates (eg hydrates).
  • the present invention is a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the above-described triazolo pyridazine derivatives of the present invention, pharmaceutically acceptable salts or solvates thereof as an active ingredient To provide.
  • the present invention provides a method for the prevention of hyperproliferative disorders comprising the above-described triazolo pyridazine derivatives of the present invention, pharmaceutically acceptable salts or solvates thereof as an active ingredient or Provided is a therapeutic pharmaceutical composition.
  • the present invention provides the above-described triazolo pyridazine derivative of the present invention, a pharmaceutically acceptable salt thereof, or a It provides a method for inhibiting c-Met tyrosine kinase activeol by administering a pharmaceutical composition comprising a solvate as an active ingredient.
  • the present invention is administered by administering a pharmaceutical composition comprising the above-described triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient, and thus hyperproliferative disorder ) To prevent or treat).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof for inhibiting c-Met tyrosine kinase activity as an active ingredient. Serves the purpose of.
  • the present invention provides a novel triazolo pyridazine derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient for preventing or treating hyper proliferative disorder. It provides a use of a pharmaceutical composition comprising. Since the novel triazole pyridazine derivatives used in the present invention have already been described above, it is omitted to avoid excessive duplication.
  • hypo proliferative disorder refers to a pathological condition caused by excessive cell growth, division and migration that is not regulated by general limiting means in a normally growing animal.
  • Aberrant proliferative diseases that are prevented or treated with the compositions of the present invention include, for example, cancer, diabetic retinopathy, prematurity retinopathy, corneal transplant rejection, neovascular glaucoma, melanoma, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune diseases , Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy, organ transplant rejection, and renal glomerulopathy All hyperproliferative diseases that arise due to abnormal proliferation of cells and excessive production of neovascularization are included. More preferably,
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the preparation, lactose dextrose, sucrose, sorbbi, manny, starch, acacia rubber, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil
  • the present invention is not limited thereto.
  • the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. in addition to the above components.
  • lubricants wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.
  • suitable pharmaceutically acceptable carriers and preparations are described in Remington's Pharmaceutical Sciences (19th). ed., 1995).
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
  • Suitable dosages of the pharmaceutical compositions of the present invention may be prescribed in various ways depending on factors such as formulation method, mode of administration, age, weight, sex, morbidity, pathology, time of administration, route of administration, rate of excretion and reaction response to the patient. Can be.
  • the daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 rag / kg.
  • the pharmaceutical composition of the present invention may be easily carried out by those skilled in the art according to the present invention. It may be prepared in unit dose form or formulated into a multi-dose container by formulating it into a conventional formulation using pharmaceutically acceptable carriers and / or excipients.
  • formulations include, for example, oral (tablets, capsules, powders), oral, sublingual, intrarectal, intravaginal, intranasal, topical or parenteral (intravenous, cavernous, intramuscular, subcutaneous). And dosage forms).
  • the compounds according to the invention may be in the form of tablets containing starch or lactose, or in the form of capsules containing singly or excipients, Or in the form of elixirs or suspending agents containing flavoring or coloring chemicals orally, orally or sublingually.
  • Liquid formulations may include suspending agents (for example, a mixture of semi-synthetic glycerides such as methylcellose, witepsol or apricot kernel oil and PEG-6 esters or PEG-8 and caprylic / And pharmaceutically acceptable additives such as glyceride mixtures such as those of capric glycerides. It is also most preferred to use it as a sterile aqueous solution when injected parenterally, for example, intravenously, intracavernosally, intramuscularly, subcutaneously, and intratracheally, wherein the solution is different in order to have isotonicity with blood. It may also contain substances (for example salts or manny, monosaccharides such as glucose).
  • suspending agents for example, a mixture of semi-synthetic glycerides such as methylcellose, witepsol or apricot kernel oil and PEG-6 esters or PEG-8 and caprylic /
  • pharmaceutically acceptable additives such
  • the present invention provides a novel triazole pyridazine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for inhibiting C- Met tyrosine kinase activity comprising the same as an active ingredient, and prevention of hyperproliferative disorder or Provided is a therapeutic pharmaceutical composition, the method comprising inhibiting C- Met tyrosine kinase activity and preventing or treating a hyperproliferative disease, comprising administering the additive composition to a subject.
  • the present invention efficiently inhibits the activity of c-Met tyrosine kinase, thereby causing various dysplastic diseases associated with excessive cell proliferation and growth due to abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. It can be usefully used as a therapeutic agent for.
  • the triazolo pyridazine derivative of Formula 1 of the present invention may be obtained by proceeding as shown in Banung Formula 1 below.
  • Formula (5) is a reaction of palladium catalysis with boronic acid or boronic acid pinacol ester substituted with substituted aryl or heteroaryl groups of 5-membered or 6-membered rings.
  • trifluoroacetic acid CF 3 C00H
  • the target formula (1) from which the paramethoxybenzyl (PMB) protecting group of the pyridooxazole group is removed can be obtained.
  • Synthesis of pyridooxazine ethyl ester represented by the formula (10) was prepared by the method disclosed in Tetrahedron 58 (2008) and 8145-8152 or US6465467 (2002). That is, 2-amino-3-hydroxypyridine and diethyl chloromalonate were heated and refluxed in the presence of an organic base to obtain Formula (10). Amide was introduced into the PMB protecting group (p-Methoxybenzyl protecting group) and reduced the amide and ester group with borane (B3 ⁇ 4) to obtain an intermediate pyridooxazine methanol (12).
  • PMB protecting group p-Methoxybenzyl protecting group
  • borane B3 ⁇ 4
  • Oxazin-2-yl) acetohydrazide (650 mg) was obtained and the following reaction was carried out without purification: It was dissolved in acetic acid (15 mL), stirred at 8C C for 18 hours, and neutralized with 2M aqueous sodium carbonate solution.
  • Trifluoroacetic acid salt (150 mg, 75%) was obtained.
  • target compound 2- (4- (3-((3,4-dihydro-2H-pyrido [3,2—b] [l, 4] oxazine—2-yl ) (Methyl)-[1,2,4] triazol gives [4,3'b] pyridazin-6-yl) -1H-pyrazol-1-yl) ethanol tripulouroacetic acid salt.
  • Example 6 Proceed as in Example 6 to the target compound 4- (4-methoxybenzyl) -2-((6- (1-methyl-1H-indol- 3-yl)-[1,2,4] triazolo [4,3—b] pyridazin-3-yl) methyl) -3,4-dihydro-211-pyrido [3,2-13] [1,4] oxazine was obtained.
  • Example 19 Proceed as in Example 19 to obtain the target compound 3-chloro-6- (3-fluorophenyl) pyridazine.
  • Example 19 Proceed as in Example 19 to obtain the target compound 3-chloro-6- (4-methoxyphenyl) pyridazine.
  • 3,6-dichloropyridazine 400 mg, 2.69 ⁇ ol was dissolved in dioxane (6 mL) and distilled water (2 mL), followed by 4-formylphenylboronic acid (321 mg, 2.15 ⁇ ol), potassium carbonate ( 920 mg, 6.71 ⁇ l ol), PdCl 2 (dppf) 2 (H0 mg, 0.13 ⁇ l ol) are added and stirred at 90 0 C. After reaction, the mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (40% EtOAc / Hexane) gave 4- (6-chloropyridazin-3-yl) benzaldehyde (148 mg, 25%) as a white solid.
  • the target compound 3- (3-((4- (4-methoxybenzyl) -3'4-dihydro-2H-pyrido [3, 2-b] [1,4 ] Oxazine-2-yl) methyl)-[1,2,4] triazolo [4,3-1)] pyridazin-6-yl) benzonitriyl.
  • the target compound 4- (4 'methoxybenzyl) _ 2 _ (( 6- (pyridin- 3 -yl) — [ 1
  • the target compound 4- (3-((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1, 4 ] Oxazine-2-yl) methyl)-[1,2,4] triazolo [4,3-1)] pyridazin-6-yl)- ⁇ 1 ⁇ -dimethylbenzeneamine.
  • Example 34 Proceed as in Example 34 to the target compound methyl 4- (4-methoxybenzyl) -2-((6- (4- (morpholinomethyl) phenyl)-[1,2,4] triazol [ 4,3-b] pyridazin-3-yl) methyl) -3 and 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine were obtained.
  • Example 62 Proceed as in Example 62 to the target compound (3- (3-((4- (4-methoxybenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone (48%) was obtained.
  • Example 65 (3- (3- ((3, 4-Dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl)-[1,2, 4] triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylperazine-1-yl) methanone
  • Time-resolved fluorescence of inhibitory activity against c-Met kinase Analysis was performed using Dissociat ion Enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), a type of fluorescence (TRF).
  • DELFIA Dissociat ion Enhanced Lanthanide Fluoro Immuno Assay
  • TRF type of fluorescence
  • the reaction was transferred to a strap-vidin-coated plate and incubated under shaking and washed three times with PBS-T complete solution (PBS 0.05% Twen 20) after 2 hours.
  • Anti-phosphotyrosine antibody with flow cytometry was diluted 1: 2, 500, added 100 mL per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% TR20).
  • Improver (enhancement solution, 100 mL) was added 5 minutes after shaking the culture, Wallac In-I 2103 (Wallac Envision 2103) unit to the 'was read at a wavelength range of 615/665 nm, of the test compound IC performing the experiment 50 was determined by two data sets and was obtained using Prism (version 5.01, GraphPad) software.
  • the IC 50 of the compound that reduces c-Met kinase enzyme activity by 50% is shown in Table 1 below.
  • 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 gentamicin were used as sig-chemical products.
  • SRB (sulforhodamine) B, Trisma base and trichloroacetic acid (TCA) reagents which are reagents used in cytotoxicity measurement experiments, were purchased from Sigma Chemical.
  • TCA trichloroacetic acid
  • CellTiter 96 R AQueous Non-Radioactive Cell Proliferation Assay was purchased from Promega.
  • T-25 culture vessels used for cell culture, 96-well folate, and disposable supernatants used for other cell cultures were manufactured by Lincoln Park (NJ).
  • the drug used in the experiment was diluted as a test 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, and gastric cancer cell lines Hs746T and MKN-45 were used. Cultures were incubated in 37 ° C and 5% carbon dioxide incubator using RPMI 1640 medium added with 10% FBS (fetal bovine serum), and maintained once every 3-4 days.
  • FBS fetal bovine serum
  • Hs746T dispenses 5X10 3 cells
  • MKN-45 dispenses 1 10 4 eel Is
  • cells adhere to the bottom.
  • the culture solution was removed, and the culture solution containing the compound of the present invention was added thereto and incubated for 72 hours.
  • cytotoxicity was measured using SRB, a protein staining reagent, or MTS assay.
  • the culture solution was removed, and treated with a cold TCA solution in each well, and left at 4 ° C for 1 hour to fix the cells.
  • 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 not bound to the cells was removed by washing with 1% acetic acid solution, and SRB was eluted by adding 10 mM Tris buffer (unbuffered) of H 10.3-10.5 to H stained cells.
  • the absorbance of each well was measured in a wavelength range of 520 nm using a microplate reader.
  • the cytotoxicity of the drug was calculated by the formula [(T-Tz) / (Tz) xi00.
  • Cancer cell proliferation inhibition measurement using MTS assay was performed as follows. Specifically after the incubation with the compound of the present invention, Promega's Cel ITiter 96 AQueous Non-Radioactive Cell Proliferation Assay product was mixed with PMS solution and MTS solution, and 20 per well was added. After leaving for 4 hours in the incubator was taken out and left for 10 minutes at room temperature. After measuring the absorbance at 490 nM using Molecular Device's SpectraMax250 model IC 50 value was calculated.
  • the IC 50 of this compound that inhibits cancer cell (Hs746T) proliferation to 503 ⁇ 4 is shown in Table 2 below.
  • the IC 50 value of the compound for cancer cells Hs746T showed a low value of 0.1 ⁇ of the compounds of Formula 2 (Example 7) and Formula 12 (Example 43), and Formula 7 (Example 17) and Formula 26 (Example 68) showed high values of 3.62 ⁇ and 9.37 ⁇ , respectively, from which the novel pyrazolopyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention inhibit the proliferation of cancer cells and the like. It can be seen that there is an excellent effect.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsules were prepared by layering the gelatine capsules according to a conventional method for preparing capsules. 1-4. Preparation of Injection
  • the solution was layered in a 5 type I ampoule made of transparent 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

The present invention relates to a novel triazolo pyridazine derivative or a pharmaceutically acceptable salt thereof, to a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity and a pharmaceutical composition for preventing or treating an abnormal proliferation disorder (hyperproliferative disorder) comprising same as an active ingredient, and to a method for preventing or treating an abnormal proliferation disorder (hyperproliferative disorder) comprising a step of administering a pharmaceutically effective amount of the pharmaceutical composition to a subject in need thereof. The present invention can advantageously be used as a therapeutic agent for various abnormal proliferation disorders such as cancer, psoriasis, rheumatoid arthritis and diabetic retinopathy which are associated with excessive cell proliferation and growth due to irregular kinase activity by effectively suppressing the activity of c-Met tyrosine kinase.

Description

【명세서】  【Specification】
【발명의 명칭】 [Name of invention]
신규한 트리아졸로 피리다진 유도체 및 그의 용도  Novel triazolo pyridazine derivatives and uses thereof
【기술분야】 Technical Field
본 특허출원은 2012년 3월 5일에 대한민국 특허청에 제출된 대한민국 특허출원 제 10-2012-0022541호에 대하여 우선권을 주장하며, 상기 특허출원의 개시 사항은 본 명세서에 참조로서 삽입된다  This patent application claims priority to Korean Patent Application No. 10-2012-0022541 filed with the Korean Patent Office on March 5, 2012, the disclosure of which is hereby incorporated by reference.
본 발명은 티로신 키나아제 억제활성을 가지는 신규한 트리아졸로 피리다진 유도체 및 이를 유효성분으로 포함하는 약제학적 조성물에 관한 것이다.  The present invention relates to a novel triazolo pyridazine derivative having tyrosine kinase inhibitory activity and a pharmaceutical composition comprising the same as an active ingredient.
【발명의 배경이 되는 기술】 [Technique to become background of invention]
간세포 성장 인자 수용체 (c-MET 또는 HGFR) 티로신 키나아게 (RTK)의 리간드는 HGF 또는 분산인자 (scatter factor) [L. Naldini , Κ.Μ. Weidner, Ε. Vigna, G. Gaud i no, A. Bar del 1 i , C. Ponzetto, G. . Michalopoulos, Eur. Mo I. Biol. Org. J. 10:2867-2878(1991); D.P. Bottaro, J.S. Rubin, D.L. Faletto, A.M. Chan, T.E. Kmiecik, G.F. Vande Woude , S.A. Aaronson, Science 251 :802-804(1991)]라고 하며， 주로 간엽세포에 의해 생산되는 이종이량체성 (disulfide-linked heterodimeric) 단백질이다. 간세포 성장인자 (HGF)는 강한 결합과 함께 c-Met과 결합하여 세포내 특정한 티로신 키나아제에 자동으로 인산화가 이루어져 활성화되면 세포성장, 생존, 신생혈관생성 상처치유, 조직재생, 분산， 세포 운동성 (motility), 침윤성 (invasion) 그리고 형태발생등을 포함하는 다양한 세포기능을 조절하게 한다. c-Met 및 HGF는 많은 조직에서 발현되지만， 그 발현은 정상적으로는 주로 상피 및 간엽세포로 구성된 조직에서 일어나며， 정상적인 포유동물의 발육에 필요하며， 세포 이동， 세포 증식 및 생존, 분화 및 조직배열에서 중요한 것으로 밝혀졌다ᅳ 또한 HGF/SF는 신생혈관생성 인자이며， 상피 세포에서의 c-Met 신호전달은 신생혈관생성에 필수적인 세포 증식, 운동성， 그리고 침윤성 등 많은 것을 유도할 수 있다. c-Met 수용체는 많은 인간 암에서 발현되는 것으로 밝혀졌다. 또한 c-Met 유전자 증폭， 돌연변이 및 재배열이 다양한 인간 암에서 관찰되었다. c-Met 및 그의 리간드인 HGF는 또한 다양한 인간암 예를 들면 뇌종양, 폐암， 위암, 췌장암， 대장암, 난소암, 신장 세포암， 전립선암 등에 과잉 발현이 보고되어 있다 (Oncology Reports, 5： 1013(1998)) . c-Met 키나제를 활성화시키는 돌연변이를 갖는 부류는 다중 신장 종양 및 다른 조직의 종양에 걸리기 쉽다. 또한, c-Met 또는 HGF의 과발현은 폐， 간, 위 및 유방을 포함한 많은 주요 인간암에서 나쁜 예후 및 질환 결과와 상관되는 것으로 밝혀졌으며， c-Met는 또한 췌장암 (R. M. Thomas, K Toney, C Fenogl i으 Preiser , M. P. Revelo-Penaf iel , S. R. Hingorani , D. A. Tuveson, S. E. Waltz, A. M. Lowy, Cancer Res 2007, 67， 6075； E. R. Camp, A. Yang, M. J. Gray, F. Fan, S. R. Hamilton, D. B. Evans , A. T. Hooper , D. S. Pereira, D. J. Hicklin, L. M. Ellis, CANCER, 109 :1031(2007))과 신경교종 (B. Wullich, H.P. Sattler, U. Fischer, E. Meese, T, Anticancer Res. 14： 577-579(1994)) 같은 치료가 어려운 암에 직접 관련되었다, 특히, 위암에서는 c-Met의 과잉 발현이나 혈청 중의 HGF수준 상승이 보고되어 있다 (/ . J. Cancer, 55： 72(1993)). Ligands of hepatocyte growth factor receptor (c-MET or HGFR) tyrosine kinase (RTK) may be HGF or scatter factor [L. Naldini, Κ.Μ. Weidner, Ε. Vigna, G. Gaud i no, A. Bar del 1 i, C. Ponzetto, G.. Michalopoulos, Eur. Mo I. Biol. Org. J. 10: 2867-2878 (1991); DP Bottaro, JS Rubin, DL Faletto, AM Chan, TE Kmiecik, GF Vande Woude, SA Aaronson, Science 251: 802-804 (1991)], which are disulfide-linked mainly produced by mesenchymal cells. heterodimeric) protein. Hepatocyte growth factor (HGF) binds to c-Met with strong binding and is automatically phosphorylated to specific intracellular tyrosine kinases. When activated, cell growth, survival, angiogenic wound healing, tissue regeneration, dispersion and cell motility Control various cell functions, including invasion and morphogenesis. c-Met and HGF are expressed in many tissues, but their expression normally occurs in tissues consisting primarily of epithelial and mesenchymal cells, and is required for normal mammalian development, and in cell migration, cell proliferation and survival, differentiation and tissue arrangement. HGF / SF is also an angiogenesis factor, and c-Met signaling in epithelial cells can induce many of the cell proliferation, motility, and invasiveness necessary for angiogenesis. c-Met receptors have been shown to be expressed in many human cancers. C-Met gene amplification, mutations and rearrangements have also been observed in various human cancers. c-Met and its ligand, HGF, have also been reported to be overexpressed in various human cancers, such as brain tumors, lung cancers, gastric cancers, pancreatic cancers, colon cancers, ovarian cancers, renal cell cancers and prostate cancers (Oncology Reports, 5: 1013). (1998)). Classes with mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues. In addition, overexpression of c-Met or HGF has been found to correlate with poor prognosis and disease outcomes in many major human cancers including lung, liver, stomach and breast, and c-Met is also associated with pancreatic cancer (RM Thomas, K Toney, C). Fenogl i Preiser, MP Revelo-Penaf iel, SR Hingorani, DA Tuveson, SE Waltz, AM Lowy, Cancer Res 2007, 67, 6075; ER Camp, A. Yang, MJ Gray, F. Fan, SR Hamilton, DB Evans , AT Hooper, DS Pereira, DJ Hicklin, LM Ellis, CANCER, 109: 1031 (2007)) and glioma (B. Wullich, HP Sattler, U. Fischer, E. Meese, T, Anticancer Res. 14: 577- 579 (1994)) have been directly linked to difficult cancers. In particular, gastric cancer has been reported to overexpress c-Met and raise HGF levels in serum (J. Cancer, 55: 72 (1993)).
그러므로 다양한 암의 성장과 세포 이동， 세포 증식 및 생존, 분화, 및 조직배열에 관여하는 간세포 성장 인자 수용체 (c— Met 또는 HGFR) 티로신 키나제 (RTK) 억제하면 종양형성의 정지 및 퇴행으로 이어지게 된다.  Therefore, inhibition of hepatocyte growth factor receptor (c—Met or HGFR) tyrosine kinase (RTK) involved in various cancer growth and cell migration, cell proliferation and survival, differentiation, and tissue alignment leads to the arrest and regression of tumorigenesis.
지금까지 개발된 HGF의 신호체계를 저해하는 화합물들이 임상과 전임상에서 개발이 진행되어 왔으며, 개발이 진행중인 저해제는 c-Met 키나아제의 힌지 (hinge) 결합 도메인에 결합하는 형태에 따라 c-Met을 포함하는 다중표적저해제와 c-Met만 저해하는 선택적저해제로 구분된다. 현재 c-Met 선택적 저해제는 ARQ-197, 파이자의 PF-02341066, PF-04217903 그리고 존슨엔존슨의 JNJ-38877605, 또한 SGX, Sanof i-Aventis, Vertex, Amgen사 등에서 보고되고 있고 현재 다양한 단계에서 임상이 진행중에 있다. 그러나 현재까지 보고된 어떠한 문헌에서도 본 발명이 특징으로 하고 있는 화합물로서, 효과적인 피리도옥사진 유도체의 합성을 개시한 바는 없다, 【발명의 내용] Compounds that inhibit the signaling system of HGF developed so far have been developed in clinical and preclinical studies, and inhibitors under development include c-Met depending on the form of binding to the hinge binding domain of c-Met kinase. Multi-target inhibitors and selective inhibitors that inhibit only c-Met. Currently, c-Met selective inhibitors are reported by ARQ-197, Paizar PF-02341066, PF-04217903 and Johnson &Johnson's JNJ-38877605, and also by SGX, Sanof i-Aventis, Vertex, Amgen, and others. This is in progress. However, no document reported to date discloses the synthesis of an effective pyridooxazine derivative as a compound characterized by the present invention. [Contents of the Invention]
【해결하고자 하는 과제】  Problem to be solved
본 발명자들은 티로신 키나아제에 대한 억제활성을 가지는 화합물을 발굴함으로써 비정상적인 티로신 키나아제의 활성에 의해 유발되는 다양한 이상증식성 질환 (hyper proliferative disorder)을 효율적으로 예방 또는 치료하기위한 조성물을 개발하기 위하여 예의 연구 노력하였다. 그 결과, 지금까지 알려지지 않은 상기 화학식 1의 신규한 트리아졸로 피리다진 유도체가 간세포 성장인자 (hepatocyte growth factor, HGF)와 결합하여 인산화를 활성화시킴으로써 세포의 증식， 이동， 침윤 및 신생혈관의 형성을 촉발하는 c— Met 키나아제의 활성을 유의하게 억제시킨다는 사실올 발견함으로써 본 발명을 완성하게 되었다. ᅳ 따라서 본 발명의 목적은 신규한 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염을 제공하는 데 있다.  The present inventors earnestly researched to develop a composition for efficiently preventing or treating various hyper proliferative disorders caused by abnormal tyrosine kinase activity by identifying compounds having inhibitory activity against tyrosine kinase. . As a result, a novel triazole pyridazine derivative of Formula 1, which is not known until now, binds to hepatocyte growth factor (HGF) to activate phosphorylation, thereby triggering cell proliferation, migration, invasion and formation of neovascularization. The present invention has been completed by discovering that c—met kinase significantly inhibits the activity of c. ᅳ Accordingly, it is an object of the present invention to provide novel triazolo pyridazine derivatives or pharmaceutically acceptable salts thereof.
본 발명의 다른 목적은 상기 신규한 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 c-Met 티로신 키나아제 활성 억제용 약제학적 조성물을 제공하는 데 있다.  Another object of the present invention is to provide a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the novel triazole pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient.
본 발명의 또 다른 목적은 상기 신규한 트리아졸로 피리다진 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 이상증식성 질환 (hyper proliferative disorder)의 예방 또는 치료용 약제학적 조성물을 제공하는 데 있다.  Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of hyperproliferative disorders comprising the novel triazole pyridazine derivatives, pharmaceutically acceptable salts or solvates thereof as an active ingredient. There is.
본 발명의 또 다른 목적은 상기 신규한 트리아졸로 피리다진 유도체 , 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물을 객체 (subject)에 투여하는 단계를 포함하는， c-Met 티로신 키나아제 활성을 억제하는 방법을 제공하는데 있다.  Another object of the present invention comprises the step of administering to the subject a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient, c- To provide a method for inhibiting Met tyrosine kinase activity.
본 발명의 또 다른 목적은 상기 신규한 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물을 객체에 투여하는 단계를 포함하는, 이상증식성 질환 (hyper proliferative disorder)을 예방 또는 치료하는 방법을 제공하는데 있다. 본 발명의 또 다른 목적은 ( fet 티로신 키나아제 활성을 억제하기 위한， 상기 신규한 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물의 용도를 제공하는데 있다. Another object of the present invention, comprising administering to the subject a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient, hyperproliferative disease (hyper To provide a method for preventing or treating proliferative disorders. Another object of the present invention is to provide the use of a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient for inhibiting fet tyrosine kinase activity. have.
본 발명의 또 다른 목적은 이상증식성 질환 (hyper proliferative disorder)을 예방 또는 치료하기 위한， 상기 신규한 트리아졸로 피리다진 유도체 , 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물의 용도를 제공하는데 있다.  Another object of the present invention is a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient for preventing or treating hyper proliferative disorder. To provide a use of.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.  Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.
【과제의 해결 수단】 [Measures of problem]
본 발명의 일 양태에 따르면， 본 발명은 하기의 화학식 1로 표시되는 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염을 제공한다.  According to one aspect of the present invention, the present invention provides a triazolo pyridazine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
Figure imgf000005_0001
Figure imgf000005_0001
상기 화학식에서， A는 5각 -10각 고리의 아릴 또는 헤테로 아릴이고; Ri 내지 R5는 각각 독립적으로 수소 또는 d-C5 알킬이며; ¾는 수소， 하이드록시, 시아노， 할로겐， d-C4 알코올， 5각 -6각 고리의 헤테로사이클로알킬, 비치환되거나 5각 -6각 고리의 헤테로사이클로알킬로 치환된 CrC5 알킬， 비치환되거나 5각 -6각 고리의 헤테로사이클로알킬로 치환된 -Cs 알콕시， d-C5 알킬 에스터， 비치환되거나 d-Cs 알킬로 치환된 아민, -(:( ))^7¾(1?7및 R8은 각각 독립적으로 수소 또는 C厂 C5 알킬이거나， R7 및 ¾이 고리로 연결된 5각 -6각 고리의 헤테로사이클로알킬이다)로 표시되는 아마이드이고; n은 0-5의 정수이다. 본 발명자들은 티로신 키나아제에 대한 억제활성을 가지는 화합물을 발굴함으로써 비정상적인 티로신 키나아제의 활성에 의해 유발되는 다양한 이상증식성 질환 (hyper proliferative disorder)을 효율적으로 예방 또는 치료용 조성물을 개발하기 위하여 예의 연구 노력하였다. 그 결과， 지금까지 알려지지 않은 상기 화학식 1의 신규한 트리아졸로 피리다진 유도체가 c-Met 키나아제의 활성을 유의하게 억제시킨다는 사실을 발견하였다. In the above formula, A is a 5- or 10-membered aryl or hetero aryl ring; Ri to R 5 are each independently hydrogen or dC 5 alkyl; ¾ is hydrogen, hydroxy, cyano, halogen, dC 4 alcohol, heterocycloalkyl of a pentagonal -hexagonal ring, CrC 5 alkyl unsubstituted or substituted with a heterocycloalkyl of a pentagonal -hexacycle, unsubstituted -Cs alkoxy substituted with heterocycloalkyl of the pentagonal -hexagonal ring, dC 5 alkyl ester, amine unsubstituted or substituted with d-Cs alkyl,-(:( ) ) ^ 7 ¾ (1? 7 and R 8 are each independently hydrogen or C厂C 5 alkyl, R 7 is a post 5 and ¾ each -6 heterocycloalkyl of each ring is connected to) amide represented by a; n is an integer of 0-5. The present inventors made diligent research efforts to develop a composition for effectively preventing or treating various hyper proliferative disorders caused by abnormal tyrosine kinase activity by discovering compounds having inhibitory activity against tyrosine kinase. As a result, the novel triazolo pyridazine derivative of the above-mentioned formula (1), which has not been known so far, was found to significantly inhibit the activity of c-Met kinase.
본 발명에 따르면, 본 발명의 화학식 1의 화합물은 간세포 성장인자 (hepatocyte growth factor, HGF)와 결합하여 인산화를 활성화시킴으로써 세포의 증식， 이동, 침윤 및 신생혈관의 형성을 촉발하는 c-Met 키나아제의 활성을 유의하게 억제한다. 따라서， 본 발명의 화합물은 세포의 이상증식 및 과도한 혈관신생을 매개로 하는 다양한 이상증식성 질환을 치료 또는 예방하는 데에 유용하게 이용될 수 있다.  According to the present invention, the compound of formula 1 of the present invention binds to hepatocyte growth factor (HGF) to activate phosphorylation of c-Met kinase that triggers cell proliferation, migration, invasion and neovascularization Significantly inhibit activity. Therefore, the compounds of the present invention can be usefully used to treat or prevent various aproliferative diseases mediated by cell proliferation and excessive angiogenesis.
본 명세서에서 용어 "아릴" 은 전체적으로 또는 부분적으로 불포화되고 방향성 (&1"01 ^(；^ )를 가지는 치환 또는 비치환된 모노사이클릭 또는 폴리사이클릭 탄소 고리를 의미한다. As used herein, the term "aryl" refers to a substituted or unsubstituted monocyclic or polycyclic carbon ring which is wholly or partially unsaturated and has aromatic (& 1 " 01 ^ (; ^).
본 명세서에서 용어 "헤테로아릴" 은 헤테로원자로서 고리 내에 산소, 황 또는 질소를 포함하는 헤테로사이클릭 방향족기를 의미한다. 바람직하게는, 헤테로원자는 질소 또는 산소이다. 헤테로원자의 개수는 1-4이며, 바람직하게는 1-2이다. 헤테로아릴에서 아릴은 바람직하게는 모노아릴 또는 비아릴이다.  As used herein, the term "heteroaryl" refers to a heterocyclic aromatic group containing oxygen, sulfur or nitrogen in the ring as a heteroatom. Preferably, the heteroatom is nitrogen or oxygen. The number of heteroatoms is 1-4, preferably 1-2. In heteroaryl aryl is preferably monoaryl or biaryl.
본 명세서에서 용어 "알킬" 은 직쇄 또는 분쇄의 포화 탄화수소기를 의미하며, 예를 들어， 메틸, 에틸, 프로필， 이소부틸 펜틸 또는 핵실 등을 포함한다. d-Cs 알킬은 탄소수 1 내지 5의 알킬 유니트를 가지는 알킬기를 의미하며 , d-C5 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. 화학식 1에서 , ¾내지 위치의 d-Cs알킬은 바람직하게는 Ci-C3알킬， 보다 바람직하게는 Ci-C2알킬이다. As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon group, and includes, for example, methyl, ethyl, propyl, isobutyl pentyl or nuclear chambers and the like. d-Cs alkyl means an alkyl group having an alkyl unit having 1 to 5 carbon atoms, and when dC 5 alkyl is substituted, carbon atoms of the substituent are not included. In formula (1), d-Csalkyl at ¾-position is preferably Ci-C 3 alkyl, more preferably Ci-C 2 alkyl.
본 명세서에서 용어 "i:로겐" 은 할로겐족 원소를 나타내며, 예컨대， 플루오로， 클로로， 브로모 및 요오도를 포함한다.  As used herein, the term “i: gen” refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.
본 명세서에서 용어 "헤테로사이클로알킬" 은 헤테로원자로서 고리 내에 산소， 황 또는 질소를 포함하는 포화 탄소고리를 의미한다. 바람직하게는, 헤테로원자는 질소 또는 산소이다. 헤테로원자의 개수는The term "heterocycloalkyl" as used herein means a saturated carbon ring containing oxygen, sulfur or nitrogen in the ring as a heteroatom. Preferably, the heteroatom is nitrogen or oxygen. The number of heteroatoms
1-4이며， 바람직하게는 1-2이다. "5각 -6각 고리의 헤테로사이클로알킬" 은 고리를 이루는 탄소 및 헤테로원자의 숫자의 합이 5-6개임을 의미한다. 1-4, Preferably it is 1-2. "Heterocycloalkyl of a 5-6 hexacyclic ring" means that the sum of the numbers of carbon and heteroatoms constituting the ring is 5-6.
본 명세서에서 용어 "알콕시" 는 알코올에서 수소가 제거되어 형성된 라디칼을 의미하며, d-C3 알콕시가 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. As used herein, the term "alkoxy" refers to a radical formed by the removal of hydrogen from an alcohol, and does not include the carbon number of the substituent when dC 3 alkoxy is substituted.
본 명세서에서 용어 "d— c5 알킬 에스터" 는 아실기 (-c(o)-)에 d-C5 알콕시기가 결합한 에스터를 의미한다. As used herein, the term “d—c 5 alkyl ester” means an ester having a dC 5 alkoxy group bonded to an acyl group (—c (o) —).
본 발명의 바람직한 구현예에 따르면， 본 발명의 화학식 1의 A는 페닐， 피라졸, 피리딘, 인돌 또는 인다졸이고; ¾내지 ¾는 수소이며; R6는 수소， 하이드록시, 시아노， 할로겐， d— C2 알코을, 피페리딘， 피페라진， 몰폴린， 비치환되거나 피페리딘， 피페라진 또는 몰폴린으로 치환된 d-C3 알킬， 비치환되거나 피페리딘, 피페라진 또는 몰플린으로 치환된 d-C2 알콕시， d— C3 알킬 에스터， d-C3 알킬로 치환된 아민, -C(=0)NR7R8(R7 및 ¾은 각각 독립적으로 수소 또는 d-C3 알킬이거나, R7 및 ¾이 고리로 연결된 피페라진이다)로 표시되는 아마이드이고; n은 1-3의 정수이다. 본 발명의 보다 바람직한 구현예에 따르면, 본 발명의 화학식 1로 표시되는 트리아졸로 피리다진 유도체는 하기의 화학식 2 내지 26으로 표시되는 화합물로 구성된 군으로부터 선택된다: According to a preferred embodiment of the present invention, A in formula 1 of the present invention is phenyl, pyrazole, pyridine, indole or indazole; ¾ to ¾ are hydrogen; R 6 is hydrogen, hydroxy, cyano, halogen, d—C 2 alcohol, piperidine, piperazine, morpholine, dC 3 alkyl unsubstituted or substituted with piperidine, piperazine or morpholine, unsubstituted Or dC 2 alkoxy substituted with piperidine, piperazine or morphine, d—C 3 alkyl ester, amine substituted with dC 3 alkyl, —C (= 0) NR 7 R 8 (R 7 and ¾ are each independently Hydrogen or dC 3 alkyl, or R 7 and ¾ are piperazine linked by rings; n is an integer of 1-3. According to a more preferred embodiment of the present invention, the triazolo pyridazine derivative represented by formula 1 of the present invention is selected from the group consisting of compounds represented by formulas 2 to 26:
Figure imgf000007_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000008_0001
화학식 10 화학식 11
Figure imgf000008_0002
Formula 10 Formula 11
Figure imgf000008_0002
Figure imgf000009_0001
Figure imgf000009_0001
화학식 18 화학식 19
Figure imgf000009_0002
Formula 18 Formula 19
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000010_0001
화학식 24 화학식 25
Figure imgf000010_0002
Chemical Formula 24 Chemical Formula 25
Figure imgf000010_0002
화학식 26
Figure imgf000010_0003
가장 바람직하게는， 본 발명의 상기 트리아졸로 피리다진 유도체는 상기의 화학식 2 내지 5， 14 내지 16， 18， 20, 22 및 26으로 표시되는 화합물로 이루어진 군으로부터 선택된다. Formula 26
Figure imgf000010_0003
Most preferably, the triazolo pyridazine derivatives of the present invention are selected from the group consisting of compounds represented by the formulas 2 to 5, 14 to 16, 18, 20, 22 and 26.
본 발명에 따르면， 상기 나열한 11가지 화합물은 c-Met 키나아제 저해활성에 있어서 Ο.ΙμΜ 이하의 매우 낮은 IC50 값을 가진다. 따라서 이들은 다양한 이상증식성 질환의 매우 효과적인 치료 조성물로 이용될 수 있다. 본 발명의 트리아졸로 피리다진 유도체는 약학적으로 허용 가능한 염의 형태로 사용될 수 있으며， 염으로는 약학적으로 허용 가능한 유리산 (free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있다. 바람직하게는, 본 발명의 트리아졸로 피리다진 유도체의 약제학적 허용 가능한 염은 염산염 , 브름산염 , 황산염 , 인산염， 구연산염 아세트산염, 트리플루오로아세트산염, 젖산염， 주석산염， 말레인산염, 푸마린산염， 글루콘산염, 메탄설폰산염, 글리콘산염, 숙신산염， 4-를루엔설폰산염， 글루투론산염 '엠본산염， 글루탐산염 , 또는 아스파트산염으로 구성된 군으로부터 선택될 수 있으나, 이에 제한되지 않고 당업계에서 통상적으로 사용되는 다양한 무기산 및 유기산을 이용하여 형성되는 염이 모두 포함된다. According to the present invention, the eleven compounds listed above have very low IC 50 values of Ο.ΙμΜ or less in c-Met kinase inhibitory activity. Thus, they can be used as very effective therapeutic compositions for various dysplastic diseases. Triazolo pyridazine derivatives of the present invention may be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as salts. Inorganic acids and organic acids can be used as the free acid. Preferably, the pharmaceutically acceptable salts of the triazolopyridazine derivatives of the present invention are hydrochlorides, bromates, sulfates, phosphates, citrate acetates, trifluoroacetates, lactates, tartarates, maleates, fumarates, Gluconate, methanesulfonate, glyconate, succinate, 4-luluenesulfonate, gluturonate ' embonate, glutamate, or aspartate, but may be selected from the group consisting of, but not limited to All salts formed using various inorganic and organic acids commonly used in the art are included.
또한, 본 발명의 트리아졸로 피리다진 유도체는 용매화물 (예를 들면 수화물)의 형태로도 존재할 수 있다.  The triazolo pyridazine derivatives of the present invention may also exist in the form of solvates (eg hydrates).
본 발명의 또 다른 양태에 따르면， 본 발명은 상술한 본 발명의 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 c-Met 티로신 키나아제 활성 억제용 약제학적 조성물을 제공한다.  According to another aspect of the present invention, the present invention is a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the above-described triazolo pyridazine derivatives of the present invention, pharmaceutically acceptable salts or solvates thereof as an active ingredient To provide.
본 발명의 또 다른 양태에 따르면， 본 발명은 상술한 본 발명의 트리아졸로 피리다진 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 이상증식성 질환 (hyper proliferative disorder)의 예방또는 치료용 약제학적 조성물을 제공한다.  According to another aspect of the present invention, the present invention provides a method for the prevention of hyperproliferative disorders comprising the above-described triazolo pyridazine derivatives of the present invention, pharmaceutically acceptable salts or solvates thereof as an active ingredient or Provided is a therapeutic pharmaceutical composition.
본 발명의 또 다른 양태에 따르면， 본 발명은 상술한 본 발명의 트리아졸로 피리다진 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물을 투여하여， c-Met 티로신 키나아제 활성올 억제하는 방법을 제공한다. According to another aspect of the present invention, the present invention provides the above-described triazolo pyridazine derivative of the present invention, a pharmaceutically acceptable salt thereof, or a It provides a method for inhibiting c-Met tyrosine kinase activeol by administering a pharmaceutical composition comprising a solvate as an active ingredient.
본 발명의 또 다른 양태에 따르면， 본 발명은 상술한 트리아졸로 피리다진 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물을 투여하여， 이상증식성 질환 (hyper proliferative disorder)을 예방 또는 치료하는 방법을 제공한다.  According to another aspect of the present invention, the present invention is administered by administering a pharmaceutical composition comprising the above-described triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient, and thus hyperproliferative disorder ) To prevent or treat).
본 발명의 다른 양태에 따르면， 본 발명은 c-Met 티로신 키나아제 활성을 억제하기 위한, 상기 신규한 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물의 용도를 제공한다.  According to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising the novel triazolo pyridazine derivative, pharmaceutically acceptable salt thereof, or solvate thereof for inhibiting c-Met tyrosine kinase activity as an active ingredient. Serves the purpose of.
본 발명의 또 다른 양태에 따르면， 본 발명은 이상증식성 질환 (hyper proliferative disorder)을 예방 또는 치료하기 위한, 상기 신규한 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물의 용도를 제공한다. 본 발명에서 사용되는 신규한 트리아졸로 피리다진 유도체에 대해서는 이미 상술하였으므로, 과도한 중복을 피하기 위하여 이를 생략한다.  According to another aspect of the present invention, the present invention provides a novel triazolo pyridazine derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient for preventing or treating hyper proliferative disorder. It provides a use of a pharmaceutical composition comprising. Since the novel triazole pyridazine derivatives used in the present invention have already been described above, it is omitted to avoid excessive duplication.
본 명세서에서 용어 "이상증식성 질환 (hyper proliferative disorder)" 은 정상적으로 성장 중인 동물체 내에서 일반적인 제한수단에 의해 조절되지 않는 과도한 세포의 성장， 분열 및 이동에 기인하여 유발되는 병적 상태를 의미한다. 본 발명의 조성물로 예방 또는 치료되는 이상증식성 질환에는 예를 들어 암, 당뇨병성 망막증, 미숙아 망막증， 각막 이식 거부, 신생혈관성 녹내장, 홍색증， 증식성 망막증, 건선， 류마티스 관절염, 골관절염， 자가면역 질환， 크론씨병， 재발협착증, 아테름성 동맥경화， 장관 접착， 궤양， 간경병증, 사구체신염, 당뇨병성 신장병증, 악성 신경화증， 혈전성 미소혈관증, 기관 이식 거부 및 신사구체병증이 있으나， 이에 제한되지 않고 세포의 비정상적인 증식 및 신생혈관의 과도한 생성으로 인해 발생하는 모든 이상증식성 질환이 포함된다. 보다 바람직하게는， 본 발명의 조성물로 예방 및 치료할 수 있는 이상증식성 질환의 하나인 암은 폐암, 위암， 췌장암， 대장암， 난소암, 신장 세포암， 전립선암 또는 뇌종양이다. As used herein, the term "hyper proliferative disorder" refers to a pathological condition caused by excessive cell growth, division and migration that is not regulated by general limiting means in a normally growing animal. Aberrant proliferative diseases that are prevented or treated with the compositions of the present invention include, for example, cancer, diabetic retinopathy, prematurity retinopathy, corneal transplant rejection, neovascular glaucoma, melanoma, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune diseases ， Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy, organ transplant rejection, and renal glomerulopathy All hyperproliferative diseases that arise due to abnormal proliferation of cells and excessive production of neovascularization are included. More preferably, the cancer which is one of the aberrant proliferative diseases which can be prevented and treated with the composition of the present invention is lung cancer, stomach cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우， 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다 . 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스 덱스트로스, 수크로스, 솔비를, 만니를， 전분 , 아카시아 고무 , 인산 칼슘， 알기네이트 , 젤라틴 , 규산 칼슘 , 미세결정성 샐를로스, 폴리비닐피를리돈， 샐를로스， 물, 시럽， 메틸 셀를로스, 메틸히드록시벤조에이트， 프로필히드록시벤조에이트, 활석， 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제， 습윤제， 감미제， 향미제， 유화제， 현탁제 , 보존제 등을 추가로 포함할 수 있다, 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed. , 1995)에 상세히 기재되어 있다.  When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the preparation, lactose dextrose, sucrose, sorbbi, manny, starch, acacia rubber, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil However, the present invention is not limited thereto. The pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and preparations are described in Remington's Pharmaceutical Sciences (19th). ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며， 비경구 투여인 경우에는 정맥내 주입， 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다.  The pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법， 투여 방식， 환자의 연령, 체중， 성, 병적 상태， 음식ᅳ 투여 시간, 투여 경로, 배설 속도 및 반웅 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 1일 투여량은 예컨대 0.001-100 rag/kg이다, 본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및 /또는 부형제를 이용하여 통상적인 제제로 제형화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 통상적인 제형이라 함은 예를 들면 경구 (정제， 캡술제, 분말제), 구강 내, 혀 밑, 직장 내， 질 내， 비강 내， 국소 또는 비경구 (정맥 내, 해면체 내, 근육 내， 피하 및 관 내를 포함) 투여 제형을 일컫는다. 예를 들면， 본 발명에 따른 화합물은 전분 또는 락토오즈를 함유하는 정제 형태로， 또는 단독 또는 부형제를 함유하는 캡슐 형태로, 또는 맛을 내거나 색을 띄게 하는 화학 약품을 함유하는 엘릭시르 또는 현탁제 형태로 경구， 구강 내 또는 혀 밑 투여될 수 있다. 액체 제제는 현탁제 (예를 들면， 메틸셀를로오즈， 위텝솔 (witepsol)과 같은 반합성 글리세라이드 또는 행인유 (apricot kernel oil)와 PEG-6 에스테르의 흔합물 또는 PEG-8과 카프릴릭 /카프릭 글리세라이드의 흔합물과 같은 글리세라이드 흔합물)와 같은 약제학적으로 허용 가능한 첨가제와 함께 제조된다. 또한 비경구적으로 예를 들면， 정맥 내， 해면체 내, 근육 내, 피하 및 관내를 통하여 주사되는 경우 무균의 수용액 형태로서 사용하는 것이 가장 바람직하며, 이때 상기 용액은 혈액과의 등장성을 갖기 위하여 다른 물질들 (예를 들면 염 (salt) 또는 만니를， 글루코오스와 같은 단당류)를 함유할 수도 있다. Suitable dosages of the pharmaceutical compositions of the present invention may be prescribed in various ways depending on factors such as formulation method, mode of administration, age, weight, sex, morbidity, pathology, time of administration, route of administration, rate of excretion and reaction response to the patient. Can be. The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 rag / kg. The pharmaceutical composition of the present invention may be easily carried out by those skilled in the art according to the present invention. It may be prepared in unit dose form or formulated into a multi-dose container by formulating it into a conventional formulation using pharmaceutically acceptable carriers and / or excipients. Conventional formulations include, for example, oral (tablets, capsules, powders), oral, sublingual, intrarectal, intravaginal, intranasal, topical or parenteral (intravenous, cavernous, intramuscular, subcutaneous). And dosage forms). For example, the compounds according to the invention may be in the form of tablets containing starch or lactose, or in the form of capsules containing singly or excipients, Or in the form of elixirs or suspending agents containing flavoring or coloring chemicals orally, orally or sublingually. Liquid formulations may include suspending agents (for example, a mixture of semi-synthetic glycerides such as methylcellose, witepsol or apricot kernel oil and PEG-6 esters or PEG-8 and caprylic / And pharmaceutically acceptable additives such as glyceride mixtures such as those of capric glycerides. It is also most preferred to use it as a sterile aqueous solution when injected parenterally, for example, intravenously, intracavernosally, intramuscularly, subcutaneously, and intratracheally, wherein the solution is different in order to have isotonicity with blood. It may also contain substances (for example salts or manny, monosaccharides such as glucose).
[발명의 효과】 [Effects of the Invention】
본 발명의 특징 및 이점을 요약하면 다음과 같다:  The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 신규한 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염， 이들을 유효성분으로 포함하는 C-Met 티로신 키나아제 활성 억제용 약제학적 조성물 및 이상증식성 질환 (hyper proliferative disorder)의 예방 또는 치료용 약제학적 조성물을 제공하며, 상가 조성물을 객체에 투여하는 단계를 포함하는, C-Met 티로신 키나아제 활성을 억제하고 이상증식성 질환을 예방 또는 치료하는 방법을 제공한다. (a) The present invention provides a novel triazole pyridazine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for inhibiting C- Met tyrosine kinase activity comprising the same as an active ingredient, and prevention of hyperproliferative disorder or Provided is a therapeutic pharmaceutical composition, the method comprising inhibiting C- Met tyrosine kinase activity and preventing or treating a hyperproliferative disease, comprising administering the additive composition to a subject.
(b) 본 발명은 c-Met 티로신 키나아제의 활성을 효율적으로 억제함으로써 비정상적인 키나제의 활성으로 인한 과도한 세포 증식 및 성장과 관련된 다양한 이상증식성 질환， 예를 들어 암, 건선， 류마티스 관절염, 당뇨병성 망막증 등의 치료제로 유용하게 이용될 수 있다.  (b) The present invention efficiently inhibits the activity of c-Met tyrosine kinase, thereby causing various dysplastic diseases associated with excessive cell proliferation and growth due to abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. It can be usefully used as a therapeutic agent for.
【발명을 실시하기 위한 구체적인 내용】 [Specific contents to carry out invention]
이하， 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다. 실시예 Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. . Example
트리아졸로 피리다진 유도체의 합성경로  Synthesis route of triazolo pyridazine derivative
본 발명의 상기 화학식 1로 트리아졸로 피리다진 유도체는 아래 반웅식 1에서 나타낸 바와 같이 진행하여 얻을 수 있다.  The triazolo pyridazine derivative of Formula 1 of the present invention may be obtained by proceeding as shown in Banung Formula 1 below.
<반웅식 1> <Banungsik 1>
Figure imgf000015_0001
Figure imgf000015_0001
상기 반응식 1에 사용된 상기 화학식 (2)， (6)으로 표시되는 중요한 중간체의 합성은 본 발명자들에 의해 처음으로 개시되었다. 화학식 (3)으로 표시된 3-클로로 -6—히드라지닐피리다진은 상업적으로 구매하거나 J. Med. Chem. 30, 239-249 (1987)에 예시되어있는 방법으로 제조하였다. 화학식 4의 제조는 먼저 화학식 2와 화학식 3을 H0BT(Hydr oxybenzot r i azo 1 e ) , EDCI{l-Ethyl-3-(3-dimethyl - aminopropyl)carbodiimide}을 사용한 결합 (EDCI coupling)반웅을 통하여 얻을 수 있고， 아세트산 용매하에서 가열하면 클로로기 (C1)가 치환된 트리아졸로피리다진 유도체 5를 얻을 수 있다. 화학식 (5)는 치환된 5각 또는 6각 고리의 아릴 또는 헤테로아릴기가 치환된 보론산 (boronic acid)나 보론산 피나콜에스터 (boronic acid pinacol ester)와 팔라듐 촉매 반웅을 진행하면 화학식 (9)를 얻을 수 있으며， 트리플루오로아세트산 (CF3C00H)을 가하고 가열하면 피리도옥사졸기의 파라메톡시벤질 (PMB) 보호기가 제거된 목적물 화학식 (1)을 얻올 수 있다. The synthesis of the important intermediates represented by Formulas (2) and (6) used in Scheme 1 was first initiated by the inventors. 3-Chloro-6—hydrazinylpyridazine represented by the formula (3) is commercially available or prepared from J. Med. Chem. 30, 239-249 (1987). Preparation of Chemical Formula 4 is carried out through the reaction of Chemical Formulas 2 and 3 using EDCI coupling using H0BT (Hydr oxybenzot ri azo 1 e) and EDCI {l-Ethyl-3- (3-dimethyl-aminopropyl) carbodiimide} The triazolopyridazine derivative 5 in which the chloro group (C1) is substituted can be obtained by heating in an acetic acid solvent. Formula (5) is a reaction of palladium catalysis with boronic acid or boronic acid pinacol ester substituted with substituted aryl or heteroaryl groups of 5-membered or 6-membered rings. When trifluoroacetic acid (CF 3 C00H) is added and heated, the target formula (1) from which the paramethoxybenzyl (PMB) protecting group of the pyridooxazole group is removed can be obtained.
또한 화학식 (2)의 메틸에스터 화합물 (6)으로부터 동일한 화합물 (9)를 얻을 수 있으며, 메틸에스터를 널리 공지된 방법으로 히드라진 (N¾N¾)와 반웅시켜 히드라자이드 (7)을 얻은 후 화학식 (8)과 부탄올 (n-BuOH)에서 가열 환류하며 목적 화합물 (9)를 얻을 수 있다. 이때 치환된 클로로피리다진은 2，6-디클로로피리다진과 다양한 치환체가 도입된 보로닉에시드나 보로닉에시드 피나콜에스트와 팔라듐 촉매하에서 반웅하여 얻을 수 있다.  It is also possible to obtain the same compound (9) from the methyl ester compound (6) of the formula (2), and to react the methyl ester with hydrazine (N¾N¾) by a well-known method to obtain hydrazide (7), and then to formula (8) It was heated to reflux in and butanol (n-BuOH) to obtain the target compound (9). Substituted chloropyridazine can be obtained by reacting under boronic acid or boronic acid pinacol est and palladium catalyst to which 2,6-dichloropyridazine and various substituents are introduced.
또한 상기 반응식 1에서 화학식 (2)는 하기 반웅식 2와 같은 방법으로 제조 할 수 있다.  In addition, Chemical Formula (2) in Scheme 1 may be prepared by the same method as in Scheme 2 below.
<반웅식 2〉 Banungsik 2
Figure imgf000016_0001
화학식 (10)으로 표시된 피리도옥사진 에틸에스트의 합성은 Tetrahedron 58(2008) 및 8145-8152나 US6465467(2002)에 개시되어있는 방법으로 제조하였다. 즉， 2-아미노 -3-히드록시피리딘 (2-amino-3- hydroxypyridine)과 디에틸클로로말로네이트 (diethyl chloromalonate)를 유기염기 존재하에서 가열 환류하여 화학식 (10)을 얻었다. 아마이드는 PMB보호기 (p-Methoxybenzyl protecting group)를 도입하고 보레인 (B¾)으로 아마이드와 에스터기를 환원하여 중간체인 피리도옥사진 메탄올 (12)를 얻었다. 한 개의 메틸기를 확장하기 위해 알코올에 토실기 (P- toluensulfonyl)를 도입한 후 소디움시아나이드 (NaCN)를 가하여 치환하면 화학식 (13)을 얻는다. -CN기를 DIBAL-H(Diisopropylaluminium hydride)로 환원하여 알데하이드를 얻은 다음 NaCl202를 사용한 산화반웅으로 카르복실산 (2)를 얻었다.
Figure imgf000016_0001
Synthesis of pyridooxazine ethyl ester represented by the formula (10) was prepared by the method disclosed in Tetrahedron 58 (2008) and 8145-8152 or US6465467 (2002). That is, 2-amino-3-hydroxypyridine and diethyl chloromalonate were heated and refluxed in the presence of an organic base to obtain Formula (10). Amide was introduced into the PMB protecting group (p-Methoxybenzyl protecting group) and reduced the amide and ester group with borane (B¾) to obtain an intermediate pyridooxazine methanol (12). To extend one methyl group, introduce a tosyl group (P-toluensulfonyl) to alcohol, and then add sodium cyanide (NaCN) to substitute the compound (13). The -CN group was reduced with DIBAL-H (Diisopropylaluminum hydride) to obtain an aldehyde, and then carboxylic acid (2) was obtained by oxidation reaction using NaCl 2 0 2 .
상술한 합성 모식도 (반웅식 1 및 2)를 통해서 합성된 트리아졸로 피리다진 유도체는 다음과 같다:  The triazolo pyridazine derivatives synthesized through the above synthetic schematic diagrams (Ref. 1 and 2) are as follows:
(1) 2-((6-(1-메틸— 1H-피라졸 -4—일) -[1，2,4]트리아졸로 [4，3- b]피리다진 -3-일)메틸) -3,4-디히드로 -2H-피리도 [3,2-b][l,4]옥사진;  (1) 2-((6- (1-methyl- 1H-pyrazol-4-yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl)- 3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine;
Figure imgf000017_0001
Figure imgf000017_0001
2-(4-(3-((3, 4-디히드로 -2H-피리도 [3 , 2-b] [1,4]옥사진 -2 일)메틸) - [ 1 , 2， 4]트리아졸로 [4， 3-b]피리다진— 6-일 )-1Η-피라졸 -1-일 )에탄을;  2- (4- (3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2 yl) methyl)-[1,2,4] tria Solo [4, 3-b] pyridazine- 6-yl) -1Η-pyrazol-1-yl) ethane;
Figure imgf000017_0002
Figure imgf000017_0002
(3) 2-( (6-( 1- (피페리딘 -4-일 )-1Η-피라출 -4-일 )-[ 1， 2，4]트리아졸로  (3) 2- ((6- (1- (piperidin-4-yl) -1Η-pyrazol-4-yl)-[1, 2,4] triazolo
[4， 3-b]피리다진— 3-일 )메틸 )-3 , 4-디히드로 -2H-피리도 [3 , 2-b] [ 1， 4]옥사진； [4, 3-b] pyridazine- 3-yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine;
Figure imgf000018_0001
Figure imgf000018_0001
(4) 4— (3-((3，4-디히드로— 2H-피리도 [3,2-b][l,4]옥사진 -2-일)메틸) - [ 1ᅳ 2 , 4]트리아졸로 [4， 3-b]피리다진— 6-일 )-2-플루오로페놀  (4) 4— (3-((3,4-dihydro— 2H-pyrido [3,2-b] [l, 4] oxazin-2-yl) methyl)-[1 ᅳ 2, 4] Triazolo [4,3-b] pyridazine— 6-yl) -2-fluorophenol
Figure imgf000018_0002
Figure imgf000018_0002
(5) 2-( (6— (3—플루오로 -4-(2-(4—메틸피페라진— 1-일)에특시 )페닐) - [1，2,4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3,4-디히드로-2H- 피리도[3,2-b][l，4]옥사진 (5) 2- ((6— (3—fluoro-4- (2- (4—methylpiperazin— 1-yl)) phenyl)-[1,2,4] triazolo [4,3 -b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine
Figure imgf000018_0003
Figure imgf000018_0003
(6) 2ᅳ((6— (1-메틸 -1H-인돌 -3-일) -[1，2，4]트리아졸로 [4,3- b]피리다진 -3-일 )메틸) -3 , 4-디히드로 -2H-피리도 [3， 2-b] [ 1 , 4]옥사진 ;  (6) 2 ′ ((6— (1-methyl-1H-indol-3-yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3 , 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine;
Figure imgf000018_0004
Figure imgf000018_0004
(7) 2-((6-페닐 -[l,2,4]트리아졸로[4,3-b]피리다진-3-일)메틸)-3，4- 디히드로ᅳ 2H-피리도 [3， 2-b] [1,4]옥사진； (7) 2-((6-phenyl- [l, 2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydrox 2H-pyrido [3 , 2-b] [1,4] oxazine;
Figure imgf000019_0001
Figure imgf000019_0001
(8) 2-((6-(4—플루오로페닐 )-[1，2，4]트리아졸로 [4,3-b]피리다진 -3- 일 )메틸) -3， 4-디히드로 -2H-피리도 [3， 2-b] [ 1 , 4]옥사진；  (8) 2-((6- (4—fluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine;
Figure imgf000019_0002
Figure imgf000019_0002
(9) 2-((6-(3-플루오로페닐 )-[l，2,4]트리아졸로[4，3-b]피리다진-3- 일)메틸)—3，4-디히드로-2H-피리도[3,2-b][l,4]옥사진;  (9) 2-((6- (3-fluorophenyl)-[l, 2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro- 2H-pyrido [3,2-b] [l, 4] oxazine;
Figure imgf000019_0003
Figure imgf000019_0003
(10) 2-((6-(3，5-디플루오로페닐)-[1,2，4]트리아졸로[4,3- b]피리다진 -3-일 )메틸) -3 , 4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진；  (10) 2-((6- (3,5-difluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4- Dihydro-2H-pyrido [3, 2-b] [1,4] oxazine;
Figure imgf000019_0004
Figure imgf000019_0004
(11) 2-((6-(3-플루오로-4—메틸페닐)-[1,2,4]트리아졸로[4，3_ b]피리다진 -3-일 )메틸 )-3， 4-디히드로 -2H-피리도 [3 , 2-b] [1,4]옥사진； (11) 2-((6- (3-fluoro-4—methylphenyl)-[1,2,4] triazolo [4,3_b] pyridazin-3-yl) methyl) -3,4-di Hydro-2H-pyrido [3, 2-b] [1,4] oxazine;
Figure imgf000020_0001
Figure imgf000020_0001
(12) 3-(3-((3，4-디히드로 -2H-피리도 [3,2-b][l,4]옥사진 -2ᅳ일 )메틸) - [1,2,4]트리아졸로 [4, 3-b]피리다진 -6-일)벤조나이트라일;  (12) 3- (3-((3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine-2 ylyl) methyl)-[1,2,4] tria Solo [4, 3-b] pyridazin-6-yl) benzonitrayl;
Figure imgf000020_0002
Figure imgf000020_0002
(13) 2-( (6- (피리딘 -4-일 )-[1,2, 4]트리아졸로 [4， 3-b]피리다진 -3- 일)메틸) -3,4—디히드로 -2H-피리도 [3,2-b][l,4]옥사진;  (13) 2- ((6- (pyridin-4-yl)-[1,2, 4] triazolo [4, 3-b] pyridazin-3-yl) methyl) -3,4—dihydro- 2H-pyrido [3,2-b] [l, 4] oxazine;
Figure imgf000020_0003
Figure imgf000020_0003
(14) 2ᅳ ((6— (피리딘 -3-일) -[1，2, 4]트리아졸로 [4, 3-b]피리다진 -3- 일 )메틸) -3， 4-디히드로 -2H-피리도 [3， 2-b] [ 1 , 4]옥사진；  (14) 2 '((6— (pyridin-3-yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine;
Figure imgf000020_0004
Figure imgf000020_0004
(15) 2-((6-(4-메록시페틸) -[1ᅳ 2,4]트리아졸로 [4,3-b]피리다진-3- 일)메틸 )-3， 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진； (15) 2-((6- (4-Methoxyfetyl)-[1'2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine;
Figure imgf000021_0001
Figure imgf000021_0001
(16) 4-(3—((3，4-디히드로- -피리도[3，2-13][1，4]옥사진-2-일)메틸)- [1,2, 4]트리아졸로 [4,3-b]피리다진 -6-일) -Ν,Ν-디메틸벤젠아민;  (16) 4- (3 — ((3,4-dihydro-pyrido [3,2-13] [1,4] oxazin-2-yl) methyl)-[1,2,4] tria Solo [4,3-b] pyridazin-6-yl) -Ν, Ν-dimethylbenzeneamine;
Figure imgf000021_0002
Figure imgf000021_0002
(17) 메틸 4-(3-((3，4—디히드로 -2Η-피리도 [3,2-b][l,4]옥사진 -2- 일)메틸) -[1,2, 4]트리아졸로 [4,3-b]피리다진— 6-일)벤조에이트;  (17) Methyl 4- (3-((3,4—dihydro-2Η-pyrido [3,2-b] [l, 4] oxazin-2-yl) methyl)-[1,2, 4 ] Triazolo [4,3-b] pyridazine- 6-yl) benzoate;
Figure imgf000021_0003
Figure imgf000021_0003
(18) 메틸 3-(3-((3,4-디히드로—211-피리도[3，2-1)][1,4]옥사진-2- 일)메틸) -[1，2, 4]트리아졸로 [4,3-b]피리다진 -6-일)벤조에이트  (18) methyl 3- (3-((3,4-dihydro-211-pyrido [3,2-1)] [1,4] oxazin-2-yl) methyl)-[1,2, 4] triazolo [4,3-b] pyridazine-6-yl) benzoate
Figure imgf000021_0004
Figure imgf000021_0004
( 19) (4-(3-((3， 4-디히드로 -2Η-피리도 [3 , 2-b] [1,4]옥사진 -2- 일)메틸) -[1，2，4]트리아졸로 [4,3-b]피리다진 -6-일)페닐)메탄을; (19) (4- (3-((3,4-dihydro-2Η-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl)-[1,2,4 ] Triazol [4,3-b] pyridazin-6-yl) phenyl) methane;
Figure imgf000022_0001
Figure imgf000022_0001
(20) 2-((6-(4- (몰폴리노메틸)페닐) -[l,2，4]트리아졸로[4，3- b]피리다진-3-일)메틸)-3，4-디히드로—2H-피리도[3，2-b][l,4]옥사진;  (20) 2-((6- (4- (morpholinomethyl) phenyl)-[l, 2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4 -Dihydro—2H-pyrido [3,2-b] [l, 4] oxazine;
Figure imgf000022_0002
Figure imgf000022_0002
(21)(3ᅳ(3— ((3,4-디히드로-2^피리도[3,2-Z?][l,4]옥사진-2-일)메틸)- [l,2,4]트리아졸로[4，3-)]피리다진-6-일)페닐)(4-메틸페라진-l-일)메타논 (21) (3 ′ (3 — ((3,4-dihydro-2 ^ pyrido [3,2-Z?] [L, 4] oxazin-2-yl) methyl)-[l, 2, 4] triazolo [4,3- ) ] pyridazin-6-yl) phenyl) (4-methylperazine-1-yl) methanone
Figure imgf000022_0003
Figure imgf000022_0003
(22) (4-(3-( (3，4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진 -2- 일)메틸) _[1，2，4]트리아졸로 [4,3-b]피리다진 -6-일)페닐) (4-메틸 -1- 일)메탄온;  (22) (4- (3- ((3,4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazin-2-yl) methyl) _ [1,2,4 ] Triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methyl-1-yl) methanone;
Figure imgf000022_0004
(23) 3-(3-((3 , 4-디히드로 -2H-피리도 [3 , 2-b] [1,4]옥사진 -2-일 )메틸) - [1，2，4]트리아졸로 [4,3-b]피리다진 -6-일) -N—에틸벤자아미드;
Figure imgf000022_0004
(23) 3- (3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl)-[1,2,4] Triazolo [4,3-b] pyridazin-6-yl) -N—ethylbenzaamide;
Figure imgf000023_0001
Figure imgf000023_0001
(24) (3-(3-((3， 4—디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진 -2- 일)메틸) -[1， 2,4]트리아졸로 [4,3-b]피리다진 -6-일)페닐) (4-메틸피페라진 -1ᅳ 일)메탄온;  (24) (3- (3-((3, 4—dihydro-2H-pyrido [3, 2-b] [1,4] oxazin-2-yl) methyl)-[1, 2,4 ] Triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylpiperazin-1xyl) methanone;
Figure imgf000023_0002
Figure imgf000023_0002
(25) 2-( (6-( 1—메틸 -1H—인다졸— 3-일 )- [ 1， 2， 4]트리아졸로 [4 , 3- b]피리다진 -3-일)메틸) -3，4-디히드로 -2H-피리도 [3,2-b][l,4]옥사진; (25) 2-((6- (1-methyl-1H-indazol— 3-yl)-[1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl) methyl)- 3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine;
Figure imgf000023_0003
각각의 트리아졸로 피리다진 유도체의 구체적 합성방법
Figure imgf000023_0003
Specific synthesis method of each triazolo pyridazine derivative
실시예 1. 에틸 3-옥소 -3 , 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진- 2-카르복실에스트
Figure imgf000024_0001
Example 1. Ethyl 3-oxo-3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine- 2-carboxyester
Figure imgf000024_0001
2-아미노 -3—히드특시피리딘 (5 g, 45.4 mmol)을 에탄을 (90 mL)에 용해시킨 후 트리에틸아민 (6.3 mL, 45.4 mmol)과 디에틸 2- 클로로말로네이트 (7.3 mL, 45.4 mmol)를 가한 다음 16시간 가열 환류하였다. 실온으로 온도를 낮춘 뒤 형성된 고체를 여과하고 차가운 에탄올로 씻어주어 에틸 3ᅳ옥소 -3,4-디히드로-2H-피리도[3，2-b][l，4]옥사진-2- 카르복실에스트(6.41 g, 64%)를 얻었다. 2-amino-3-hydricpyridine (5 g, 45.4 mmol) was dissolved in ethane (90 mL), followed by triethylamine (6.3 mL, 45.4 mmol) and diethyl 2-chloromalonate (7.3 mL, 45.4 mmol) was added and then heated to reflux for 16 hours. After lowering the temperature to room temperature, the solid formed was filtered and washed with cold ethanol to give ethyl 3-ioxo-3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine-2-carbox. Compound ester (6.41 g, 64%) was obtained.
-赚 (300 MHz, CDCls) δ 11.65 (brs, 1H), 8.12 (d, / = 6.0 Hz, 1H), 7.41 (d, 8.0 Hz, 1H) , 7.02 (dd, J = 9.0, 6,0 Hz, 1H) , 4.27 (q, J= 7.5 Hz, 2H) 3.83 (s, 1H), 1.26 (t( J = 7.5 Hz, 3H) 실시예 2. (4- (4-메톡시벤질) -3， 4-디히드로 -2H-피리도 [3, 2- b][l, 4]옥사진 -2-일)메탄올
Figure imgf000024_0002
-赚 (300 MHz, CDCls) δ 11.65 (brs, 1H), 8.12 (d, / = 6.0 Hz, 1H), 7.41 (d, 8.0 Hz, 1H), 7.02 (dd, J = 9.0, 6,0 Hz , 1H), 4.27 (q, J = 7.5 Hz, 2H) 3.83 (s, 1H), 1.26 (t ( J = 7.5 Hz, 3H) Example 2 (4- (4-methoxybenzyl) -3) 4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazin-2-yl) methanol
Figure imgf000024_0002
3-옥소 -3， 4-디히드로 -2H-피리도 [3 , 2-b] [1,4]옥사진 -2 카르복실에스트 (9.1 g, 40.95 隱 ol)를 DMF(70 mL)에 녹인 후 포타슘카보네이트 (17 g, 122.8 隱 ol)와 4-메록시벤질클로라이드 (PMBC1, 5.8 mL, 43 隱 ol)를 가하고 50°C에서 2시간 동안 교반하였다. 반응 후 에틸아세테이트를 가한 후 유기층을 소금물로 수번 세척한 후 무수황산나트륨으로 건조하고 감압하에서 용매를 제거하였다. 잔사를 컬럼클로마토그래피 (20% EtOAc/hexane)로 정제하여 목적화합물인 에틸 4- (4-메록시벤질 )-3-옥소 -3 , 4-디히드로 -2H-피리도 [3 , 2-b] [ 1， 4]옥사진 -2- 카르복실레이트 (12.2 g, 87%)를 얻었다. 3-oxo-3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-2 carboxylate (9.1 g, 40.95 隱 ol) dissolved in DMF (70 mL) Then potassium carbonate (17 g, 122.8 隱 ol) and 4-methoxybenzylchloride (PMBC1, 5.8 mL, 43 隱 ol) were added and stirred at 50 ° C for 2 hours. After the reaction, ethyl acetate was added, the organic layer was washed several times with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (20% EtOAc / hexane) to give the title compound ethyl 4- (4-methoxybenzyl) -3-oxo-3, 4-dihydro-2H-pyrido [3, 2- b] [1,4] oxazine-2-carboxylate (12.2 g, 87%) was obtained.
Ή-N R (300 MHz, CDC13) δ 8.06 (d, J = 6.0 Hz, 1H)， 7.39 (d, J = 8.8 Hz, 2H)ᅳ 7.33 (d, J = 8.0 Hz, 1H), 6.96 (dd, / = 8.0, 6.0 Hz 1H), 6.80(d, J = 8.8 Hz, 2H), 5.27 (ABq, / = 14.0 Hz, 2H)， 5.26 (s 1H), 4.21 (q, / = 7.0 Hz, 2H), 3.76 (s, 3H), 1.24 (t, J= 7.0 Hz, 3H). 에틸 4_ ( 4_메록시벤질 )_3_옥소 _3， 4ᅳ디히드로 -2H-피리도 [3， 2- b] [1,4]옥사진 -2-카르복실레이트 (27 g, 78.9 mmol)를 건조된 테트라히드로퓨란 (250 mL)에 녹인 후 BH3SMe2 (2.0 M in THF, 178 mL, 355 隱 ol)를 천천히 가하고 48시간 가열환류하였다. 반웅 후 0°C로 넁각한 다음 2N-탄산칼슘 수용액을 조심스럽게 가하여 과량의 BH3SMe2를 분해한 다음 에틸아세테이트를 가하고 유기층을 소금물로 수번 세척하였다. 유기층을 무수황산나트륨으로 건조하고 감압 농축한 후 잔사를 컬럼크로마토그래피 (3OT EtOAC/hexane)로 정제하여 목적화합물인 (4— (4- 메록시벤질) -3， 4-디히드로 -2H-피리도 [3 , 2-b] [ 1， 4]옥사진 -2-일 )메탄올 ( 16.5 g, 73%)을 무색 오일로 얻었다. Ή-NR (300 MHz, CDC1 3 ) δ 8.06 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H) ᅳ 7.33 (d, J = 8.0 Hz, 1H), 6.96 (dd , / = 8.0, 6.0 Hz 1H), 6.80 (d, J = 8.8 Hz, 2H), 5.27 (ABq, / = 14.0 Hz, 2H), 5.26 (s 1H), 4.21 (q, / = 7.0 Hz, 2H), 3.76 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H). Ethyl 4 _ ( 4 _ hydroxybenzyl) _ 3 _ oxo _ 3 , 4 ᅳ dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-2-carboxylate (27 g, 78.9 mmol) was dissolved in dried tetrahydrofuran (250 mL), and BH 3 SMe 2 (2.0 M in THF, 178 mL, 355 mL) was added slowly and heated to reflux for 48 hours. After reaction, the mixture was stirred at 0 ° C., and 2N-calcium carbonate aqueous solution was carefully added to decompose excess BH 3 SMe 2 , ethyl acetate was added, and the organic layer was washed several times with brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (3OT EtOAC / hexane) to obtain the title compound (4— (4- methoxybenzyl) -3, 4-dihydro-2H-pyrido. [3, 2-b] [1, 4] oxazine-2-yl) methanol (16.5 g, 73%) was obtained as a colorless oil.
Hi-證 (300 MHz, CDC13) δ 7.79 (dd, / = 4.9, 0.8 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H)( 6.84 (d, J = 8.5 Hz, 2H), 6.55 (dd, J = 7.5, 5.0 Hz, 1H) , 4.79 (ABq, J = 14.0 Hz, 2H) , 4.19 (m, 1H), 3.79 (s, 3H), 3.75 (m, 2H), 3.26 (m, 2H). 실시예 3. 2-(4-(4-메록시벤질) -3, 4一디히드로—2H-피리도 [3， 2~ b][l, 4]옥사진 -2 -일)아세토나이트릴 Hi- 證 (300 MHz, CDC1 3 ) δ 7.79 (dd, / = 4.9, 0.8 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H) ( 6.84 (d, J = 8.5 Hz, 2H), 6.55 (dd, J = 7.5, 5.0 Hz, 1H), 4.79 (ABq, J = 14.0 Hz, 2H), 4.19 (m, 1H), 3.79 (s, 3H) , 3.75 (m, 2H), 3.26 (m, 2H) Example 3. 2- (4- (4-methoxybenzyl) -3,4didihydro—2H-pyrido [3, 2 to b] [l, 4] oxazine-2 -day) acetonitrile
Figure imgf000025_0001
Figure imgf000025_0001
(4-(4-메특시벤질) -3 , 4-디히드로 -2H-피리도 [3 , 2— b] [ 1， 4]옥사진 -2- 일)메탄올 (16,5 g, 57.5隱 ol)을 디클로로메탄 (Γ70 mL)에 녹인 후 0 0C에서 4-를로엔설포닐클로라이드 (TsCl, 14.3 g, 74.8 mmol), DMAP(702 mg, 5.75 mmol) 및 트리에틸아민 (12.03 mL, 86.3 画 ol)을 차례로 가한 다음 실온에서 3시간 동안 교반하였다. 반웅 후 반응 용액을 물과 소금물로 세척한 후 유기층을 무수 황산나트륨으로 건조한 다음 감압농축하고 컬럼크로마토그래피 (20% EtOAC/hexane)로 정제하여 목적화합물인 (4-(4_ 메특시벤질) -3， 4-디히드로 -2^피리도 [3， 2-b] [ 1， 4]옥사진 -2-일 )메틸 -4- 메틸벤젠슬포네이트 (25 g, 93%)를 연노란 고체로 얻었다.(4- (4-Methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2—b] [1,4] oxazin-2-yl) methanol (16,5 g, 57.5 隱ol) was dissolved in dichloromethane (Γ70 mL) and then 4-chloroenesulfonylchloride (TsCl, 14.3 g, 74.8 mmol), DMAP (702 mg, 5.75 mmol) and triethylamine (12.03 mL, at 0 0 C). 86.3 μl ol) were added sequentially and stirred at room temperature for 3 hours. After reaction, the reaction solution was washed with water and brine, and then the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (20% EtOAC / hexane) to obtain the title compound (4- (4_methoxybenzyl) -3). 4-dihydro-2 ^ pyrido [3,2-b] [1,4] oxazin-2-yl) methyl-4- Methylbenzenesulfonate (25 g, 93%) was obtained as a light yellow solid.
-證 (300 腿 z, CDCls) δ 7.78 (m, 3H), 7.75 (d, J = 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 1H), 6.86 (m, 3H), 6.53 (dd, J = 7.6, 5.0 Hz 1H), 4.79 (ABq, J = 14.0 Hz, 2H), 4.27 (m, 1H), 4.17-4.00 (m, 2H), 3.79 (s, 3H), 3.27 (dd, J= 12.2， 2.7 Hz, 1H), 3.14 (dd, J = 12.2, 7.0 Hz, 1H), 2.45 (s, 3H).  -證 (300 腿 z, CDCls) δ 7.78 (m, 3H), 7.75 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 9.0 Hz, 1H), 6.86 (m, 3H), 6.53 ( dd, J = 7.6, 5.0 Hz 1H), 4.79 (ABq, J = 14.0 Hz, 2H), 4.27 (m, 1H), 4.17-4.00 (m, 2H), 3.79 (s, 3H), 3.27 (dd, J = 12.2, 2.7 Hz, 1H), 3.14 (dd, J = 12.2, 7.0 Hz, 1H), 2.45 (s, 3H).
(4-(4-메록시벤질) -3， 4-디히드로 -2^피리도 [3 , 2-b] [1,4]옥사진 -2- 일)메틸 -4-메틸벤젠슬포네이트 (3 g, 6.81 隱 ol)를 DMS0(30 mL)에 녹인 후 소디움시아나이드 (NaCN, 1.74 g, 35.41 圍 ol)를 가하고 50°C에서 2시간 동안 교반하였다. 반웅 후 쎄틸아세테이트를 가하여 희석하고 포화 소디움바이카보네이트 (NaHC03) 수용액과 소금물로 수 번 세척한 다음 무수 황산나트륨으로 건조하고 감압 농축하였다. 잔사를 컬럼크로마토그래피 (20% EtOAc/hexane)로 정제하여 목적화합물인 2-(4-(4- 메톡시벤질) -3， 4-디히드로 -2^피리도 [3， 2-b] [ 1 , 4]옥사진 -2- 일)아세토나이트릴 (1.52 g, 75 %)을 노란색 오일로 얻었다. (4- (4-methoxybenzyl) -3,4-dihydro-2 ^ pyrido [3,2-b] [1,4] oxazin-2-yl) methyl-4-methylbenzenesulfonate ( 3 g, 6.81 μl ol) was dissolved in DMS0 (30 mL), and sodium cyanide (NaCN, 1.74 g, 35.41 μl) was added and stirred at 50 ° C. for 2 hours. After reaction, cetyl acetate was added and diluted, washed several times with saturated aqueous sodium bicarbonate (NaHC0 3 ) solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc / hexane) to give the title compound 2- (4- (4-methoxybenzyl) -3,4-dihydro-2 ^ pyrido [3, 2-b] [ 1,4] oxazine-2-yl) acetonitrile (1.52 g, 75%) was obtained as a yellow oil.
一匿 (300 MHz, CDCI3) δ 7.85 (dd, J = 4.9， 1.4 Hz ， 1H), 7.22 (d, / = 8.6 Hz, 2H), 7.01 (dd, J = 7.7, 1.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.59 (dd, / = 7.7, 4.9 Hz, 1H) , 4.79 (s, 2H), 4.38 (m, 1H), 3.79 (s, 3H), 3.41 (dd, J = 12.2, 2.7 Hz, 1H), 3.22 (dd, J = 12.2， 7.0 Hz, 1H), 2.68 (t, 6.5 Hz, 2H). 실시예 4. 2-(4-(4-메특시벤질) -3, 4-디히드로 -2H-피리도 [3， 2_ b][l, 4]옥사진 -2-일)아세트산 (300 MHz, CDCI 3 ) δ 7.85 (dd, J = 4.9, 1.4 Hz, 1H), 7.22 (d, / = 8.6 Hz, 2H), 7.01 (dd, J = 7.7, 1.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.59 (dd, / = 7.7, 4.9 Hz, 1H), 4.79 (s, 2H), 4.38 (m, 1H), 3.79 (s, 3H), 3.41 (dd , J = 12.2, 2.7 Hz, 1H), 3.22 (dd, J = 12.2, 7.0 Hz, 1H), 2.68 (t, 6.5 Hz, 2H). Example 4. 2- (4- (4-Methoxybenzyl) -3,4-dihydro-2H-pyrido [3, 2_b] [l, 4] oxazin-2-yl) acetic acid
Figure imgf000026_0001
Figure imgf000026_0001
2-(4-(4-메톡시벤질) -3, 4-디히드로 -2^피리도 [3,2-6] [1,4]옥사진—2- 일)아세토나이트릴 (2.85 g, 9.66 mmol)를 무수 디클로로메탄 (100 mL)에 녹인 후 -78 °(：에서 다이발 (DIBAL-H, 3.4 mL, 19.33 mmol)을 적가한 후 한 시간 동안 교반한다음 이소프로필알코올 (2 mL)을 적가한다. 증류수 (2 mL)를 가하고 실온에서 한 시간 동안 교반한 후 실리카겔 (5 g)과 무수 황산마그네슘 (MgS04, 5 g)을 가한 다음 실온에서 한 시간 더 교반한다. 반응액을 실라이트 (celite)를 통해 여과하고 여액을 감압 농축한 후 컬럼크로마토그래피 (5% EtOAc/hexane)로 정제하여 목적화합물인 2— (4-(4- 메특시벤질) -3 , 4-디히드로 -2y 피리도 [3 , 2-b] [ 1 , 4]옥사진 -2- 일)아세트알데하이드 (2.3 g, 80 %)를 얻었다. 2- (4- (4-methoxybenzyl) -3,4-dihydro-2 ^ pyrido [3,2-6] [1,4] oxazine—2-yl) acetonitrile (2.85 g, 9.66 mmol) was dissolved in anhydrous dichloromethane (100 mL), then dival (DIBAL-H, 3.4 mL, 19.33 mmol) was added dropwise at -78 ° C and stirred for an hour, followed by isopropyl alcohol (2 mL). Add distilled water (2 mL) was added and stirred at room temperature for 1 hour, followed by addition of silica gel (5 g) and anhydrous magnesium sulfate (MgS0 4 , 5 g), followed by further stirring at room temperature. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and then purified by column chromatography (5% EtOAc / hexane) to give the title compound 2— (4- (4- mesocibenzyl) -3, 4 -Dihydro-2y pyrido [3,2-b] [1,4] oxazin-2-yl) acetaldehyde (2.3 g, 80%) was obtained.
2-(4— (4-메록시벤질) -3， 4-디히드로 -2v 피리도 [3， 2~b] [1,4]옥사진 -2- 일)아세트알데하이드 (1.3 g, 4.36 画 ol)에 부탄올 (11 mL)과. 2-메틸 -2- 부틴 (11 mL)을 가하고 0 °(：에서 NaC102 (1.97 g, 21.79 瞧 ol)을 가한 후 10분간 교반 한 다음 K¾P04 ( 2.96 g, 21.79 画 ol)를 증류수 (11 mL)에 녹여 반웅 용액에 적가하고 실온에서 2시간 동안 교반하였다. 반응 후 용액올 감압 농축하고 물을 조금 가한 후 5N-염산 수용액으로 pH 3~4로 맞춘 후 디클로로메탄을 가하고 소금물로 수번 세척한 다음 무수 황산나트륨으로 건조 후 감압농축하여 노란색 2-(4-(4—메톡시벤질) -3，4-디히드로ᅳ2^ 피리도 [3,2-b][l,4]옥사진 2-일)아세트산 (0.73 gᅳ 53 %)을 얻었다.2- (4— (4-methoxybenzyl) -3,4-dihydro-2v pyrido [3,2 to b] [1,4] oxazin-2-yl) acetaldehyde (1.3 g, 4.36 画ol) with butanol (11 mL). 2-Methyl-2-butyne (11 mL) was added, NaC10 2 (1.97 g, 21.79 瞧 ol) was added at 0 ° (:), stirred for 10 minutes, and K¾P0 4 (2.96 g, 21.79 画 ol) was added to distilled water (11 mL), added dropwise to the reaction solution, and stirred at room temperature for 2 hours.After the reaction, the solution was concentrated under reduced pressure, a little water was added, the pH was adjusted to 3-4 with 5N hydrochloric acid solution, and dichloromethane was added and washed several times with brine. Then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give yellow 2- (4- (4—methoxybenzyl) -3,4-dihydro ᅳ 2 ^ pyrido [3,2-b] [l, 4] oxazine 2- I) acetic acid (0.73 g ᅳ 53%) was obtained.
-證 (300 MHz, DMS0-d6) δ 7.67 (dd, J = 4.9, 1.5 Hz ， 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.93 (dd, J = 7.7， 1.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.51 (dd, J二 7.7, 4.9 Hz, 1H), 4.83 (d, A of ABq, / = 15.0 Hz, 1H), 4.70 (d, B of ABq, / = 15.0 Hz, 1H), 4.39 (m, 1H), 3.68 (s, 3H), 3.41 (dd, / = 12.2, 2.7 Hz, 2H), 3.22 (dd, / = 12.2, 7.0 Hz, 2H). 실시예 5. 2-( (6-클로로 - [ 1 , 2 , 4]트리아졸로 [4 , 3-b]피리다진 -3- 일)메틸) -4-(4-메톡시벤질) -3, 4—디히드로—2H-피리도 [3， 2-b ][1, 4 ]옥사진 -證 (300 MHz, DMS0-d 6 ) δ 7.67 (dd, J = 4.9, 1.5 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.93 (dd, J = 7.7, 1.4 Hz, 1H ), 6.85 (d, J = 8.6 Hz, 2H), 6.51 (dd, J 二 7.7, 4.9 Hz, 1H), 4.83 (d, A of ABq, / = 15.0 Hz, 1H), 4.70 (d, B of ABq, / = 15.0 Hz, 1H), 4.39 (m, 1H), 3.68 (s, 3H), 3.41 (dd, / = 12.2, 2.7 Hz, 2H), 3.22 (dd, / = 12.2, 7.0 Hz, 2H ). Example 5. 2-((6-Chloro- [1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -4- (4-methoxybenzyl) -3, 4—dihydro—2H-pyrido [3 ， 2-b] [1, 4] oxazine
Figure imgf000027_0001
Figure imgf000027_0001
2- (4- (4-메록시벤질) -3 , 4-디히드로 -2^피리도 [3， 2-Z?] [ 1， 4]옥사진 -2- 일)아세트산 (0.5 g, 1.59 mmol)을 DMF(15 mL)에 녹인 후 히드록시벤조트리아졸 (HOBT, 0.33 g, 2.387 mmol), 1-에틸— 3-(3- 디메틸아미노프로필) 카르보디이미드 (EDCI, 0.45 g (2.39 圆 ol), 3-클로로- 6-히드라지닐피리다진 (0.28 g, 1.91 mmol), 그리고 트리에틸아민 (0.45 mL, 3.18 麵 ol)을 가한 다음 실온에서 12시간 교반하였다. 반웅 후 에틸아세테이트로 회석하고 소금물로 수번 세척한 후 무수 황산나트륨으로 건조하여 yV'-(6-클로로피리다진 -3-일 )— 2-(4-(4—메록시벤질) -3， 4-디히드로- 2^피리도 [3, 2-Z?] [1,4]옥사진 -2-일)아세토히드라자이드 (650 mg)를 얻고 정제 없이 다음반웅을 진행하였다. 아세트산 (15 mL)에 녹인 후 8C C에서 18시간 교반 한 후 2M-탄산나트륨 수용액으로 중화한 다음 에틸아세테이트를 가하여 추출하였다. 유기층을 무수 황산나트륨으로 건조한 후 감압농축하고 컬럼 크로마토그래피 (3% Me0H/CH2Cl2)로 정제하여 목적화합물인 2— ((6-클로로 -[1,2ᅳ 4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) - 4— (4—메록시벤질)—3， 4-디히드로 -2^피리도 [3， 2— 1,4]옥사진 (285 mg, 46 ¾>)을 얻었다.2- (4- (4-Methoxybenzyl) -3,4-dihydro-2 ^ pyrido [3,2-Z?] [1,4] oxazin-2-yl) acetic acid (0.5 g, 1.59 mmol) in DMF (15 mL) Hydroxybenzotriazole (HOBT, 0.33 g, 2.387 mmol), 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide (EDCI, 0.45 g (2.39 圆 ol), 3-chloro-6-hydrazinyl Pyridazine (0.28 g, 1.91 mmol), and triethylamine (0.45 mL, 3.18 麵 ol) were added, followed by stirring at room temperature for 12 hours, after reaction, distilled with ethyl acetate, washed several times with brine, and dried over anhydrous sodium sulfate. yV '-(6-chloropyridazin-3-yl) — 2- (4- (4—methoxybenzyl) -3, 4-dihydro-2 ^ pyrido [3, 2-Z?] [1, 4] Oxazin-2-yl) acetohydrazide (650 mg) was obtained and the following reaction was carried out without purification: It was dissolved in acetic acid (15 mL), stirred at 8C C for 18 hours, and neutralized with 2M aqueous sodium carbonate solution. Ethyl acetate was added for extraction and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography (3% Me0H / CH 2 Cl 2 ), and Red compound 2— ((6-chloro- [1,2 ᅳ 4] triazolo [4,3-b] pyridazin-3-yl) methyl)-4— (4—methoxybenzyl) —3, 4 -Dihydro-2 ^ pyrido [3, 2-1,4] oxazine (285 mg, 46 ¾>) was obtained.
-NMR (300 MHz, CDC13) δ 8.58 (d, / = 6.0 Hz, 1H), 8.25 (d, J-NMR (300 MHz, CDC1 3 ) δ 8.58 (d, / = 6.0 Hz, 1H), 8.25 (d, J
= 6.0 Hz, 1H), 7.80 (dd, J = 4.8， 1.4 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.99 (dd, J = 7.7, 1.4 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H) , 6.54 (dd, J 7.7, 4.8 Hz, 1H), 4.73 (ABq, J = 14.9 Hz, 2H), 4.53 (m, 1H), 3.79 (s, 3H), 3.35 (dd, J= 12.2， 2.7 Hz, 1H), 3.18 (dd, / = 12.2' 7.0 Hz, 1H), 2.53 (m, 2H). 실시예 6. 4-(4-메톡시벤질) -2-((6-(l-메틸 -1H-피라졸 -4-일) - [1,2, 4]트리이졸로 [4 , 3-b]피리다진 -3-일)메틸) -3 , 4-디히드로 -2Η- 피리도 [3,2-b][l,4]옥사진 = 6.0 Hz, 1H), 7.80 (dd, J = 4.8, 1.4 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.99 (dd, J = 7.7, 1.4 Hz, 1H), 6.83 (d , J = 8.6 Hz, 2H), 6.54 (dd, J 7.7, 4.8 Hz, 1H), 4.73 (ABq, J = 14.9 Hz, 2H), 4.53 (m, 1H), 3.79 (s, 3H), 3.35 ( dd, J = 12.2, 2.7 Hz, 1H), 3.18 (dd, / = 12.2 ′ 7.0 Hz, 1H), 2.53 (m, 2H). Example 6. 4- (4-methoxybenzyl) -2-((6- (l-methyl-1H-pyrazol-4-yl)-[1,2,4] triazolo [4, 3-b ] Pyridazin-3-yl) methyl) -3,4-dihydro-2Η- pyrido [3,2-b] [l, 4] oxazine
Figure imgf000028_0001
Figure imgf000028_0001
2-( (6-클로로- [ 1， 2， 4]트리아졸로 [4， 3-b]피리다진 -3-일)메틸 )-4-(4- 메록시벤질)-3，4-디히드로-2^피리도[3，2-/?][1，4]옥사진(0.5, 1.18 匪 ol)을 감압튜브에 넣고 디메록시에탄 (DME^ 20 mL)과 증류수 (5 mL)를 가해 녹인 다음 4-피라졸 보로닉에시드 피나콜에스트 (390 mg, 1.77 麵 ol), 소디움카보네이트 (0.38 g, 3.54 mmol), 그리고 PdCl2(Ph3)2(42 mg, 0.057 mmol)을 가한 후 반응액에 질소가스를 불어넣어 산소를 제거하고 밀봉하여 80°C에서 8시간 교반하였다. 반웅 후 에틸아세테이트를 가하고 소금물로 세척한 다음 유기층을 무수 황산나트륨올 건조하고 감압농축하였다. 잔사를 컬럼 크로마토그래피 (3% MeOH/CH2Cl2)로 정제하여 목적화합물인 4- (4-메록시벤질) -2-((6-(1-메틸— 피라졸 -4-일) -[1，2，4]트리아졸로 [4,3- ^피리다진 -3-일)메틸) -3,4-디히드로 -2^피리도 [3，2- ] [1,4]옥사진 (200 mg, 36 %)을 얻었다. 2- ((6-chloro- [1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -4- (4- Methoxybenzyl) -3,4-dihydro-2 ^ pyrido [3,2-/?] [1,4] oxazine (0.5, 1.18 匪 ol) was placed in a reduced pressure tube and dimethoxyethane (DME ^ 20 mL) and distilled water (5 mL) were dissolved and then 4-pyrazole boronic acid pinacol est (390 mg, 1.77 麵 ol), sodium carbonate (0.38 g, 3.54 mmol), and PdCl 2 (Ph 3 ) 2 ( 42 mg, 0.057 mmol) was added, and nitrogen gas was blown into the reaction solution to remove oxygen, sealed, and stirred at 80 ° C for 8 hours. After reaction, ethyl acetate was added, washed with brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (3% MeOH / CH 2 Cl 2) to give the title compound 4- (4-methoxybenzyl) -2-((6- (1-methyl-pyrazol-4-yl)-[ 1,2,4] triazolo [4,3- ^ pyridazin-3-yl) methyl) -3,4-dihydro-2 ^ pyrido [3,2-] [1,4] oxazine (200 mg, 36%).
¾-NMR (300 應2， CDC13) δ 8.05 (d, J = 9.6 Hz, 1H) , 7.97 (s, 1H), 7.89 (s, 1H), 7.80 (dd, J二 4.8， 1.4 Hz, 1H), 7.30 (d, J = 9.6 Hz 1H), 7.18 (d, J = 8.6 Hz, 2H) , 6.89 (d, J = 7.7 Hz, 1H)， 6.74 (d, / = 8.6 Hz, 2H), 6.52 (dd, J = 7.7, 4.8 Hz, 1H) , 4.89 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H) , 4.01 (s, 3H), 3.76 (s, 3H), 3.63 (m, 1H), 3.48-3.36 (m, 3H). 실시예 7. 2-( (6-( 1-메틸 -1H-피라졸 -4-일) - [ 1， 2 , 4]트리아졸로 [4 , 3- b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H-피리도 [3, 2-b] [ 1, 4]옥사진
Figure imgf000029_0001
¾-NMR (300 應 2, CDC1 3 ) δ 8.05 (d, J = 9.6 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.80 (dd, J 二 4.8, 1.4 Hz, 1H ), 7.30 (d, J = 9.6 Hz 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 7.7 Hz, 1H), 6.74 (d, / = 8.6 Hz, 2H), 6.52 (dd, J = 7.7, 4.8 Hz, 1H), 4.89 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H ), 4.01 (s, 3H), 3.76 (s, 3H), 3.63 (m, 1H), 3.48-3.36 (m, 3H). Example 7. 2- ((6- (1-Methyl-1H-pyrazol-4-yl)-[l, 2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000029_0001
4-(4-메특시벤질) -2-( (6-( 1—메틸 -L 피라졸— 4-일 ) - [1，2，4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3ᅳ 4-디히드로 -2^  4- (4-Methoxybenzyl) -2-((6- (1-methyl-L pyrazol- 4-yl)-[1,2,4] triazolo [4,3-b] pyridazine-3 -Yl) methyl) -3'4-dihydro-2 '
피리도 [3，2ᄀ [1,4]옥사진 (200 mg, 0.43 讓 ol)을 트리플루오로아세트산 (CF3C00H, 10 mL)에 녹인 후 60 0C에서 12시간 교반한 다음 감압 농축한 후 에틸 에테르를 가하여 형성된 고체를 여과, 건조하여 목적화합물 2-((6-(1-메틸 -1H-피라졸 -4-일;卜 [1,2,4]트리아졸로 [4，3- b]피리다진 -3-일 )메틸) -3 , 4—디히드로 -2Η-피리도 [3 , 2-b] [ 1ᅳ 4]옥사진 Pyrido [3,2a [1,4] oxazine (200 mg, 0.43 讓 ol) was dissolved in trifluoroacetic acid (CF 3 C00H, 10 mL), stirred at 60 0 C for 12 hours, and concentrated under reduced pressure. After adding ethyl ether, the solid formed was filtered and dried to give the desired compound 2-((6- (1-methyl-1H-pyrazol-4-yl; 卜 [1,2,4] triazol [4,3- b] pyridazin-3-yl) methyl) -3, 4-dihydro-2Η-pyrido [3, 2-b] [1 ᅳ 4] oxazine
트리플루오로아세트산염 (150 mg, 75%)을 얻었다.Trifluoroacetic acid salt (150 mg, 75%) was obtained.
-匿 (300 MHz, DMSO-de) δ 8.49 (s, 1H), 8.32 (d, J = 9.7 Hz, 1H), 8.12 (s, 1H), 7.68 (d, J = 9.7 Hz, 1H)， 7.59 (dd, J= 6.0, 1.2 Hz 1H), 7.24 (d, /= 6.7 Hz, 1H), 6.59 (dd, J = 7.7， 6.0 Hz, 1H) , 4.80 (m 1H), 3.90 (s, 3H), 3.79-3.50 (m, 4H). 실시예 8. tert-부틸 4-(4-(3-( (4-(4-메톡시벤질) -3 ,4-디히드로 -2H- 피리도 [3, 2-b][l, 4]옥사진 -2- °d)메틸) -[1， 2, 4]트리아졸로 [4, 3-b]피리다진- 6-일) -1H-피라졸로 -1-일)피페리딘 -1—카르복실레이트  -匿 (300 MHz, DMSO-de) δ 8.49 (s, 1H), 8.32 (d, J = 9.7 Hz, 1H), 8.12 (s, 1H), 7.68 (d, J = 9.7 Hz, 1H), 7.59 (dd, J = 6.0, 1.2 Hz 1H), 7.24 (d, / = 6.7 Hz, 1H), 6.59 (dd, J = 7.7, 6.0 Hz, 1H), 4.80 (m 1H), 3.90 (s, 3H) , 3.79-3.50 (m, 4H). Example 8 tert-butyl 4- (4- (3- ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3, 2-b] [l, 4] Oxazine-2- ° d) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) -1H-pyrazolo-1-yl) piperidine-1— Carboxylate
Figure imgf000030_0001
Figure imgf000030_0001
실시예 6와 동일한 방법으로 진행하여 목적화합물 tert—부틸 4-(4-(3- ( (4-(4-메톡시벤질) -3 , 4-디히드로 -2H-피리도 [3， 2— b] [ 1， 4]옥사진 -2- 일)메틸) -[ 1 , 2 , 4]트리아졸로 [4 , 3-b]피리다진 -6-일 )-1Η-피라졸로 -1— 일)피페리딘 -1-카^복실레이트를 얻었다. Proceed in the same manner as in Example 6 tert—butyl 4- (4- (3-((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2—] b] [1, 4] oxazin-2-yl) methyl)-[1, 2, 4] triazolo [4, 3-b] pyridazine-6-yl) -1Η-pyrazolo-1-1) Piperidine-1-ca ^ carboxylate was obtained.
-匿 (300 丽 z, CDCls) δ 8.12 (s, 1H) , 8.07 (s, 1Η)' 8.03 (d, J = 9.7 Hz , 1H), 7.78 (dd, J = 4.8, 1.4 Hz, 1H), 7.29 (d, J = 9.7 Hz, 1H), 7.18 (d, J - 8.6 Hz, 2H), 6.87 (d, J = 7.7, 1.4 Hz, 1H), 6.73 (d, J - 8.6 Hz, 2H), 6.52 (dd, J = 7.7， 4.8 Hz, 1H), 4.86 (d, A of ABq, J = 14.7 Hz, 1H), 4.81 (m, 1H), 4.65 (d, B of ABq, J = 14.7 Hz, 1H) , 4.27 (m, 3H), 4.02 (s, 3H), 3.63 (m, 1H) , 3.47-3.36 (m, 3H), 2.92 (m, 2H), 2.20 (m, 2H), 2.01 (m, 2H), 1.29 (s, 9H),  -匿 (300 liza z, CDCls) δ 8.12 (s, 1H), 8.07 (s, 1Η) '8.03 (d, J = 9.7 Hz, 1H), 7.78 (dd, J = 4.8, 1.4 Hz, 1H), 7.29 (d, J = 9.7 Hz, 1H), 7.18 (d, J-8.6 Hz, 2H), 6.87 (d, J = 7.7, 1.4 Hz, 1H), 6.73 (d, J-8.6 Hz, 2H), 6.52 (dd, J = 7.7, 4.8 Hz, 1H), 4.86 (d, A of ABq, J = 14.7 Hz, 1H), 4.81 (m, 1H), 4.65 (d, B of ABq, J = 14.7 Hz, 1H), 4.27 (m, 3H), 4.02 (s, 3H), 3.63 (m, 1H), 3.47-3.36 (m, 3H), 2.92 (m, 2H), 2.20 (m, 2H), 2.01 (m , 2H), 1.29 (s, 9H),
^살시예 2-((6-(1- (피페리딘 -4-일) -1H—피라졸 -4-일)^ Salciye 2-((6- (1- (piperidin-4-yl) -1H—pyrazol-4-yl)
[1,2, 4]트리 졸로 [4, 3-b ]피리다진ᅳ 3-일)메틸) -3， 4-디히드로 -2H- 피리도 [3， 2-b ][1, 4]옥사진 [1,2,4] trizolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] jade Picture
Figure imgf000031_0001
Figure imgf000031_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(1- (피페리딘 -4—일 )-1Η-피라졸 -4-일 )-[ 1 , 2 , 4]트리아졸로 [4 , 3-b]피리다진—3- 일 )메틸 )-3， 4-디히드로— 2H-피리도 [3， 2-b] [1,4]옥사진 트리플루오로아세트산 염을 얻었다.Proceed in the same manner as in Example 7, target compound 2-((6- (1- (piperidin-4—yl) -1Η-pyrazol-4-yl)-[1, 2, 4] triazolo [ 4, 3-b] pyridazine- 3-yl) methyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1,4] oxazine trifluoroacetic acid salt was obtained.
-賺 (300 MHz, DMS0-ds) δ 8.80 (s, 1H), 8.39 (s, 1H), 8.31 (d J = 9.7 Hz, 1H), 7.67 (d, J 9.7 Hz, 1H), 7.58 (dd, J = 6.0, 1.2 Hz, 1H), 7.24 (d, J 7.7 Hz, 1H), 7.59 (dd, J = 7.7， 6.0 Hz, 1H) , 4.80 (m 1H), 4.44 (m, 1H), 3.80-3.51 (m, 4H), 3.32 (m, 2H), 3.02 (m, 2H), 2.30-2.02 (m, 4H) . 실시예 10. 4- ( 4-메톡시벤질) -2- ( ( 6- ( 1 ( 2- (테트라히드로 -2H-피란 -2- 일옥시)에틸) -1H-피라졸 -4-일) -[1, 24]트리아출로 [4, 3-b]피리다진 -3- 일)메틸 3, 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진 -賺 (300 MHz, DMS0-d s ) δ 8.80 (s, 1H), 8.39 (s, 1H), 8.31 (d J = 9.7 Hz, 1H), 7.67 (d, J 9.7 Hz, 1H), 7.58 ( dd, J = 6.0, 1.2 Hz, 1H), 7.24 (d, J 7.7 Hz, 1H), 7.59 (dd, J = 7.7, 6.0 Hz, 1H), 4.80 (m 1H), 4.44 (m, 1H), 3.80-3.51 (m, 4H), 3.32 (m, 2H), 3.02 (m, 2H), 2.30-2.02 (m, 4H). Example 10. 4- (4-methoxybenzyl) -2-((6- (1 (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-pyrazol-4-yl) [4, 3-b] pyridazin-3-yl) methyl 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine
Figure imgf000031_0002
Figure imgf000031_0002
실시예 6와 동일한 방법으로 진행하여 목적화합물 4-(4-메특시벤질) - 2-( (6-( 1-(2- (테트라히드로 -2Hᅳ피란 -2-일옥시 )에틸) -1H-피라졸 -4-일 ) - [ 1,2，4]트리아졸로 [4, 3-b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H- 피리도 [3ᅳ 2-b][l,4]옥사진을 얻었다. Proceed in the same manner as in Example 6, target compound 4- (4-methoxybenzyl) -2-((6- (1- (2- (tetrahydro-2Hpypyran-2-yloxy) ethyl) -1H -Pyrazol-4-yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3 ′ 2 -b] [l, 4] oxazine was obtained.
-墜 (300 MHz, CDCls) δ 8.17 (s, 1H), 8.12 (s, 1H), 8.03 (d, /= 9.5 Hz , 1H), 7.78 (dd, J= 4.8， 1.4 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 7.19 (d, /= 8.6 Hz, 2H), 6.88 (dd, /= 7.7, 1.4 Hz, 1H), 6.74 (d, / = 8.6 Hz, 2H), 6.54 (dd, J = 7.7, 4.8 Hz, 1H), 4.85 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 4.72 (m, 1H), 4.57 (m, 1H), 4.32 (m, 2H), 4.12 (m, 1H) , 4.02 (s, 3H), 3.59 (m, 1H), 3.68 (m, 1H), 3.48 (m, 1H), 3.43 (m, 1H), 3.47-3.36 (m, 3H), 1.79-1.45 (m, 6H). 실시예 11. 2-(4-(3-((3,4-디히드로-2{-피리도[3,2-1)][1,4]옥사진-2- 일)메틸) -[1, 2, 4]트리아졸로 [4, 3-b]피리다진 -6_일) -1H-피라졸 -1-일)에탄올 -墜 (300 MHz, CDCls) δ 8.17 (s, 1H), 8.12 (s, 1H), 8.03 (d, / = 9.5 Hz, 1H), 7.78 (dd, J = 4.8, 1.4 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 7.19 (d, / = 8.6 Hz, 2H), 6.88 (dd, / = 7.7, 1.4 Hz, 1H), 6.74 (d, / = 8.6 Hz, 2H), 6.54 (dd, J = 7.7, 4.8 Hz, 1H), 4.85 (d, A of ABq, J = 14.7 Hz, 1H), 4.82 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 4.72 (m, 1H) , 4.57 (m, 1H), 4.32 (m, 2H), 4.12 (m, 1H), 4.02 (s, 3H), 3.59 (m, 1H), 3.68 (m, 1H), 3.48 (m, 1H), 3.43 (m, 1 H), 3.47-3.36 (m, 3 H), 1.79-1.45 (m, 6 H). Example 11. 2- (4- (3-((3,4-dihydro-2 {-pyrido [3,2-1)] [1,4] oxazin-2-yl) methyl)-[ 1, 2, 4] triazolo [4, 3-b] pyridazine-6_yl) -1H-pyrazol-1-yl) ethanol
Figure imgf000032_0001
Figure imgf000032_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-(4-(3-((3,4- 디히드로 -2H-피리도 [3,2— b][l, 4]옥사진—2-일)메틸) -[1, 2,4]트리아졸로 [4,3ᅳ b]피리다진 -6-일) -1H-피라졸 -1-일)에탄올 트리풀루오로아세트산염을 얻었다。 Proceed in the same manner as in Example 7, target compound 2- (4- (3-((3,4-dihydro-2H-pyrido [3,2—b] [l, 4] oxazine—2-yl ) (Methyl)-[1,2,4] triazol gives [4,3'b] pyridazin-6-yl) -1H-pyrazol-1-yl) ethanol tripulouroacetic acid salt.
-證 (300 MHz, DMSO-de) δ 8.59 (s, 1H), 8.32 (d, / = 9,6 Hz, 1H), 8.31 (s, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.59 (dd, J = 6.0， 1.2 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.60 (dd, J 7.7, 6.0 Hz, 1H), 4.80 (m, 1H), 4.16 (m, 2H), 3.77 (m, 2H), 3.80-3.51 (m, 4H) . 실시예 12. 2-플루오로 -4-(3-((4-(4-메톡시벤질) -3,4-디히드로- - 피리도 [3,2-b][l, 4]옥사진 -2-일)메틸) -[1,2, 4]트리아졸로 [4 , 3-b]피리다진- -證 (300 MHz, DMSO-de) δ 8.59 (s, 1H), 8.32 (d, / = 9,6 Hz, 1H), 8.31 (s, 1H), 7.66 (d, J = 9.6 Hz, 1H) , 7.59 (dd, J = 6.0, 1.2 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.60 (dd, J 7.7, 6.0 Hz, 1H), 4.80 (m, 1H), 4.16 (m , 2H), 3.77 (m, 2H), 3.80-3.51 (m, 4H). Example 12. 2-Fluoro-4- (3-((4- (4-methoxybenzyl) -3,4-dihydro-pyrido [3,2-b] [l, 4] oxazine -2-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-
6-일)페놀 6-yl) phenol
Figure imgf000032_0002
Figure imgf000032_0002
실시예 5에서 얻은 2-((6-클로로 -[1，2，4]트리아졸로 [4,3-b]피리다진- 3-일)메틸) -4-(4-메톡시벤질) -3, 4-디히드로 -2^피리도 [3, 2- [1,4]옥사진과 2-플루오로 -4-(4，4，5，5-테트라메틸 -1，3，2-디옥사보로란 -2-일)페놀을 실시예 6과 동일한 방법으로 스즈키결합을 진행하여 목적화합물 2-플루오로 -4-(3- ( (4-(4-메특시벤질) -3， 4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진 -2- 일)메틸) -[1，2，4]트리아졸로 [4,3-b]피리다진 -6-일)페놀을 얻었다.2-((6-chloro- [1,2,4] triazolo [4,3-b] pyridazine- obtained in Example 5 3-yl) methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2 ^ pyrido [3,2- [1,4] oxazine and 2-fluoro-4- (4 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol was subjected to Suzuki bond in the same manner as in Example 6 to give the target compound 2-fluoro-4- ( 3- ((4- (4-mesoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl)-[1, 2,4] triazole gave [4,3-b] pyridazine-6-yl) phenol.
-證 (300 MHz, CDCI3) δ 8.10 (d, J = 9.7 Hz, 1H), 7.95 (m, 2H), 7.88 (d, J二 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H)' 7.48 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.48 (dd, /= 6.8, 5.0 Hz, 1H), 4.85 (d, A of ABq; J = 14.7 Hz, 1H), 4.79 (m, 1H), 4.84 (d, B of ABq, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.62 (m, 1H), 3.47-3.33 (m, 3H). 실시예 13. 4-(3-( (3， 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진 -2- 일)메틸) -[1, 2, 4]트리아졸로 [4, 3-b]피리다진 -6-일) -2-플루오로페놀 -證 (300 MHz, CDCI 3 ) δ 8.10 (d, J = 9.7 Hz, 1H), 7.95 (m, 2H), 7.88 (d, J 2 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H) '7.48 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H) , 6.48 (dd, / = 6.8, 5.0 Hz, 1H), 4.85 (d, A of ABq ; J = 14.7 Hz, 1H), 4.79 (m, 1H), 4.84 (d, B of ABq, J = 14.7 Hz , 1H), 3.74 (s, 3H), 3.62 (m, 1H), 3.47-3.33 (m, 3H). Example 13. 4- (3- ((3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl)-[1, 2, 4 ] Triazolo [4, 3-b] pyridazin-6-yl) -2-fluorophenol
Figure imgf000033_0001
Figure imgf000033_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 4-(3_((3，4ᅳ 디히드로 -2H—피리도 [3， 2-b] [1,4]옥사진 -2-일)메틸) -[1,2,4]트리아졸로 [4ᅳ 3ᅳ b]피리다진 -6—일) -2-플루오로페놀을 얻었다. Proceed in the same manner as in Example 7 4- (3 _ ((3,4'dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl)- [4,3, b] pyridazine-6-yl) -2-fluorophenol was obtained with [1,2,4] triazol.
-賺 (300 MHz, CDCI3) δ 8.10 (d, / = 9.7 Hz, 1H) , 7.95 (m, 2H), 7.88 (d, / = 8.0 Hz, 1H), 7.48 (m, 2H), 6.86 (d, J = 7.8 Hz, 1H), 6.48 (dd, ·/= 5.0, 6.8 Hz, 1H), 4.79 (m, 1H)， 3.81-3.52 (m, 4H) . 실시예 2-( (6-(3-플루오로 -4-(2-(4-메틸피페라진 -1 일)에톡시)페닐 )ᅳ[1, 2, 4]트리아졸로 [4, 3-b]피리다진 -3- °)메틸) -4-(4- 메록시벤질) -3, 4-디히드로 -2H-피리도 [3， 2-b][l, 4]옥사진 -賺 (300 MHz, CDCI 3 ) δ 8.10 (d, / = 9.7 Hz, 1H), 7.95 (m, 2H), 7.88 (d, / = 8.0 Hz, 1H), 7.48 (m, 2H), 6.86 ( d, J = 7.8 Hz, 1H), 6.48 (dd, / = 5.0, 6.8 Hz, 1H), 4.79 (m, 1H), 3.81-3.52 (m, 4H). Example 2- ((6- (3-fluoro-4- (2- (4-methylpiperazin-1 yl) ethoxy) phenyl) ᅳ [1, 2, 4] triazolo [4, 3-b ] Pyridazine-3- °) methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine
Figure imgf000034_0001
Figure imgf000034_0001
실시예 5에서 얻은 2-((6-클로로 -[1，2,4]트리아졸로 [4,3-b]피리다진- 3ᅳ일)메틸)— 4-(4-메톡시벤질) -3,4-디히드로 -2^피리도 [3,2-b][l,4]옥사진과 1-(2— (2ᅳ프루오로 -4-(4 ,4,5, 5-테트라메틸 -1， 3 , 2-디옥사보로란 -2- 일)페녹시)에틸) -4-메틸피페라진을 실시예 6과 동일한 방법으로 스즈키결합을 진행하여 목적화합물 2-((6-(3—플루오로 -4-(2-(4- 메틸피페라진 -1-일)에록시)페닐) -[1, 2，4]트리아졸로 [4,3-b]피리다진 -3- 일)메틸 )-4-(4—메톡시벤질) -3， 4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진을 얻었다.  2-((6-chloro- [1,2,4] triazolo [4,3-b] pyridazin-3xyl) methyl) obtained in Example 5—4- (4-methoxybenzyl) -3, 4-dihydro-2 ^ pyrido [3,2-b] [l, 4] oxazine and 1- (2— (2 ᅳ fluoro-4- (4,4,5,5-tetramethyl-1) , 3,2-dioxaborolan-2-yl) phenoxy) ethyl) -4-methylpiperazine was subjected to Suzuki bonding in the same manner as in Example 6 to give the desired compound 2-((6- (3— Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) 4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine was obtained.
^-NMR (300 MHz, CDC13) δ 8.10 (d, J = 9.7 Hz, 1H), 7.81 (m,^ -NMR (300 MHz, CDC1 3 ) δ 8.10 (d, J = 9.7 Hz, 1H), 7.81 (m,
2H), 7.74 (d, J= 9.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (m, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.49 (dd, / = 7.7, 4.8 Hz, 1H), 4.87 (d, A of ABq, J二 14.7 Hz, 1H), 4.83 (m, 1H) , 4.65 (d, B of ABq, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.63 (m, 1H), 3.59 (t, / = 14.8 Hz, 2H) , 3.48-3.36 (m, 3H), 2.67 (t, J = 14.8 Hz, 2H), 2.39-2.52 (m, 8H), 2.21 (s, 3H). 실시예 15. 2-( (6-(3-플루오로 -4-(2ᅳ (4-메틸피페라진 -1- 일)에톡시)페닐) -[1, 2, 4]트리아졸로 [4， 3-b]피리다진 -3-일)메틸 )-3, 4- 디히드로 -2H-피리도 [3, 2-b][ 1, 4]옥사진 2H), 7.74 (d, J = 9.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (m, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.49 (dd, / = 7.7, 4.8 Hz, 1H), 4.87 (d, A of ABq, J 二 14.7 Hz, 1H), 4.83 (m, 1H), 4.65 (d, B of ABq, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.63 (m, 1H), 3.59 (t, / = 14.8 Hz, 2H), 3.48 -3.36 (m, 3H), 2.67 (t, J = 14.8 Hz, 2H), 2.39-2.52 (m, 8H), 2.21 (s, 3H). Example 15. 2- ((6- (3-fluoro-4- (2 ′ (4-methylpiperazin-1-yl) ethoxy) phenyl)-[1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000034_0002
Figure imgf000034_0002
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(3- 플루오로 -4-(2-(4-메틸피페라진 -1-일)에록시)페닐)ᅳ [l,2，4]트리아졸로[4,3ᅳ b]피리다진— 3-일 )메틸 )-3， 4-디히드로 -2H-피리도 [3， 2-b] [ 1， 4]옥사진을 얻었다. In the same manner as in Example 7, the target compound 2-((6- (3-fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) ᅳ [l, 2, 4] triazolo [4,3 ᅳ b] pyridazine- 3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine.
H-NMR (300 MHz, CDC13) δ 8.00 (d, J = 9.7 Hz, 1H), 7.80 (m, 2H), 7.66 (d, J = 9.7 Hz, 1H)， 7.27 (m, 2H)， 6.88 (d, J = 7.8 Hz, 1H), 6.48 (dd, J = 7.7， 4.8 Hz, 1H), 4.87 (m, 1H), 3.59 (t, J = 14.8 Hz, 2H), 3.81-3.52 (m, 4H), 2.67 (t, J = 14.8 Hz, 2H), 2.39—2.52 (m, 8H), 2.21 (s, 3H). 실시예 16. 4-(4-메톡시벤질) -2-((6-(l-메틸 -IH-인돌 -3-일) - [1,2, 4]트리아졸로[ 4, 3-b ]피리다진 -3-일)메틸) -3, 4-디히드로 -2H- 피리도 [3， 2-b][l, 4]옥사진 H-NMR (300 MHz, CDC1 3 ) δ 8.00 (d, J = 9.7 Hz, 1H), 7.80 (m, 2H), 7.66 (d, J = 9.7 Hz, 1H), 7.27 (m, 2H), 6.88 (d, J = 7.8 Hz, 1H), 6.48 (dd, J = 7.7, 4.8 Hz, 1H), 4.87 (m, 1H), 3.59 (t, J = 14.8 Hz, 2H), 3.81-3.52 (m, 4H), 2.67 (t, J = 14.8 Hz, 2H), 2.39—2.52 (m, 8H), 2.21 (s, 3H). Example 16. 4- (4-methoxybenzyl) -2-((6- (l-methyl-IH-indol-3-yl)-[1,2,4] triazolo [4, 3-b] Pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazine
Figure imgf000035_0001
Figure imgf000035_0001
실시예 6와 동일한 방법으로 진행하여 목적화합물 4-(4-메톡시벤질) - 2-((6-(1-메틸 -1H-인돌— 3-일) -[1，2，4]트리아졸로 [4,3— b]피리다진 -3- 일)메틸)-3,4-디히드로-211-피리도[3，2-13][1，4]옥사진을 얻었다.  Proceed as in Example 6 to the target compound 4- (4-methoxybenzyl) -2-((6- (1-methyl-1H-indol- 3-yl)-[1,2,4] triazolo [4,3—b] pyridazin-3-yl) methyl) -3,4-dihydro-211-pyrido [3,2-13] [1,4] oxazine was obtained.
¾-NMR (300 MHz, CDC13) δ 8.34 (d, J = 9.7 Hz , IH) , 7.97 (s, IH), 7.89 (s, IH), 7.80 (dd, J = 4.8, 1.4 Hz, IH), 7.30 (d, J = 9.7 Hz, IH), 7.18 (d, /= 8.6 Hz, 2H), 6.89 (dd, J = 7.7， 1.4 Hz, IH), 6.74 (d, J二 8.6 Hz, 2H), 6.52 (dd, J = 7.7, 4.8 Hz, IH), 4.89 (d, A of ABq, J = 14.7 Hz, IH), 4.82 (m, IH) , 4.66 (d, B of ABq, / = 14.7 Hz, IH), 4.01 (s, 3H), 3.76 (s, 3H), 3.63 (m, IH), 3.48-3.36 (in, 2H). 실시예 17. 2-((6-(1-^] -1H- l :-3- ^ -fl, 2, 4] ^ ^[4r 3- b]피리다진 -3ᅳ일)메틸) -3, 4-디히드로 -2H-피리도 [3, 2-b][ 1, 4]옥사진 ¾-NMR (300 MHz, CDC1 3 ) δ 8.34 (d, J = 9.7 Hz, IH), 7.97 (s, IH), 7.89 (s, IH), 7.80 (dd, J = 4.8, 1.4 Hz, IH) , 7.30 (d, J = 9.7 Hz, IH), 7.18 (d, / = 8.6 Hz, 2H), 6.89 (dd, J = 7.7, 1.4 Hz, IH), 6.74 (d, J 二 8.6 Hz, 2H) , 6.52 (dd, J = 7.7, 4.8 Hz, IH), 4.89 (d, A of ABq, J = 14.7 Hz, IH), 4.82 (m, IH), 4.66 (d, B of ABq, / = 14.7 Hz , IH), 4.01 (s, 3H), 3.76 (s, 3H), 3.63 (m, IH), 3.48-3.36 (in, 2H). Example 17. 2-((6- (1-^]-1H-1: -3-^-fl, 2, 4] ^^ [ 4r 3-b] pyridazine-3xylyl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000036_0001
Figure imgf000036_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(1-메틸 -1H- 인돌 -3-일 )- [ 1 , 2， 4]트리아졸로 [4， 3-b]피리다진 -3-일 )메틸 )—3， 4-디히드로- 2H-피리도 [3,2— b] [1,4]옥사진 트리플루오로아세트산염을 얻었다. Proceed in the same manner as in Example 7 2-((6- (1-methyl-1H-indol-3-yl)-[1,2,4] triazolo [4,3-b] pyridazine- 3-yl) methyl) —3,4-dihydro-2H-pyrido [3,2—b] [1,4] oxazine trifluoroacetic acid salt was obtained.
-匪 R (300 MHz, CDCI3) δ 8.47 (d, J= 7.9 Hz , 1H) , 8.01 (d, J = 9.7 Hz, 1H), 7.67 (s, 1H), 7.66 (m, 1H), 7.48-7.34 (m, 4H)， 6.98 (d, J = 7.7, 1.4 Hz, 1H), 6.53 (dd, J 7.7, 4.8 Hz, 1H)， 4.87 (m, 1H), 3.93 (sᅳ 3H), 3.91-3.53 (m, 4H) . 실시예 18. 2-(4-(4-^}^1^^)-3, 4-^^J≡≤-2H-^ ]£[3, 2- b][l, 4]옥사진 -2-일)아세토하이드라자이드  R (300 MHz, CDCI3) δ 8.47 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 9.7 Hz, 1H), 7.67 (s, 1H), 7.66 (m, 1H), 7.48- 7.34 (m, 4H), 6.98 (d, J = 7.7, 1.4 Hz, 1H), 6.53 (dd, J 7.7, 4.8 Hz, 1H), 4.87 (m, 1H), 3.93 (s ᅳ 3H), 3.91- 3.53 (m, 4 H). Example 18. 2- (4- (4-^} ^ 1 ^^)-3, 4-^^ J≡≤-2H- ^] £ [3, 2-b] [l, 4] oxazine- 2-yl) acetohydrazide
Figure imgf000036_0002
Figure imgf000036_0002
2_(4_(4_메특시벤질) _3,4_디히드로ᅳ 2^피리도 [S^-^U]옥사진 _2- 일)아세트산 (1.08 g, 3.44 隱 ol)을 벤젠 /메탄을 (2/1; 12 mL)에 녹인 후 트리메틸살릴 디아조메테인 (TMSCHN2 in 2M in diethyl ether; 4.6 mL, 12.02 隱 ol)을 적가하고 실온에서 한 시간 동안 교반하였다. 반응 후 용매를 감압농축하고 컬럼 크로마토그래피 (2OT EtOAc/Hexane)로 정제하여 메틸 ^(^( -메톡시벤질；卜 ^디히드로^ 피리도^^- ，^옥사진-^ 일)아세테이트 (530 mg, 47 %)를 얻었다. 2 _ (4 _ (4 _ mesobic benzyl) _3, 4 _ dihydro ᅳ 2 ^ pyrido [S ^-^ U] oxazine _ 2 -yl) acetic acid (1.08 g, 3.44 隱 ol) benzene / methane Was dissolved in (2/1; 12 mL), and trimethylsalyl diazomethane (TMSCHN 2 in 2M in diethyl ether; 4.6 mL, 12.02 隱 ol) was added dropwise and stirred at room temperature for 1 hour. After the reaction, the solvent was concentrated under reduced pressure, purified by column chromatography (2OT EtOAc / Hexane), and purified by methyl ^ (^ (-methoxybenzyl; 卜 ^ dihydro ^ pyrido ^^-, ^ oxazine- ^ yl) acetate (530 mg, 47%).
—證 (300 MHz, CDCI3) δ 7.79 (m, 1H), 7.23 (d, / = 8.5 Hz, 2H), 6.94 (m, 1H), 6.84 (d, / = 8.5 Hz, 2H) , 6.53 (m, 1H) , 4,79 (ABq, J 15.1 Hz, 2H), 4.54 (m, 1H), 3.78 (s, 3H) , 3.69 (s, 3H), 3.34 (m, 1H), 3.11 (m, 1H), 2.69 (dd, /= 15.7， 7.4 Hz, 1H), 2.52 (dd, / = 15.7 5.5 Hz, 1H). — 證 (300 MHz, CDCI3) δ 7.79 (m, 1H), 7.23 (d, / = 8.5 Hz, 2H), 6.94 (m, 1H), 6.84 (d, / = 8.5 Hz, 2H), 6.53 (m , 1H), 4,79 (ABq, J 15.1 Hz, 2H), 4.54 (m, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.34 (m, 1H), 3.11 (m, 1H ), 2.69 (dd, / = 15.7, 7.4 Hz, 1H), 2.52 (dd, / = 15.7 5.5 Hz, 1H).
메틸 2-(4-(4-메록시벤질) -3 , 4-디히드로 -2ν¥"피리도 [3 , 2- b][l, 4]옥사진—2—일)아세테이트 (300 mg, 0.91 mmol)를 메탄올 (6 mL)에 녹인 후 80% 히드라진 하이드레이트 (N¾N¾.¾0; 0.28 mL, 4.57 隱 ol)을 가하고 50°C에서 한 시간 동안 교반하였다. 반웅 후 용매를 감압 농축하여 노란색 고체 290 mg(96«을 얻었으며 더 이상 정제없이 다음반응을 진행하였다.Methyl 2- (4- (4-methoxybenzyl) -3,4-dihydro-2ν ¥ "pyrido [3, 2-b] [l, 4] oxazine—2—yl) acetate (300 mg, 0.91 mmol) was dissolved in methanol (6 mL) and 80% hydrazine hydrate (N¾N¾.¾0; 0.28 mL, 4.57 μl) was added and stirred for 1 hour at 50 ° C. After reaction, the solvent was concentrated under reduced pressure to give a yellow solid 290. mg (96 «was obtained and the next reaction proceeded without further purification.
-腿 (300 MHz, CDCI3) δ 7.80 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.08 (brs, 1H), 6.95 (d, J = 7.6 Hz, 1H) , 6.83 (d, J =-腿 (300 MHz, CDCI 3 ) δ 7.80 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.08 (brs, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.83 (d, J =
8.6 Hz, 2H), 6.53 (dd, J - 7.6, 4.8 Hz, 1H), 4.75 (ABq, / = 14.8 Hz, 2H), 4.51 (m, 1H), 3.79 (s, 3H), 3.34 (dd, / = 12.1, 2.6 Hz, 1H), 3.12 (dd, J= 12.1， 7.1 Hz, 1H), 2.51-2.40 (m, 2H). 실시예 19. 3-클로로 -6-(4-플루오로페닐)피리다진
Figure imgf000037_0001
8.6 Hz, 2H), 6.53 (dd, J-7.6, 4.8 Hz, 1H), 4.75 (ABq, / = 14.8 Hz, 2H), 4.51 (m, 1H), 3.79 (s, 3H), 3.34 (dd, / = 12.1, 2.6 Hz, 1H), 3.12 (dd, J = 12.1, 7.1 Hz, 1H), 2.51-2.40 (m, 2H). Example 19. 3-Chloro-6- (4-fluorophenyl) pyridazine
Figure imgf000037_0001
3, 6-디클로로피리다진 (0.2 g, 1.34 醒 ol)을 디옥산 /증류수 (3/1; 4 mL) 에 녹인 후 4-플루오로페닐보로닉에시드 (0.15 g, 1.074 mmol), 포타슘카보네이트 (0.46 g, 3.36 匪 ol), 그리고 PdCl2(dppf)2(55 mg, 0.067 國 ol)올 가하고 90°C에서 교반하였다. 반웅 후 에틸아세테이트를 가하고 소금물로 세척한 다음 유기층을 무수 황산나트륨을 건조하고 감압 농축하였다. 잔사를 컬럼 크로마토그래피 (20% EtOAc/hexane)로 정제하여 목적화합물인 3-클로로 -6-(4-플루오로페닐)피리다진 (123 mg, 55 %)을 얻었다.Dissolve 3, 6-dichloropyridazine (0.2 g, 1.34) ol) in dioxane / distilled water (3/1; 4 mL) and then 4-fluorophenylboronic acid (0.15 g, 1.074 mmol), potassium carbonate (0.46 g, 3.36 匪 ol), and PdCl 2 (dppf) 2 (55 mg, 0.067 ol ol) were added and stirred at 90 ° C. After reaction, ethyl acetate was added, the resultant was washed with brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc / hexane) to obtain 3-chloro-6- (4-fluorophenyl) pyridazine (123 mg, 55%) as a target compound.
-醒 (300 MHz, DMSO-de) δ 8.33 (d, J = 9.1 Hz, 1H) , 8.21 (dd, J= 8.9, 5.5 Hz, 2H), 8.01 (d, /= 9.1 Hz, 1H) , 7.41 (t, J = 11.4 Hz, 2H). 실시예 20. 3-클로로—6-페닐피리다진
Figure imgf000038_0001
-醒 (300 MHz, DMSO-de) δ 8.33 (d, J = 9.1 Hz, 1H), 8.21 (dd, J = 8.9, 5.5 Hz, 2H), 8.01 (d, / = 9.1 Hz, 1H), 7.41 (t, J = 11.4 Hz, 2H). Example 20. 3-Chloro-6-phenylpyridazine
Figure imgf000038_0001
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로 -6- 페닐피리다진을 얻었다.  Proceed as in Example 19 to obtain the target compound 3-chloro-6-phenylpyridazine.
^-NMR (300 MHz, CDC13) δ 8.04 (m, 2H)， 7.81 (d, / = 9.1 Hz, 1H), 7.57 (m, 4H), 7.55 (d, J = 9.1 Hz, 1H). 실시예 21. 3-클로로 -6-(3ᅳ플로로페닐)피리다진 ^ -NMR (300 MHz, CDC1 3 ) δ 8.04 (m, 2H), 7.81 (d, / = 9.1 Hz, 1H), 7.57 (m, 4H), 7.55 (d, J = 9.1 Hz, 1H). Example 21. 3-Chloro-6- (3 ᅳ fluorophenyl) pyridazine
Figure imgf000038_0002
Figure imgf000038_0002
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로 -6-(3- 플로로페닐)피리다진을 얻었다. Proceed as in Example 19 to obtain the target compound 3-chloro-6- (3-fluorophenyl) pyridazine.
-NMR(300 MHz, CDC13) δ 7.93(m, 1H), 7.82(d, J = 9.0 Hz, 1H), 7.80 (m, 1H), 7.59 (d, / = 9.0 Hz, 1H), 7.54— 7.49 (m, 1H), 7.25-7.19 (m, 1H). 실시예 22. 3-클로로 -6-(3， 5-디플로로페닐)피리다진 -NMR (300 MHz, CDC1 3 ) δ 7.93 (m, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.80 (m, 1H), 7.59 (d, / = 9.0 Hz, 1H), 7.54— 7.49 (m, 1 H), 7.25-7.19 (m, 1 H). Example 22. 3-Chloro-6- (3, 5-difluorophenyl) pyridazine
Figure imgf000038_0003
Figure imgf000038_0003
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로 -6-(3,5- 디플로로페닐)피리다진을 얻었다. Proceed in the same manner as in Example 19, to obtain the title compound 3-chloro-6- (3,5-difluorophenyl) pyridazine.
-匿 (300 MHz, CDCI3) δ 7.79 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.01-6.93 (m, 1H). 실시예 23. 3-클로로 -6-(3-플루오로 -4-메틸페닐)피리다진
Figure imgf000039_0001
-匿 (300 MHz, CDCI 3 ) δ 7.79 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.01-6.93 (m, 1H ). Example 23. 3-Chloro-6- (3-fluoro-4-methylphenyl) pyridazine
Figure imgf000039_0001
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로 -6-(3- 플루오로 -4-메틸페닐)피리'다진을 얻었다.Proceed in the same manner as in Example 19, to obtain the title compound 3-chloro-6- (3-fluoro-4-methylphenyl) pyridine ' minced.
-證 (300 MHz, CDCls) δ 7.79 (d, J = 9.0 Hz, 1H), 7.78-7.70 (m, 2H), 7.56 (d, J = 9.0 Hz, 1H)， 7.34 (t, J = 7.7 Hz, 1H), 2.36 (s, 3H). 실시예 24. 3-(6-클로로피리다진 -3-일)벤조나이트라일
Figure imgf000039_0002
-證 (300 MHz, CDCls) δ 7.79 (d, J = 9.0 Hz, 1H), 7.78-7.70 (m, 2H), 7.56 (d, J = 9.0 Hz, 1H), 7.34 (t, J = 7.7 Hz , 1H), 2.36 (s, 3H). Example 24. 3- (6-Chloropyridazin-3-yl) benzonitriyl
Figure imgf000039_0002
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-(6- 클로로피리다진 -3—일)벤조나이트라일을 얻었다. In the same manner as in Example 19, the target compound 3- (6-chloropyridazin-3-yl) benzonitriyl was obtained.
-匪 R (300 MHz, CDCI3) δ 8.37 (s, 1H) , 8.35 (d, J = 5.4 Hz, 1H), 7.88 (d, J= 5.4 Hz, 1H), 7.83 (d, J = 4.6 Hz, 1H) , 7.65 (m, 2H)ᅳ 실시예 25. 3-클로로 -6- (피리딘 -4-일)피리다진
Figure imgf000039_0003
-匪 R (300 MHz, CDCI 3 ) δ 8.37 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.83 (d, J = 4.6 Hz , 1H), 7.65 (m, 2H) 'Example 25. 3-Chloro-6- (pyridin-4-yl) pyridazine
Figure imgf000039_0003
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로ᅳ6- (피리딘 -4-일)피리다진을 얻었다, Ή-NMR (300 MHz, CDC13) δ 8.85 (m, 2H) , 7.94 (m, 2H), 7.90 (d J= 9.0 Hz, 1H), 7.67 (d, J= 9.0 Hz, 1H). 실시예 26. 3-클로로 -6- (피리딘ᅳ 3—일)피리다진 In the same manner as in Example 19, the target compound 3-chloro 목적 6- (pyridin-4-yl) pyridazine was obtained. Ή-NMR (300 MHz, CDC1 3 ) δ 8.85 (m, 2H), 7.94 (m, 2H), 7.90 (d J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H). Example 26. 3-Chloro-6- (pyridinyl 3--yl) pyridazine
Figure imgf000040_0001
Figure imgf000040_0001
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로 -6- (피리딘— 3-일)피리다진을 얻었다. In the same manner as in Example 19, the target compound 3-chloro-6- (pyridin- 3-yl) pyridazine was obtained.
-NMR (300 MHz, CDC13) δ 9.15 (d, / = 2.3 Hz, 1H), 8.71 (dd, J = 4.8, 1.2 Hz, 1H), 8.40 (dt , / = 1.9, 8.0 Hz, 1H) , 7.83 (d, J -- 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H) , 7.44 (dd, J = 8.0, 4.8 Hz, 1H). 실시예 27. 3-클로로—6-(4-메톡시페닐)피리다진 -NMR (300 MHz, CDC1 3 ) δ 9.15 (d, / = 2.3 Hz, 1H), 8.71 (dd, J = 4.8, 1.2 Hz, 1H), 8.40 (dt, / = 1.9, 8.0 Hz, 1H), 7.83 (d, J-9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 8.0, 4.8 Hz, 1H). Example 27. 3-Chloro-6- (4-methoxyphenyl) pyridazine
Figure imgf000040_0002
Figure imgf000040_0002
실시예 19와 동일한 방법으로 진행하여 목적화합물 3-클로로 -6-(4- 메톡시페닐)피리다진을 얻었다. Proceed as in Example 19 to obtain the target compound 3-chloro-6- (4-methoxyphenyl) pyridazine.
-匿 (300 MHz, CDCI3) δ 8.01 (d, J = 6.9 Hz, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.04 (d, / = 6.9 Hz, 2H), 3.89 (s, 3H). 실시예 28. 4-(6-클로로피리다진 -3-일) -Ν,Ν-디메틸벤젠아민 -匿 (300 MHz, CDCI 3 ) δ 8.01 (d, J = 6.9 Hz, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.04 (d, / = 6.9 Hz, 2H), 3.89 (s, 3H). Example 28. 4- (6-Chloropyridazin-3-yl) -Ν, Ν-dimethylbenzeneamine
Figure imgf000040_0003
실시예 15와 동일한 방법으로 진행하여 목적화합물 4-(6- 클로로피리다진 -3-일) -Ν,Ν-디메틸벤젠아민을 얻었다.
Figure imgf000040_0003
In the same manner as in Example 15, the target compound 4- (6-chloropyridazin-3-yl) -Ν, Ν-dimethylbenzeneamine was obtained.
-證 (300 MHz, CDC13) δ 7.97 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 8.9 Hz, 2H), 3.05 (s( 6H). 실시예 29. 메틸 4-(6—클로로피리다진 -3-일)벤조에이트 -證 (300 MHz, CDC1 3 ) δ 7.97 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 8.9 Hz, 2H), 3.05 (s ( 6H) .Example 29. Methyl 4- (6—chloropyridazin-3-yl) benzoate
Figure imgf000041_0001
Figure imgf000041_0001
실시예 19와 동일한 방법으로 진행하여 목적화합물 메틸 4— (6- 클로로피리다진 -3-일)벤조에이트을 얻었다.  Proceed in the same manner as in Example 19, to obtain the target compound methyl 4— (6-chloropyridazin-3-yl) benzoate.
¾-匪 R (300 顧 z, CDC13) δ 8.20 (d, / = 8.3 Hz, 2H), 8.13 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H). 실시예 30. (4-(6-클로로피리다진ᅳ 3-일)페닐)메탄올 ¾- 匪 R (300 顧 z, CDC1 3 ) δ 8.20 (d, / = 8.3 Hz, 2H), 8.13 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H). Example 30. (4- (6-Chloropyridazin-3-yl) phenyl) methanol
Figure imgf000041_0002
Figure imgf000041_0002
3,6-디클로로피리다진 (400 mg, 2.69 闘 ol)을 다이옥산 (6 mL)과 증류수 (2 mL)에 녹인 후 4-포밀페닐보로닉에시드 (321 mg, 2.15 隱 ol), 탄산칼륨 (920 mg, 6.71 麵 ol), PdCl2(dppf )2(H0 mg, 0.13 隱 ol)을 가하고 90 0C에서 교반한다. 반웅 후 디클로로메탄으로 희석한 후 소금물로 세척한 다음 유기층을 무수 황산나트륨으로 건조하고 감압 농축하였다. 컬럼 크로마토그래피 (40% EtOAc/Hexane)로 정제하여 4-(6-클로로피리다진 -3- 일)벤잘데하이드 (148 mg, 25%)를 흰색 고체로 얻었다. 3,6-dichloropyridazine (400 mg, 2.69 闘 ol) was dissolved in dioxane (6 mL) and distilled water (2 mL), followed by 4-formylphenylboronic acid (321 mg, 2.15 隱 ol), potassium carbonate ( 920 mg, 6.71 μl ol), PdCl 2 (dppf) 2 (H0 mg, 0.13 μl ol) are added and stirred at 90 0 C. After reaction, the mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (40% EtOAc / Hexane) gave 4- (6-chloropyridazin-3-yl) benzaldehyde (148 mg, 25%) as a white solid.
H-NMR(300 MHz, CDCI3) δ 10.12(s, 1H)， 8.24(d, / = 8.1 Hz, 2H), 8.07(d, J = 8.1 Hz, 2H), 7.91(d, J = 9.0 Hz, 1H) , 7.65 (d, J 9.0 Hz, 1H). H-NMR (300 MHz, CDCI 3 ) δ 10.12 (s, 1H), 8.24 (d, / = 8.1 Hz, 2H), 8.07 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 9.0 Hz, 1H), 7.65 (d, J 9.0 Hz, 1H).
4-(6-클로로피리다진— 3-일)벤잘데하이드 (40 mg, 0.18 隱 ol)를 메탄올 /디클로로메탄 (4:1, 2 mL)에 녹이고 0°C에서 수소화붕소나트륨 (NaBH4, 10 mg, 0.26 mmol)을 서서히 가하고 실은에서 2시간 동안 교반하였다. 반웅 후 에틸아세테이트를 가하고 소금물로 세척한 후 유기층을 무수 황산나트륨으로 건조하고 감압 농축하여 (4-(6-클로로피리다진 -3- 일)페닐)메탄을 (39 mg, 98%)을 노란색 고체로 얻었다.4- (6-chloropyridazin-3-yl) ben jalde Hyde (40 mg, 0.18隱ol) in methanol / dichloromethane (4: 1, 2 mL) NaBH ( sodium borohydride at 0 ° C was dissolved in 4, 10 mg, 0.26 mmol) was added slowly and stirred for 2 hours at actual weight. After reaction, ethyl acetate was added, the mixture was washed with brine, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, (4- (6-chloropyridazin-3-yl) phenyl) methane (39 mg, 98%) was converted into a yellow solid. Got it.
-匿 (300 丽 z, CDCls) δ 8.06 (d, / = 8.4 Hz, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H),7.54 (d, J= 9.0 Hz, 1H), 4.80 (d, J = 4.2 Hz, 2H). 실시예 31. 4-(4-(6-클로로피리다진— 3—일)벤질)몰폴린
Figure imgf000042_0001
-300 (z, CDCls) δ 8.06 (d, / = 8.4 Hz, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 9.0 Hz, 1H), 4.80 (d, J = 4.2 Hz, 2H). Example 31. 4- (4- (6-chloropyridazine- 3-yl) benzyl) morpholine
Figure imgf000042_0001
실시예 30에서 얻은 4-(6-클로로피리다진 -3-일)벤잘데하이드 (100 mg, 0.46 匪 ol)와 몰폴린 (80 mg)을 디클로로메탄 (5 mL)에 녹이고 아세트산 (35 mg)을 적가한 후 실온에서 30분동안 교반한 다음 NaB(0Ac)3H(0.15 g, 0.69 瞧 ol)를 가했다. 실온에서 3시간 동안 교반한 후 5% 2C03 수용액을 가하여 pH 8로 조절한 다음 디클로로메탄을 가하여 추출하고 유기층을 무수 황산나트륨으로 건조， 감압 농축하였다. 컬럼 크로마토그래피 (4%4- (6-chloropyridazin-3-yl) benzaldehyde (100 mg, 0.46 μl ol) and morpholine (80 mg) obtained in Example 30 were dissolved in dichloromethane (5 mL) and acetic acid (35 mg) Was added dropwise and stirred at room temperature for 30 minutes, followed by addition of NaB (0Ac) 3 H (0.15 g, 0.69 Pa ol). After stirring at room temperature for 3 hours, 5% 2 CO 3 aqueous solution was added to adjust pH to 8, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column Chromatography (4%
Me0H/C¾Cl2)로 정제하여 4-(4-(6-클로로피리다진 -3-일)벤질)몰폴린 (92 mg, 69%)을 얻었다. Purification with Me0H / C¾Cl 2 ) gave 4- (4- (6-chloropyridazin-3-yl) benzyl) morpholine (92 mg, 69%).
一證 (300 MHz, CDCls) δ 8.00 (d, / = 8.3 Hz, 2H), 7.82 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 3.71 (m, 4H), 3.57 (s, 2H), 2.47 (m, 4H). 실시예 32. 메틸 3-(6ᅳ클로로피리다진 -3ᅳ일)벤조에이트
Figure imgf000043_0001
300 (300 MHz, CDCls) δ 8.00 (d, / = 8.3 Hz, 2H), 7.82 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 3.71 (m, 4H), 3.57 (s, 2H), 2.47 (m, 4H). Example 32. Methyl 3- (6'chloropyridazine-3xyl) benzoate
Figure imgf000043_0001
실시예 19와 동일한 방법으로 진행하여 목적화합물 메틸 3-(6- 클로로피리다진 -3-일)벤조에이트을 얻었다. Proceed in the same manner as in Example 19, to obtain the target compound methyl 3- (6-chloropyridazin-3-yl) benzoate.
-賺 (300 MHz, CDCI3) δ 8.65(s, 1H), 8.37(d, J= 7.7 Hz, 1H), 8.20(d, 7.7 Hz, 1H) , 7.92(d, J= 9.0 Hz, 1H), 7.64(m, 2H), 3.99(s, 3H). 실시예 33. 3-(6-클로로피리다진 -3—일) -N-에틸벤자아마이드
Figure imgf000043_0002
-賺 (300 MHz, CDCI3) δ 8.65 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.20 (d, 7.7 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.64 (m, 2 H), 3.99 (s, 3 H). Example 33. 3- (6-Chloropyridazine-3-yl) -N-ethylbenzaamide
Figure imgf000043_0002
실시예 32에서 얻은 메틸 3-(6-클로로피리다진 -3-일)벤조에이트 (100 ing, 0.4 隱 ol)를 테트라히드로퓨란 (0.6 mL)과 증류수 (0.1 mL)에 녹인 후 0°C에서 ^산화나트륨 수용액 (0.4 mL)을 가한다음 실온에서 3시간 동안 교반하였다. 반웅 후 0°C에서 1N-염산 수용액을 가하여 pH 3-4로 조절하여 흰색고체를 생성하였다. 여과하여 증류수로 씻어준 후 벤젠올 가하여 감압 농축하여 3-(6-클로로피리다진 -3-일)벤조산 (141 mg, 68%)을 흰색 고체로 얻었다. Methyl 3- (6-chloropyridazin-3-yl) benzoate (100 ing, 0.4 隱 ol) obtained in Example 32 was dissolved in tetrahydrofuran (0.6 mL) and distilled water (0.1 mL), and then at 0 ° C. ^ Aqueous sodium oxide solution (0.4 mL) was added followed by stirring at room temperature for 3 hours. After reaction, 1N hydrochloric acid aqueous solution was added at 0 ° C. to adjust pH to 3-4 to produce a white solid. After filtration and washing with distilled water, benzeneol was added and concentrated under reduced pressure to obtain 3- (6-chloropyridazin-3-yl) benzoic acid (141 mg, 68%) as a white solid.
¾-NMR (300 MHz, CDC13) δ 8.71 (s, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.72(t, J = 7.8 Hz, 1H). ¾-NMR (300 MHz, CDC1 3 ) δ 8.71 (s, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz , 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H).
3-(6-클로로피리다진 -3-일)벤조산 (141 mg, 0.601 mmol)을 티오닐클로라이드 (S0C12 ,5 mL)에 가하고 12시간 가열 환류 한다. 반웅 후 감압 농축하여 3-(6-클로로피리다진— 3-일)벤조일클로라이드 (126 mg, 86%)를 황토색 고체로 얻었으며 정제없이 다음반웅을 진행하였다. 3- (6-Chloropyridazin-3-yl) benzoic acid (141 mg, 0.601 mmol) is added to thionylchloride (S0C1 2 , 5 mL) and heated to reflux for 12 h. After reaction, the mixture was concentrated under reduced pressure to obtain 3- (6-chloropyridazine- 3-yl) benzoyl chloride (126 mg, 86%) as an ocher solid. The reaction was carried out without purification.
3-(6-클로로피리다진 -3-일)벤조일클로라이드 (60 mg, 0.24 圆 ol)를 건조된 디클로로메탄 (3 mL)에 녹인 후 00C에서 트리에틸아민 (0.06 mL, 0.48 mmol)과 에틸아민염산염 (21 mg, 0.25 侧 ol)을 가한다음 실온에서 12시간 교반하였다. 반웅 후 용매를 감압농축 한 후 에틸아세테이트를 가하고 소금물로 세척한 후 유기층을 무수 황산나트륨으로 건조하고 감압농축하였다. 컬럼 크로마토그래피 (80% EtOAc/Hexane)로 정제하여 3- (6-클로로피리다진 -3-일) - ^에틸벤자마이드 (31 mg, 50%)를 흰색고체로 얻었다. 3- (6-chloropyridazin-3-yl) benzoylchloride (60 mg, 0.24 cc ol) It was dissolved in dried dichloromethane (3 mL), triethylamine (0.06 mL, 0.48 mmol) and ethylamine hydrochloride (21 mg, 0.25 侧 ol) were added at 0 0 C, and the mixture was stirred at room temperature for 12 hours. After reaction, the solvent was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed with brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (80% EtOAc / Hexane) gave 3- (6-chloropyridazin-3-yl)-^ ethylbenzamide (31 mg, 50%) as a white solid.
¾-NMR (300 MHz, CDC13) δ 8.48 (s, 1H), 8.18 (d, / = 7.8 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 6.32 (brs, 1H)， 3.54 (m, 2H), 1.29 (d, J 7.7 Hz, 3H). 실시예 34. 4- (4- ^l^j ^ )-2-((6-^ -fl, 2, 4 jM j ].^[4> 3- b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H-피리도 [3, 2-b][l, 4]옥사진
Figure imgf000044_0001
¾-NMR (300 MHz, CDC1 3 ) δ 8.48 (s, 1H), 8.18 (d, / = 7.8 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 9.0 Hz , 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 6.32 (brs, 1H), 3.54 (m, 2H), 1.29 (d, J 7.7 Hz, 3H). Example 34. 4- (4- ^ l ^ j ^)-2-((6-^-fl, 2, 4 jM j]. ^ [4 > 3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazine
Figure imgf000044_0001
실시예 18에서 얻은 2-(4-(4-메톡시벤질) -3，4-디히드로 -2y 피리도 [3，2- [1,4]옥사진 -2-일)아세토하이드라자이드 (20 mg, 0.061 瞧 ol)와 실시예 20에서 얻은 3-클로로 -6—페닐피리다진 (11 mg, 0.055 隱 ol)을 n-부탄올 (2 mL)에 녹인 후 130 0C에서 48시간 동안 교반하였다。 반웅 후 에틸아세테이트를 가하고 포화 탄산수소나트륨 수용액으로 세척한 후 유기층을 무수 황산나트륨으로 건조한 다음 컬럼 크로마토그래피 (3% MeOH/CH2Cl2)로 정제하여 목적화합물인 4-(4-메록시벤질) -2-((6-페닐- [1,2， 4]트리아졸로 [4， 3-b]피리다진— 3-일 )메틸 )-3 , 4-디히드로 -2H- 피리도 [3,2-b][l,4]옥사진 (10 mg, 40))을 얻었다.2- (4- (4-methoxybenzyl) -3,4-dihydro-2y pyrido [3,2- [1,4] oxazin-2-yl) acetohydrazide obtained in Example 18 ( 20 mg, 0.061 μl ol) and 3-chloro-6—phenylpyridazine (11 mg, 0.055 μl ol) obtained in Example 20 were dissolved in n-butanol (2 mL) and stirred at 130 0 C for 48 hours. After reaction, ethyl acetate was added, the resultant was washed with saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over anhydrous sodium sulfate, and purified by column chromatography (3% MeOH / CH 2 Cl 2) to be the target compound, 4- (4-hydroxybenzyl). -2-((6-phenyl- [1,2,4] triazolo [4,3-b] pyridazine- 3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2 -b] [l, 4] oxazine (10 mg, 40)).
-證 (300 MHz, CDCI3) δ 8.13 (d, / = 9.7 Hz, 1H), 7.81 (dd, J-證 (300 MHz, CDCI 3 ) δ 8.13 (d, / = 9.7 Hz, 1H), 7.81 (dd, J
= 4.9， 1.4 Hz, 1H), 7.62-7.55 (m, 5H), 7.55 (d, J = 9.7 Hz, 1H) , 7.18 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 7.6， 1.1 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (dd, / = 7.6, 4.8 Hz, 1H) , 4.90 (d, A of AB q, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of AB q, J二 14.7 Hz, 1H), 3.72 (s, 3H), 3.52-3.39 (m, 4H) . 실시예 35. 2-((6-페닐 -[1, 2,4]트리아졸로 [4,3-b]피리다진 -3- 일)메틸) -3, 4-디히드로 -2H-피리도 [3， 2-b ][1, 4]옥사진 = 4.9, 1.4 Hz, 1H), 7.62-7.55 (m, 5H), 7.55 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 7.6, 1.1 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (dd, / = 7.6, 4.8 Hz, 1H), 4.90 (d, A of AB q, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of AB q, J 2 O 14.7 Hz, 1H), 3.72 (s, 3H), 3.52-3.39 (m, 4H). Example 35. 2-((6-phenyl- [1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [ 3 ， 2-b] [1, 4] jade photos
Figure imgf000045_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-페닐- [1,2，4]트리아졸로[4，3-13]피리다진-3ᅳ일)메틸)-3,4-디히드로-211- 피리도[3，2-13][1，4]옥사진 트리플루오로아세트산 염을 얻었다.
Figure imgf000045_0001
Proceed in the same manner as in Example 7, target compound 2-((6-phenyl- [1,2,4] triazolo [4,3-13] pyridazin-3xyl) methyl) -3,4-dihydro -211- pyrido [3,2-13] [1,4] oxazine trifluoroacetic acid salt was obtained.
-匪 R (300顧 z, DMS0-d6) δ 10.8 (brs, 1H)， 8.39 (d, / = 9.6 Hz 1H), 7.68 (d, /= 9.6 Hz, 1H), 7.41 (d, J= 6.2 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.64 (dd, J = 7.5, 4.8 Hz, 1H), 4.90 (m, 1H), 3.92-3.62 (m, 4H). 실시예 36. 2-((6-(4-플루오로페닐) -[1, 2, 4]트리아졸로 [4, 3~ b]피리다진 -3-일)메틸) -4-(4-메특시벤질) -3， 4-디히드로 -2H-피리도 [3, 2- b][l,4]옥사진 -匪 R (300 顧 z, DMS0-d 6 ) δ 10.8 (brs, 1H), 8.39 (d, / = 9.6 Hz 1H), 7.68 (d, / = 9.6 Hz, 1H), 7.41 (d, J = 6.2 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.64 (dd, J = 7.5, 4.8 Hz, 1H), 4.90 (m, 1H), 3.92-3.62 (m, 4H). Example 36. 2 - ((6- (4-fluorophenyl) - [1,2, 4] triazolo [4, 3 ~ b] pyridazin-3-yl) methyl) -4- (4-meteuk Sibenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine
Figure imgf000045_0002
Figure imgf000045_0002
플루오로페닐 )—[1,2,4]트리아졸로 [4,3-b]피리다진ᅳ 3-일)메틸) -4-(4- 메록시벤질 ) -3，4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진을 얻었다.  Fluorophenyl) — [1,2,4] triazolo [4,3-b] pyridazinyl 3-yl) methyl) -4- (4- methoxybenzyl) -3,4-dihydro-2H- Pyrido [3, 2-b] [1,4] oxazine was obtained.
證 (300 MHz, CDC13) δ 8.15 (d, J二 9.7 Hz, 1H), 7.92 (dd, J = 8.8， 5.2 Hz, 2H), 7.80 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 9.7 Hz, 1H) 7.20 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H) , 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of AB q, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of AB q J = 14.7 Hz, 1H)' 3.73 (s, 3H), 3.69 (m, 1H), 3.54-3.35 (m, 3H) . 실시예 37. 2-((6-(4-플루오로페닐)-[1,2,4]트리아졸로[4，3- b]피리다진 -3-일)메틸) -3， 4-디히드로 -2H-피리도 [3, 2-b][l, 4]옥사진
Figure imgf000046_0001
300 (300 MHz, CDC1 3 ) δ 8.15 (d, J 二 9.7 Hz, 1H), 7.92 (dd, J = 8.8, 5.2 Hz, 2H), 7.80 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 9.7 Hz, 1H) 7.20 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of AB q, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of AB q J = 14.7 Hz, 1H) '3.73 (s, 3H), 3.69 (m, 1H), 3.54- 3.35 (m, 3 H). Example 37. 2-((6- (4-fluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro -2H-pyrido [3, 2-b] [l, 4] oxazine
Figure imgf000046_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(4- 폴루오로페닐 )-[1，2,4]트리아졸로 [4,3— b]피리다진 -3-일)메틸) -3，4- 디히드로- -피리도[3，2-1)][1,4]옥사진 트리플루오로아세트산염을 얻었다. Proceed in the same manner as in Example 7, target compound 2-((6- (4-polourophenyl)-[1,2,4] triazolo [4,3—b] pyridazin-3-yl) methyl ) -3,4-dihydro-pyrido [3,2-1)] [1,4] oxazine trifluoroacetic acid salt was obtained.
-證 (300 MHz, CDC13) δ 10.91 (brs, 1H), 8.26 (d, J = 9.7 Hz, 1H), 7.96 (dd, /= 8.8， 5.2 Hz, 2H), 7.62 (d, J = 9.7 Hz, 1H) , 7.39 (d J = 6.2 Hz, 1H), 7.26 (m, 2H) , 7.22 (d, J = 7.6 Hz, 1H), 6.63 (dd, / = 7.6， 4.8 Hz, 1H), 4.87 (m, 1H) ' 3.89-3.78 (m, 2H), 3.70-3.61 (m, 2H). 실시예 38. 2-((6-(3- ≤^ 2, 4] S f-^[4i 3- b]피리다진 -3-일)메틸) -4-(4-메톡시벤질)ᅳ 3, 4-디히드로 -2H—피리도 [3， 2- b][l,4]옥사진
Figure imgf000046_0002
-證 (300 MHz, CDC1 3 ) δ 10.91 (brs, 1H), 8.26 (d, J = 9.7 Hz, 1H), 7.96 (dd, / = 8.8, 5.2 Hz, 2H), 7.62 (d, J = 9.7 Hz, 1H), 7.39 (d J = 6.2 Hz, 1H), 7.26 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.63 (dd, / = 7.6, 4.8 Hz, 1H), 4.87 (m, 1 H) '3.89-3.78 (m, 2H), 3.70-3.61 (m, 2H). Example 38. 2-((6- (3-≤ ^ 2, 4] S f-^ [ 4i 3-b] pyridazin-3-yl) methyl) -4- (4-methoxybenzyl) ᅳ 3 , 4-dihydro-2H—pyrido [3, 2-b] [l, 4] oxazine
Figure imgf000046_0002
실시예 34과 동일한 방법으로 진행하여 목적화합물 2-((6_(3- 플루오로페닐 )-[1，2,4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -4-(4- 메록시벤질^^^디히드로-뙈-피리도^，^ ，^옥사진을 얻었다. Ή-NMR (300 MHz, CDC13) δ 8.17(d, J= 9.7 Hz, 1H) , 7.80(dd, J= 5.0， 1.4 Hz, 1H), 7.69(d, J= 8.0 Hz, 1H), 7.65(dt, J= 9.4， 1.9 Hz, 1H) 7.54(d, J = 9.7 Hz, 1H), 7.50(m, 1H), 7.26(m, 1H), 7.18(d, J= 8.6 Hz, 2H), 6.88(dd, 7.7， 1.4 Hz, 1H), 6.74(d, J= 8.6 Hz, 2H), 6.51(dd, J= 7.6, 4.8 Hz, 1H), 4.86(d, A of ABq, J= 14.8 Hz, 1H), 4.84(m, 1H), 4.66(d, B of ABq, J= 14.8 Hz, 1H), 3.70(s, 3H) , 3.69(m, 1H) , 3.53- 3.35(ni, 3H). 실시예 39. 2-((6-(3- ^.^1 2, 4] B]^ [4, 3- b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H-피리도 [3, 2~b][l, 4]옥사진
Figure imgf000047_0001
Proceed in the same manner as in Example 34, target compound 2-((6_ (3-fluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl)- 4- (4-Methoxybenzyl ^^^ dihydro- 뙈 -pyrido ^, ^, ^ oxazine was obtained. Ή-NMR (300 MHz, CDC1 3 ) δ 8.17 (d, J = 9.7 Hz, 1H), 7.80 (dd, J = 5.0, 1.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.65 (dt, J = 9.4, 1.9 Hz, 1H) 7.54 (d, J = 9.7 Hz, 1H), 7.50 (m, 1H), 7.26 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.88 (dd, 7.7, 1.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.86 (d, A of ABq, J = 14.8 Hz , 1H), 4.84 (m, 1H), 4.66 (d, B of ABq, J = 14.8 Hz, 1H), 3.70 (s, 3H), 3.69 (m, 1H), 3.53- 3.35 (ni, 3H). Example 39. 2-((6- (3-^. ^ 1 2, 4] B] ^ [4, 3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H- Pyrido [3, 2 to b] [l, 4] oxazine
Figure imgf000047_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(3- 플루오로페닐 )-[1，2，4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3,4- 디히드로- -피리도 ^- ，^옥사진 트리플루오로아세트산염을 얻었다.  Proceed in the same manner as in Example 7, target compound 2-((6- (3-fluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro- -pyrido ^-, ^ oxazine trifluoroacetic acid salt was obtained.
¾_腿 (300 MHz, CDCI3) δ 10.'81(brs, 1H), 8.32(d, J= 9.7 Hz, 1H), 7.80-7.52 (m, 3H), 7.40(d, J = 6.0 Hz, 2H) , 7.31(m, 1H), 7.20(d, J= 8.2 Hz, 1H), 6.64(dd, /= 7.6， 4.8 Hz, 1H), 4.88(m, 1H) , 3.92-3.80(m 2H), 3.72- 3.62(m, 2H). 실시예 40. 2-((6-(3，5-디플루오로페닐)— [1,2,4]트리아졸로 [4,3 b]피리다진 일)메틸) -4-(4-메특시벤질) -3, 4-디히드로 -2H-피리도 [3 , 2- b] [1,4]옥사진
Figure imgf000047_0002
¾_腿(300 MHz, CDCI3) δ 10. '81 (brs, 1H), 8.32 (d, J = 9.7 Hz, 1H), 7.80-7.52 (m, 3H), 7.40 (d, J = 6.0 Hz, 2H), 7.31 (m, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.64 (dd, / = 7.6, 4.8 Hz, 1H), 4.88 (m, 1H), 3.92-3.80 (m 2H) , 3.72-3.62 (m, 2 H). Example 40. 2-((6- (3,5-difluorophenyl) — [1,2,4] triazolo [4,3 b] pyridazinyl) methyl) -4- (4-method Benzyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine
Figure imgf000047_0002
실시예 34와 동일한 방법으로 진행하여 목적화합물 2-((6— (3,5- 디플루오로페닐) _[1，2，4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) 4-(4- 메록시벤질)-3，4-디히드로- -피리도[3，2-13][1，4]옥사진을 얻었다. In the same manner as in Example 34, target compound 2-((6— (3,5-difluorophenyl) _ [1,2,4] triazolo [4,3-b] pyridazin-3-yl ) Methyl) 4- (4- Methoxybenzyl) -3,4-dihydro-pyrido [3,2-13] [1,4] oxazine was obtained.
¾-NMR (300 MHz, CDC13) δ 8.18 (d, J = 9.7 Hz, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.49(d, J= 9.7 Hz, 1H), 7.46(m, 1H), 7.19(d, J= 8.6 Hz, 2H), 7.02 (m, 1H), 6.87(d, /= 7.6 Hz, 1H) , 6.75(d, J= 8.6 Hz, 2H), 6.51(dd, /= 7.6, 4.8 Hz, 1H), 4.86(d, A of ABq, J= 14.8 Hz, 1H), 4.84(m, 1H), 4.66(d, B of ABq, J= 14.8 Hz, 1H), 3.70(s, 3H) , 3.66(m, 1H), 3.53-3.36 (m, 3H). 실시예 41. 2-((6-(3,5-디플루오로페닐)-[1，2,4]트리아졸로[4，3- b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H-피리도 [3, 2-b][ 1， 4]옥사진
Figure imgf000048_0001
¾-NMR (300 MHz, CDC1 3 ) δ 8.18 (d, J = 9.7 Hz, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.49 (d, J = 9.7 Hz, 1H), 7.46 (m , 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.02 (m, 1H), 6.87 (d, / = 7.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.51 (dd , / = 7.6, 4.8 Hz, 1H), 4.86 (d, A of ABq, J = 14.8 Hz, 1H), 4.84 (m, 1H), 4.66 (d, B of ABq, J = 14.8 Hz, 1H), 3.70 (s, 3H), 3.66 (m, 1H), 3.53-3.36 (m, 3H). Example 41. 2-((6- (3,5-difluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4 -Dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000048_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(3，5- 디플루오로페닐) -[l,2，4]트리아졸로[4,3—b]피리다진-3-일)메틸)-3，4- 디히드로-2H-피리도[3，2-b][l,4]옥사진 트리플루오로아세트산염을 얻었다.  Proceed in the same manner as in Example 7, target compound 2-((6- (3,5-difluorophenyl)-[l, 2,4] triazolo [4,3—b] pyridazin-3-yl ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine trifluoroacetic acid salt was obtained.
¾-NMR (300 MHz, CDC13) 6 10.90 (brs, 1H), 8.27 (d, J = 9.7 Hz,¾-NMR (300 MHz, CDC1 3 ) 6 10.90 (brs, 1H), 8.27 (d, J = 9.7 Hz,
1H), 7.57-7.44 (m, 3H)， 7.38 (mᅳ 1H), 7.18 (m, 2H), 7.03 (m, 1H)， 6.64 (dd, /= 7,6, 4.8 Hz, 1H), 4.84 (m, 1H), 3.93-3.81 (m, 2H) , 3.71- 3.63 (m, 2H). 실시예 42. 2-((6-(3- ^≤-4-^] ^J -f 2, 4] ^ ^[4> 3- b]피리다진 -3-일)메틸)— 4-(4-메톡시벤질) -3, 4-디히드로 -2H-피리도 [3， 2- b] [1,4]옥사진
Figure imgf000048_0002
실시예 34과 동일한 방법으로 진행하여 목적화합물 2-((6-(3- 플루오로 -4-메틸페닐) -[1，2，4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -4-(4- 메록시벤질) -3, 4-디히드로 -2H-피리도 [3, 2-b] [1,4]옥사진을 얻었다. 1H), 7.57-7.44 (m, 3H), 7.38 (m ᅳ 1H), 7.18 (m, 2H), 7.03 (m, 1H), 6.64 (dd, / = 7,6, 4.8 Hz, 1H), 4.84 (m, 1 H), 3.93-3.81 (m, 2 H), 3.71-3.63 (m, 2 H). Example 42. 2-((6- (3- ^ ≤-4- ^] ^ J -f 2, 4] ^ ^ [ 4> 3-b] pyridazin-3-yl) methyl) — 4- ( 4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine
Figure imgf000048_0002
Proceed as in Example 34 to the target compound 2-((6- (3-fluoro-4-methylphenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl ) Methyl) -4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine was obtained.
一匿 (300 MHz, CDC13) δ 8.15 (d, J = 9.7 Hz, 1H), 7.62 (dd, J = 4.5， 1.4 Hz, 1H), 7.64-7.62 (m, 1H), 7.60 (s, 1H), 7.54 (d, J = 9.7 Hz, 1H), 7.35 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 7.7, 1.4 Hz, 1H), 6.74 (d, / = 8.6 Hz, 2H), 6.51 (dd, J= 7.6, 4.8 Hz, 1H)， 4.88 (d, A of ABq, J= 14.7 Hz, 1H), 4.84 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 3.70 (s, 3H), 3.68 (m, 1H), 3.50-3.39 (m, 3H) , 2.38 (s, 3H). 실시예 43. 2-((6-(3-^ ^-4-^ί] ^] -fl, 2, 4] B^^≤[4, 3~ b]피리다진— 3-일)메틸) -3, 4-디히드로一 2H-피리도 [3, 2~b][l, 4]옥사진 (300 MHz, CDC1 3 ) δ 8.15 (d, J = 9.7 Hz, 1H), 7.62 (dd, J = 4.5, 1.4 Hz, 1H), 7.64-7.62 (m, 1H), 7.60 (s, 1H ), 7.54 (d, J = 9.7 Hz, 1H), 7.35 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 7.7, 1.4 Hz, 1H), 6.74 (d , / = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.84 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 3.70 (s, 3H), 3.68 (m, 1H), 3.50-3.39 (m, 3H), 2.38 (s, 3H). Example 43. 2-((6- (3- ^ ^ -4- ^ ί] ^] -fl, 2, 4] B ^^ ≤ [4, 3 to b] pyridazine- 3-yl) methyl) -3,4-dihydrol 2H-pyrido [3, 2 to b] [l, 4] oxazine
Figure imgf000049_0001
Figure imgf000049_0001
실시예 7과 동일한 방법으로 진행하여 목적화합물 2-((6-(3 플루오로 -4-메틸페닐) -[1,2,4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3，4- 디히드로 -2H-피리도 [3, 2-b] [1,4]옥사진 트리플루오로아세트산염을 얻었다. Proceed in the same manner as in Example 7, target compound 2-((6- (3 fluoro-4-methylphenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt was obtained.
-匿 (300 MHz, CDCI3) δ 10.90(brs, 1H)， 8.26(d, 9.7 Hz, 1H), 7.66-7.42(m, 4H) , 7.54(d, J= 9.7 Hz, 1H)， 7.22(m, 1H), 6.64(dd, J= 7.6, 4.8 Hz, 1H), 4.88(111， 1H), 3.92-3.80(m, 2H), 3.72-3.62(m, 2H), 2.35 (s, 3H). 실시예 44. 3-(3-((4-(4-메톡시벤질) -3， 4-디히드로 -2H-피리도 [3， 2- b][l, 4]옥사진 -2-일)메틸) -[1， 2, 4]트리아졸로 [4， 3-b]피리다진 -6- 일)벤조나이트라일
Figure imgf000050_0001
-MHz (300 MHz, CDCI3) δ 10.90 (brs, 1H), 8.26 (d, 9.7 Hz, 1H), 7.66-7.42 (m, 4H), 7.54 (d, J = 9.7 Hz, 1H), 7.22 (m , 1H), 6.64 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (111, 1H), 3.92-3.80 (m, 2H), 3.72-3.62 (m, 2H), 2.35 (s, 3H). Example 44. 3- (3-((4- (4-methoxybenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazin-2-yl ) Methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) benzonitriyl
Figure imgf000050_0001
실시예 34와 동일한 방법으로 진행하여 목적화합물 3-(3-((4-(4- 메록시벤질 )-3ᅳ 4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진 -2-일 )메틸) - [1，2,4]트리아졸로[4，3-1)]피리다진-6-일)벤조나이트라일을 얻었다. In the same manner as in Example 34, the target compound 3- (3-((4- (4-methoxybenzyl) -3'4-dihydro-2H-pyrido [3, 2-b] [1,4 ] Oxazine-2-yl) methyl)-[1,2,4] triazolo [4,3-1)] pyridazin-6-yl) benzonitriyl.
—證 (300 MHz, CDCls) δ 8.23 (d, J = 9.7 Hz, 1H), 8.22 (m, 1H), 8.15 (dd, J = 8.0, 1.0 Hz, 1H), 7.87-7.80 (m, 2H) ' 7.68 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 9.7 Hz, 1H), 7.19 (d, / = 8.6 Hz, 2H), 6.85 (dd, J二 7.7, 1.4 Hz, 1H), 6.75 (d, / = 8.6 Hz, 2H), 6.51 (dd, J = 7.6 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.85 (m, 1H) , 4.68 (d, B of ABq, / = 14.7 Hz, 1H), 3.75 (s, 3H), 3.69 (m, 1H), 3.50-3.39 (m, 3H). 실시예 45. 3ᅳ (3-( (3 , 4-디히드로 -2H피리도 [3 , 2-b] [ 1， 4]옥사진 -2- 일)메틸)—[1, 2, 4]트리아졸로 [4， 3— b]피리다진 -6-일)벤조나이트라일  — 證 (300 MHz, CDCls) δ 8.23 (d, J = 9.7 Hz, 1H), 8.22 (m, 1H), 8.15 (dd, J = 8.0, 1.0 Hz, 1H), 7.87-7.80 (m, 2H) '7.68 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 9.7 Hz, 1H), 7.19 (d, / = 8.6 Hz, 2H), 6.85 (dd, J 二 7.7, 1.4 Hz, 1H) , 6.75 (d, / = 8.6 Hz, 2H), 6.51 (dd, J = 7.6 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.85 (m, 1H), 4.68 (d, B of ABq, / = 14.7 Hz, 1H), 3.75 (s, 3H), 3.69 (m, 1H), 3.50-3.39 (m, 3H). Example 45. 3 ′ (3- ((3, 4-dihydro-2Hpyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl) — [1, 2, 4] Triazolo [4,3—b] pyridazine-6-yl) benzonitriyl
Figure imgf000050_0002
Figure imgf000050_0002
실시예 7과 동일한 방법으로 진행하여 목적화합물 3-(3-((3,4- 디히드로 -2H-피리도 [3, 2-b] [1,4]옥사진 -2-일)메틸) -[ 1,2,4]트리아졸로 [4,3- b]피리다진 -6-일)벤조나이트라일 트리플루오로아세트산염을 얻었다. Proceed in the same manner as in Example 7 3- (3-((3,4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazin-2-yl) methyl) [4,3-b] pyridazin-6-yl) benzonitriyl trifluoroacetic acid salt was obtained with-[1,2,4] triazol.
-賺 (300 MHz, CDCI3) 8 10.78 (brs, 1H), 8.34 (d, / = 9.7 Hz, 1H), 8.33 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H) , 7.88 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 9.7 Hz, 1H) , 7.40 (d, / = 6.2 Hz, 1H), 6.66 (dd, / = 7.6, 4.8 Hz, 1H), 4.89 (m, 1H) , 3.92-3.62 (m, 4H). 실시예 46. 4-(4-메톡시벤질) -2-((6- (피리딘 -4-일)ᅳ-賺 (300 MHz, CDCI3) 8 10.78 (brs, 1H), 8.34 (d, / = 9.7 Hz, 1H), 8.33 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.88 (d , J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 9.7 Hz, 1H), 7.40 (d, / = 6.2 Hz, 1H), 6.66 (dd, / = 7.6, 4.8 Hz, 1H), 4.89 (m, 1H), 3.92-3.62 (m, 4H). Example 46. 4- (4-methoxybenzyl) -2-((6- (pyridin-4-yl))
[1, 2, 4]트리아졸로 [4， 3-b]피리다진 -3-일)메틸) -3， 4-디히드로 -2H- 피리도 [3, 2-b][l, 4]옥사진 [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [l, 4] jade Picture
Figure imgf000051_0001
Figure imgf000051_0001
실시예 34와 동일한 방법으로 진행하여 목적화합물 4-(4- 메특시벤질) -2-((6- (피리딘 -4—일)— [1,2,4]트리아졸로 [4,3-b]피리다진 -3- 일)메틸) ， 디히드로- -피리도^，^ ，^옥사진을 얻었다. Proceed in the same manner as in Example 34, and then proceed to Compound 4- (4-Methoxybenzyl) -2-((6- (pyridin-4-yl) — [1,2,4] triazolo [4,3-b ] Pyridazine-3-yl) methyl), dihydro-pyrido ^, ^, ^ oxazine.
-NMR (300 MHz, CDC13) δ 8,83 (d, / = 6.0 Hz, 2H), 8.24 (d, J = 9.7 Hz, 1H), 7.80 (m, 3H), 7.58 (d, 9.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.86 (dd, J= 7.6， 1.2 Hz, 1H) , 6.75 (d, J = 8.6 Hz, 2H), 6.50 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of ABq, J二 14.7 Hz, 1H), 4.86 (m, 1H), 4.68 (d, B of ABq, J = 14.7 Hz, 1H), 3.75 (s, 3H), 3.69 (m, 1H), 3.51-3.40 (m, 3H). 실시예 47. 2-((6- (피리딘 -4—일) -[1，2,4]트리아졸로 [4, 3-b]피리다진- 3ᅳ일)메틸) -3, 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진 -NMR (300 MHz, CDC1 3 ) δ 8,83 (d, / = 6.0 Hz, 2H), 8.24 (d, J = 9.7 Hz, 1H), 7.80 (m, 3H), 7.58 (d, 9.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.86 (dd, J = 7.6, 1.2 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.50 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (d, A of ABq, J 二 14.7 Hz, 1H), 4.86 (m, 1H), 4.68 (d, B of ABq, J = 14.7 Hz, 1H), 3.75 (s, 3H) , 3.69 (m, 1 H), 3.51-3.40 (m, 3 H). Example 47. 2-((6- (Pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazine- 3 ᅳ yl) methyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000051_0002
Figure imgf000051_0002
PMB 보호기 제거 반응은 실시예 7과 동일한 방법으로 진행하여 2- ((6- (피리딘 -4-일) -[1，2，4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3ᅳ 4- 디히드로 -2H—피리도 [3,2-b][l,4]옥사진 트리플루오로아세트산염을 얻었다.  PMB protecting group removal reaction was carried out in the same manner as in Example 7, 2-((6- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl ) Methyl) -3'4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine trifluoroacetic acid salt was obtained.
¾-NMR (300 MHz, CDC13) δ 10.82 (brs, 1H), 8.93 (d, /= 6.0 Hz, 2H), 8.40 (d, J二 9.7 Hz, 1H), 8.07 (d, J= 6.0 Hz, 2H), 7.69 (d, J = 9.7 Hz, 1H), 7.41 (d, J二 6.0 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.66 (dd, / = 7.6, 4.8 Hz, 1H), 4.91 (m, 1H), 3.90-3.66 (m, 4H). 실시예 48. 4-(4-메톡시벤질) -2ᅳ ( (6- (피리딘 -3-일) -¾-NMR (300 MHz, CDC1 3 ) δ 10.82 (brs, 1H), 8.93 (d, / = 6.0 Hz, 2H), 8.40 (d, J 二 9.7 Hz, 1H), 8.07 (d, J = 6.0 Hz , 2H), 7.69 (d, J = 9.7 Hz, 1H), 7.41 (d, J 二 6.0 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.66 (dd, / = 7.6, 4.8 Hz , 1H), 4.91 (m, 1H), 3.90-3.66 (m, 4H). Example 48. 4- (4-methoxybenzyl) -2 '((6- (pyridin-3-yl)-)
[1,2, 4]트리아졸로 [4 , 3— b]피리다진 -3-일)메틸)—3 , 4-디히드로ᅳ 2H- 피리도 [3， 2-b][l, 4]옥사진 [1,2, 4] triazolo [4, 3—b] pyridazin-3-yl) methyl) —3,4-dihydrosub 2H-pyrido [3, 2-b] [l, 4] jade Picture
Figure imgf000052_0001
Figure imgf000052_0001
실시예 34와 동일한 방법으로 진행하여 목적화합물 4-(4ᅳ 메록시벤질) _2_((6- (피리딘 -3-일)— [1|2,4]트리아졸로 [4，3— b]피리다진 -3- 일)메틸)-3ᅳ4-디히드로— -피리도[3，2-1)][1，4]옥사진을 얻었다.In the same manner as in Example 34, the target compound 4- (4 'methoxybenzyl) _ 2 _ (( 6- (pyridin- 3 -yl) — [ 1 | 2 , 4 ] triazolo [ 4 , 3 — b ] Pyridazine- 3 -yl) methyl) -3 ᅳ 4-dihydro--pyrido [3,2-1)] [1,4] oxazine was obtained.
-匿 (300 MHz, CDCI3) δ 9.27(s, 1H) , 8.72(S> 1H) , 8.54(d, J= 6.7 Hz, 1H), 8.25(d, J= 9.7 Hz, 1H), 7.81(m, 1H), 7.61(m, 1H) , 7.58(d, J = 9.7 Hz, 1H), 7.19(d, J= 8.6 Hz, 2H) , 6.87(d, J= 7.6 Hz, 1H), 6.73(d, J = 8.6 Hz, 2H), 6.52(dd, J= 7.6， 4.8 Hz, 1H), 4.91(d, A of ABq, /= 14.7 Hz, 1H), 4.87(m, 1H), 4.68(d, B of ABq, J = 14.7 Hz, 1H), 3.75(s, 3H), 3.68(III, 1H), 3.52-3.41(m, 3H). 실시예 49. 2-((6-(^Js ^-3-^)-[l,2, 4] ^^} ^[4,
Figure imgf000052_0002
-匿 (300 MHz, CDCI 3 ) δ 9.27 (s, 1H), 8.72 ( S> 1H), 8.54 (d, J = 6.7 Hz, 1H), 8.25 (d, J = 9.7 Hz, 1H), 7.81 ( m, 1H), 7.61 (m, 1H), 7.58 (d, J = 9.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.73 ( d, J = 8.6 Hz, 2H), 6.52 (dd, J = 7.6, 4.8 Hz, 1H), 4.91 (d, A of ABq, / = 14.7 Hz, 1H), 4.87 (m, 1H), 4.68 (d , B of ABq, J = 14.7 Hz, 1H), 3.75 (s, 3H), 3.68 (III, 1H), 3.52-3.41 (m, 3H). Example 49. 2-((6-(^ Js ^ -3-^)-[l, 2, 4] ^^} ^ [4,
Figure imgf000052_0002
3-일)메틸) -3， 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진 3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000052_0003
Figure imgf000052_0003
ΡΜΒ 보호기 제거 반응은 실시예 7과 동일한 방법으로 진행하여 2- ((6- (피리딘 -3-일) -[1，2，4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3，4- 디히드로 -2H—피리도 [3,2-b][l,4]옥사진 트리플루오로아세트산염을 얻었다.  ΡΜΒ protecting group removal reaction was carried out in the same manner as in Example 7, 2-((6- (pyridin-3-yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine trifluoroacetic acid salt was obtained.
¾-證 (300 MHz, CDCI3) δ 10.63(brs, 1H), 9.40(s, 1H) , 8.90(s, 1H), 8.56(d, J= 6.6 Hz, 1H), 8.42(d, 9.7 Hz, 1H), 7.78(m, 1H)， 7.72(d, J= 9.7 Hz, 1H), 7.4(d, J: 6.4 Hz, 1H), 7.21(d, J= 7.8 Hz, 1H) 6.67 (dd, J= 7.6, 4.8 Hz, 1H), 4.90(m, 1H), 3.89-3.62(m, 4H) . 실시예 50. 4ᅳ(4-메록시벤질) -2-((6ᅳ(4-메특시페닐)ᅳ ¾- 證 (300 MHz, CDCI3) δ 10.63 (brs, 1H), 9.40 (s, 1H), 8.90 (s, 1H), 8.56 (d, J = 6.6 Hz, 1H), 8.42 (d, 9.7 Hz, 1H), 7.78 (m, 1H) 7.72 (d, J = 9.7 Hz, 1H), 7.4 (d, J : 6.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H) 6.67 (dd, J = 7.6, 4.8 Hz, 1H), 4.90 (m, 1 H), 3.89-3.62 (m, 4 H). Example 50. 4 '(4-Methoxybenzyl) -2-((6' (4-methoxyphenyl)) '
[1,2, 4]트리아졸로 [4, 3-b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H- 피리도 [3， 2-b][l, 4]옥사진 [1,2, 4] triazolo [4, 3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] jade Picture
Figure imgf000053_0001
Figure imgf000053_0001
실시예 34와 동일한 방법으로 진행하여 목적화합물 4-(4- 메톡시벤질) -2— ((6-(4-메톡시페닐) -[1，2,4]트리아졸로 [4,3-b]피리다진-3- 일)메틸)—3,4-디히드로 -2H—피리도 [3 ,2-b] [1,4]옥사진을 얻었다. Proceed in the same manner as in Example 34 to obtain the title compound 4- (4-methoxybenzyl) -2 — ((6- (4-methoxyphenyl)-[1,2,4] triazolo [4,3-b ] Pyridazin-3-yl) methyl) —3,4-dihydro-2H—pyrido [3,2-b] [1,4] oxazine was obtained.
-匪 R (300 MHz, CDCls) δ 8.10(d, J二 9.7 Hz, 1H), 7.89(d, J= 6.8 Hz, 2H), 7,80(dd, J: 4.9, 1.4 Hz, 1H) , 7.55(d, J= 9.7 Hz, 1H) , 7.18(d, J= 8.6 Hz, 2H) , 7.04(d, J= 6.8 Hz, 2H), 6.91(d, /= 7.6 Hz, 1H) 6.74(d, J= 8.6 Hz, 2H), 6.50(dd, 7.6, 4.8 Hz, 1H), 4.90(d, A of ABq J= 14.7 Hz, 1H), 4.87(m, 1H), 4.67(d, B of ABq, J= 14.7 Hz, 1H), 3.90(s, 3H), 3.74(s, 3H)ᅳ 3.69(m, 1H), 3.52-3.39 (m, 3H). 실시예 51. 2-((6-(4-메톡시페닐)-[1,2,4]트리아졸로[4，3- b]피리다진 -3-일)메틸 )-3ᅳ4-디히드로 -2H-피리도 [3,2-b][l,4]옥사진 R (300 MHz, CDCls) δ 8.10 (d, J 9.7 Hz, 1H), 7.89 (d, J = 6.8 Hz, 2H), 7,80 (dd, J : 4.9, 1.4 Hz, 1H), 7.55 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 6.8 Hz, 2H), 6.91 (d, / = 7.6 Hz, 1H) 6.74 (d , J = 8.6 Hz, 2H), 6.50 (dd, 7.6, 4.8 Hz, 1H), 4.90 (d, A of ABq J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of ABq , J = 14.7 Hz, 1H), 3.90 (s, 3H), 3.74 (s, 3H) ᅳ 3.69 (m, 1H), 3.52-3.39 (m, 3H). Example 51. 2-((6- (4-methoxyphenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3 ᅳ 4-dihydro -2H-pyrido [3,2-b] [l, 4] oxazine
Figure imgf000053_0002
Figure imgf000053_0002
PMB 보호기 제거 반웅은 실시예 7과 동일한 방법으로 진행하여 2- ((6-(4-메록시페닐) -[1, 2,4]트리아졸로 [4,3-b]피리다진 -3-일)메틸) -3,4- 디히드로 -2H-피리도 [3,2-b][l,4]옥사진 트리플루오로아세트산염을 얻었다.  PMB protecting group removal reaction was carried out in the same manner as in Example 7, 2-((6- (4-methoxyphenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl ) Methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine trifluoroacetic acid salt was obtained.
¾-NMR (300 MHz, CDC13) δ 10.75(brs, 1H) , 8.28(d, J= 9.7 Hz, 1H), 7.92(d, /= 8.7 Hz, 2H), 7.68(d, J= 9.7 Hz, 1H), 7.39(d, J= 6.4 Hz 1H), 7.19(d, J= 7.6 Hz, 1H), 7.06(d, J= 8.7 Hz, 2H), 6.74(d, /= 8.6 Hz 2H), 6.63(dd, J= 7.6； 4.8 Hz, 1H), 4.80(m, 1H), 3.91(s, 3H), 3.79- 3.61(m, 4H). 실시예 52. 4-(3-((4-(4-메톡시벤질) -3， 4-디히드로 -2H-피리도 [3, 2- b][l, 4]옥사진 -2-일)메틸) -[1，2, 4]트리아졸로 [4， 3-b]피리다진 -6-일)— Ν,Ν- 디메틸벤젠아민 ¾-NMR (300 MHz, CDC1 3 ) δ 10.75 (brs, 1H), 8.28 (d, J = 9.7 Hz, 1H), 7.92 (d, / = 8.7 Hz, 2H), 7.68 (d, J = 9.7 Hz, 1H), 7.39 (d, J = 6.4 Hz 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.74 (d, / = 8.6 Hz 2H), 6.63 (dd, J = 7.6; 4.8 Hz, 1H), 4.80 (m, 1H), 3.91 (s, 3H) , 3.79-3.61 (m, 4 H). Example 52. 4- (3-((4- (4-methoxybenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazin-2-yl ) Methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) —Ν, Ν-dimethylbenzeneamine
Figure imgf000054_0001
Figure imgf000054_0001
실시예 34와 동일한 방법으로 진행하여 목적화합물 4-(3-((4-(4- 메록시벤질) -3， 4-디히드로 -2H-피리도 [3， 2-b] [ 1， 4]옥사진 -2—일 )메틸) - [1，2,4]트리아졸로[4，3-1)]피리다진-6-일)-^1^-디메틸벤젠아민을 얻었다.  In the same manner as in Example 34, the target compound 4- (3-((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3, 2-b] [1, 4 ] Oxazine-2-yl) methyl)-[1,2,4] triazolo [4,3-1)] pyridazin-6-yl)-^ 1 ^ -dimethylbenzeneamine.
一賺 (300 MHz, CDCls) δ 8.02 (d, J = 9.7 Hz, 1H) , 7.83 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 5.3, 1.2 Hz, 1H), 7.53 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.92 (dd, J= 7.7， 1.2 Hz, 1H), 6.77 (d, J = 8.7 Hz, 2H), 6.73 (d, J= 8.6 Hz, 2H), 6.52 (dd, J = 7.6， 4.8 Hz, 1H), 4.88 (d, A of ABq, J二 14.7 Hz, 1H) , 4.86 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 3.72 (s, 3H), 3.68 (m, 1H), 3.51-3.33 (m, 3H) , 3.08 (s, 6H). 실시예 53. 4-(3-( (3 , 4-디히드로 -2H-피리도 [3， 2-b] [ 1 , 4]옥사진 -2- 일)메틸) -[1， 2, 4]트리아졸로 [4, 3-b]피리다진 -6-일) -N, N-디메틸벤젠아민  (300 MHz, CDCls) δ 8.02 (d, J = 9.7 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 5.3, 1.2 Hz, 1H), 7.53 (d , J = 9.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.92 (dd, J = 7.7, 1.2 Hz, 1H), 6.77 (d, J = 8.7 Hz, 2H), 6.73 (d , J = 8.6 Hz, 2H), 6.52 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (d, A of ABq, J 二 14.7 Hz, 1H), 4.86 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H), 3.72 (s, 3H), 3.68 (m, 1H), 3.51-3.33 (m, 3H), 3.08 (s, 6H). Example 53. 4- (3-((3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl)-[1, 2, 4 ] Triazolo [4, 3-b] pyridazin-6-yl) -N, N-dimethylbenzeneamine
Figure imgf000054_0002
Figure imgf000054_0002
PMB 보호기 제거 반웅은 실시예 7과 동일한 방법으로 진행하여 4-(3- ( (3 , 4-디히드로 -2H-피리도 [3， 2-b] [ 1， 4]옥사진 -2-일 )메틸) - [1，2，4]트리아졸로 [4,3-1)]피리다진-6-일)-^^디메틸벤젠아민 PMB protecting group removal reaction was carried out in the same manner as in Example 7 4- (3- ((3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-2-yl ) Methyl)- [1,2,4] triazolo [4,3-1)] pyridazin-6-yl)-^^ dimethylbenzeneamine
트리플루오로아세트산염을 얻었다.Trifluoroacetic acid salt was obtained.
-賺 (300 MHz, CDCI3) δ 10.87 (brs, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.62 (d, J= 9.7 Hz, 1H), 7.37 (d, J = 6.2 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 8.9 Hz, 2H) , 6.60 (dd, J = 7.5， 4.8 Hz, 1H), 4.86(111， 1H)， 3.86— 3.76 m, 2H), 3.67-3.57(m( 2H), 3.09(s, 6H). 실시예 54. 메틸 4-(3-((4-(4- ^]^J 4- ^ ^≡S.-2H- 피리도 [3, 2-b][l, 4]옥사진 -2-일 )메틸) -[1, 2, 4]트리아졸로 [4, 3-b]피리다진- 6-일)벤조에이트 -賺 (300 MHz, CDCI3) δ 10.87 (brs, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 9.7 Hz, 1H ), 7.37 (d, J = 6.2 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 8.9 Hz, 2H), 6.60 (dd, J = 7.5, 4.8 Hz, 1H ), 4.86 (111, 1H), 3.86— 3.76 m, 2H), 3.67-3.57 (m ( 2H), 3.09 (s, 6H) .Example 54. Methyl 4- (3-((4- (4- ^] ^ J 4- ^ ^ ≡S.-2H-pyrido [3, 2-b] [l, 4] oxazin-2-yl) methyl)-[1, 2, 4] triazolo [4, 3-b] pyridazin-6-yl) benzoate
Figure imgf000055_0001
Figure imgf000055_0001
실시예 34과 동일한 방법으로 진행하여 목적화합물 메틸 4-(3-((4- (4-메톡시벤질) -3， 4-디히드로 -2H-피리도 [3 ,2-b] [1,4]옥사진—2-일)메틸) - [1，2，4]트리아졸로 [4, 3-b]피리다진 -6-일)벤조에이트을 얻었다.  In the same manner as in Example 34, the target compound methyl 4- (3-((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1, 4] oxazine-2-yl) methyl)-[1,2,4] triazol gave [4,3-b] pyridazin-6-yl) benzoate.
¾-NMR (300 MHz, CDCI3) δ 8.22 (d, / = 8.4 Hz, 2H) , 8.16 (d, J = 9.7 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.79 (dd, / = 4.9， 1.2 Hz, 1H), 7.61 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 7.6, 1.2 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.51 (dd, / = 7.6, 4.8 Hz, 1H), 4.92 (d, A of ABq, J = 14.7 Hz, 1H), 4.91 (m, 1H) , 4.67 (d, B of ABq, J - 14.7 Hz, 1H), 3.98 (s, 3H), 3.71 (s, 3H), 3.72 (m, 1H) , 3.53- 3.34 (m, 3H). 실시예 55. 메틸 4- (3- ((3, 4-디히드로 -2H-피리도 [3， 2-b ][1, 4 ]옥사진 2-일)메틸) -[1， 2, 4]트리아졸로[ 4, 3-b]피리다진 -6-일)벤조에이트 ¾-NMR (300 MHz, CDCI3) δ 8.22 (d, / = 8.4 Hz, 2H), 8.16 (d, J = 9.7 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.79 (dd, / = 4.9, 1.2 Hz, 1H), 7.61 (d, J = 9.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 7.6, 1.2 Hz, 1H), 6.73 ( d, J = 8.6 Hz, 2H), 6.51 (dd, / = 7.6, 4.8 Hz, 1H), 4.92 (d, A of ABq, J = 14.7 Hz, 1H), 4.91 (m, 1H), 4.67 (d , B of ABq, J-14.7 Hz, 1H), 3.98 (s, 3H), 3.71 (s, 3H), 3.72 (m, 1H), 3.53- 3.34 (m, 3H). Example 55. Methyl 4- (3- ((3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin 2-yl) methyl)-[1, 2, 4 ] Triazolo [4, 3-b] pyridazine-6-yl) benzoate
Figure imgf000056_0001
Figure imgf000056_0001
PMB 보호기 제거 반웅은 실시예 7과 동일한 방법으로 진행하여 메틸 4-(3-((3 , 4-디히드로 -2H-피리도 [3 , 2-b] [1,4]옥사진 -2-일 )메틸) - [1,2, 4]트리아졸로 [4,3-b]피리다진 -6-일)벤조에이트  PMB protecting group removal reaction was carried out in the same manner as in Example 7, methyl 4- (3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-2- Yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzoate
트리플루오로아세트산염을 얻었다.Trifluoroacetic acid salt was obtained.
-匪 R (300 MHz, DMSO-de) δ 8.62 (d, J = 9.7 Hz, 1H), 8.54 (d, J = 8.4 Hz, 2H), 8.51 (d, J = 8.4 Hz, 2H), 8.05 (d, / = 9.7 Hz, 1H), 7.62 (d, J二 6.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H)， 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 Cm, 1H)， 3.93 (s, 3H), 3.72-3.50 (m, 4H) . 실시 ^ J 56. 메틸 3- (3- ((4- (4-^J^J ^1 )-3, 4- ^ ^J≡≤ -2H~ 피리도 [3, 2-b][l, 4]옥사진 -2-일 )메틸) -[1， 2, 4]트리아졸로 [4, 3-b]피리다진- 6-일)벤조에이트 -匪 R (300 MHz, DMSO-de) δ 8.62 (d, J = 9.7 Hz, 1H), 8.54 (d, J = 8.4 Hz, 2H), 8.51 (d, J = 8.4 Hz, 2H), 8.05 ( d, / = 9.7 Hz, 1H), 7.62 (d, J 二 6.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 Cm , 1H), 3.93 (s, 3H), 3.72-3.50 (m, 4H). Implementation ^ J 56. Methyl 3- (3- ((4- (4- ^ J ^ J ^ 1) -3, 4- ^ ^ J≡≤ -2H ~ pyrido [3, 2-b] [l, 4] oxazin-2-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzoate
Figure imgf000056_0002
Figure imgf000056_0002
실시예 34와 동일한 방법으로 진행하여 목적화합물 메틸 3-(3-((4- (4_메톡시벤질;卜 3 4_디히드 S_2H_피리도 [3 2_b][1 4]옥사진 _2_일)메틸) -In the same manner as in Example 34 , the target compound methyl 3- (3-((4- (4 _methoxybenzyl; 卜3 4 _ dihydrate S _ 2H _ pyrido [ 3 2 _ b] [ 1 4 ] Oxazine _ 2 _yl) methyl)-
[1,2,4]트리아졸로 [4,3-b]피리다진— 6-일)벤조에이트를 얻었다.[4,3-b] pyridazine- 6-yl) benzoate was obtained with [1,2,4] triazole.
-證 (300 MHz, CDCls) δ 8.58 (s, 1H), 8.22 (m, 2H), 8.16 (d, J = 9.7 Hz, 1H), 7.78 (dd, J = 4.9, 1.2 Hz, 1H), 7.64 (d, J = 9.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.18 (d, J= 8.6 Hz, 2H) , 6.89 (dd, J = 7.6， 1.2 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (dd, J - 7.6, 4.8 Hz, 1H), 4.91 (d, A of ABq, J = 14.7 Hz, 1H)， 4.90 (m, 1H)， 4.67 (d, B of ABq, J二 14.7 Hz, 1H), 3.99 (s, 3H), 3.73 (s, 3H), 3.74 (m, 1H), 3.52- 3.37 (m, 3H). 실시예 57. 메틸 3ᅳ(3—( (3 , 4-디히드로 -2H-피리도 [3， 2-b] [ 1 , 4]옥사진- 2-일) ^틸 )-[1, 2, 4]트리아졸로 [4， 3-b]피리다진 -6-일)벤조에이트 -證 (300 MHz, CDCls) δ 8.58 (s, 1H), 8.22 (m, 2H), 8.16 (d, J = 9.7 Hz, 1H), 7.78 (dd, J = 4.9, 1.2 Hz, 1H), 7.64 (d, J = 9.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.89 (dd, J = 7.6, 1.2 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.50 (dd, J-7.6, 4.8 Hz, 1H), 4.91 (d, A of ABq, J = 14.7 Hz, 1H), 4.90 (m, 1H), 4.67 ( d, B of ABq, J 二 14.7 Hz, 1H), 3.99 (s, 3H), 3.73 (s, 3H), 3.74 (m, 1H), 3.52- 3.37 (m, 3 H). Example 57. Methyl 3 ′ (3— ((3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl)-[1, 2 , 4] triazolo [4, 3-b] pyridazine-6-yl) benzoate
Figure imgf000057_0001
Figure imgf000057_0001
PMB 보호기 제거 반웅은 실시예 7과 동일한 방법으로 진행하여 메틸 3-(3-((3，4-디히드로 -2H-피리도 [3，2-b][l,4]옥사진-2-일)메틸)—  The PMB protecting group removal reaction was carried out in the same manner as in Example 7, and the methyl 3- (3-((3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine-2- Methyl) —
[l,2, 4]트리아졸로 [4， 3-b]피리다진 -6-일 )벤조에이트 [l, 2,4] triazolo [4, 3-b] pyridazin-6-yl) benzoate
트리플루오로아세트산염을 얻었다. Trifluoroacetic acid salt was obtained.
¾_匿 (300 MHz, DMSO-de) δ 8.62(s, 1H), 8.51(d, J= 9.7 Hz, 1H) 8.40 (d, J= 7.8 Hz, 1H), 8.18(d, J = 7.8 Hz, 1H), 8.05(d, J = 9.7 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.62(d, J = 6.0 Hz, 1H), 7.33(dd, J二 7.6 Hz, 1H), 6.72(dd, J= 7.6, 4.8 Hz, 1H), 4.88(m, 1H), 3.93(s, 3H), 3.72-3.50(m, 4H). 실시예 58. (4-(3-((4-(4- ^Ι^-Λ] ^^)-3, 4- ^ ^J≡≤ -2H-^ £[ , 2- b][l, 4]옥사진 -2-일)메틸 )-[1ᅳ 2, 4]트리아졸로 [4, 3-b]피리다진 -6- 일)페닐)메탄올  ¾_ 匿 (300 MHz, DMSO-de) δ 8.62 (s, 1H), 8.51 (d, J = 9.7 Hz, 1H) 8.40 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 7.8 Hz , 1H), 8.05 (d, J = 9.7 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.33 (dd, J 二 7.6 Hz, 1H) ), 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (m, 1H), 3.93 (s, 3H), 3.72-3.50 (m, 4H). Example 58. (4- (3-((4- (4- ^ Ι ^ -Λ) ^^)-3, 4-^^ J≡≤ -2H- ^ £ [, 2-b] [l, 4] oxazin-2-yl) methyl)-[1′2,4] triazolo [4,3-b] pyridazine-6-yl) phenyl) methanol
Figure imgf000057_0002
Figure imgf000057_0002
상기 화합물을 실시예 34와 동일한 방법으로 진행하여 목적화합물 (4-(3-( (4— (4-메록시벤질) -3， 4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진 -2- 일)메틸) -[1, 2,4]트리아졸로 [4, 3-b]피리다진 -6—일)페닐)메탄올 (38%)을 얻었다. The compound was proceeded in the same manner as in Example 34 to obtain the target compound (4- (3- ((4— (4-methoxybenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b]). [1,4] oxazine-2-yl) methyl)-[1,2,4] triazol gave [4,3-b] pyridazine-6-yl) phenyl) methanol (38%).
-醒(300 MHz, CDCls) i8.15(d, J=9.7Hz, 1H), 7.92(d, J=8.4Hz, 2H), 7.80(dd, J=4.5, 1.2Hz, 1H), 7.58(q, J=9.7Hz, 1H), 7.53(d, J=8.4Hz 2H), 7.17(d, J=8.6Hz, 2H), 6.90(dd, J=7.6, 1.4Hz, 1H) , 6.72(d, J=8.6Hz 2H), 6.51(dd, J=7.6, 4.8Hz, 1H), 4.91(d, A of ABq, J=14.7Hz, 1H) , 4.88(m, 1H), 4.83(brs, 2H), 4.65(d, B of ABq, J= 14.7Hz, 1H), 3.76(s, 3H), 3.74(111， 1H), 3.51-3.39(m, 3H). 실시예 59. (4-(3-((3, 4-디히드로 -2H-피리도 [3， 2~b][l, 4]옥사진 -2- 일)메틸) -[1, 2, 4]트리아졸로 [4, 3-b]피리다진 -6-일)페닐)메탄올 醒 (300 MHz, CDCls) i8.15 (d, J = 9.7 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.80 (dd, J = 4.5, 1.2 Hz, 1H), 7.58 (q, J = 9.7 Hz, 1H), 7.53 (d, J = 8.4 Hz 2H), 7.17 (d, J = 8.6 Hz, 2H ), 6.90 (dd, J = 7.6, 1.4 Hz, 1H), 6.72 (d, J = 8.6 Hz 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.91 (d, A of ABq, J = 14.7 Hz, 1H), 4.88 (m, 1H), 4.83 (brs, 2H), 4.65 (d, B of ABq, J = 14.7 Hz, 1H), 3.76 (s, 3H), 3.74 (111, 1H) , 3.51-3.39 (m, 3 H). Example 59. (4- (3-((3,4-Dihydro-2H-pyrido [3, 2 - b] [l, 4] oxazin-2-yl) methyl)-[1, 2, 4] triazolo [4, 3-b] pyridazin-6-yl) phenyl) methanol
Figure imgf000058_0001
Figure imgf000058_0001
PMB 보호기 제거 반응은 실시예 7과 동일한 방법으로 진행하여 (4- PMB protecting group removal reaction was carried out in the same manner as in Example 7 (4-
(3-((3， 4-디히드로 -2H—피리도 [3， 2-b] [1,4]옥사진 -2-일 )메틸) - [1，2，4]트리아졸로 [4,3-b]피리다진 -6-일)페닐)메탄올 (3-((3,4-dihydro-2H—pyrido [3, 2-b] [1,4] oxazin-2-yl) methyl)-[1,2,4] triazolo [4, 3-b] pyridazine-6-yl) phenyl) methanol
트리플루오로아세트산염을 얻었다.Trifluoroacetic acid salt was obtained.
-NMR (300 MHz, CDC13) δ 10.91 (brs, 1Η), 8.25 (d, J = 9.7 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H) , 7.63 (d, J二 9.7 Hz, 1H) , 7.60 (d, J二 8.4 Hz, 2H), 7.38 (d, J = 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 6.62 (dd, J= 7.5, 4.8 Hz, 1H)ᅳ 5.46(s, 2H), 4.85(m, 1H), 3.86-3.79 (m, 2H), 3.70-3.63(m, 2H). 실시예 60. 4-(4-메톡시벤질) -2-((6-(4- (몰폴리노메틸)페닐) --NMR (300 MHz, CDC1 3 ) δ 10.91 (brs, 1Η), 8.25 (d, J = 9.7 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.63 (d, J 二 9.7 Hz, 1H), 7.60 (d, J 2 8.4 Hz, 2H), 7.38 (d, J = 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 6.62 (dd, J = 7.5, 4.8 Hz, 1H) ᅳ 5.46 (s, 2H), 4.85 (m, 1H), 3.86-3.79 (m, 2H), 3.70-3.63 (m, 2H). Example 60. 4- (4-methoxybenzyl) -2-((6- (4- (morpholinomethyl) phenyl)-
[1,2, 4]트리아졸로 [4, 3-b]피리다진 -3-일)메틸) -3， 4-디히드로 -2H- 피리도 [3， 2-b][l, 4]옥사진 [1,2, 4] triazolo [4, 3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] jade Picture
Figure imgf000058_0002
실시예 34과 동일한 방법으로 진행하여 목적화합물 메틸 4-(4- 메톡시벤질) -2-((6-(4- (몰폴리노메틸)페닐) -[1，2，4]트리아졸로 [4，3- b]피리다진 -3-일 )메틸 )-3 , 4-디히드로 -2H-피리도 [3， 2-b] [1,4]옥사진을 얻었다.
Figure imgf000058_0002
Proceed as in Example 34 to the target compound methyl 4- (4-methoxybenzyl) -2-((6- (4- (morpholinomethyl) phenyl)-[1,2,4] triazol [ 4,3-b] pyridazin-3-yl) methyl) -3 and 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine were obtained.
-證 (300 匪 z, CDCls) δ 8.13 (d, J = 9.7 Hz, 1H)， 7.87 (d, J = 8.1 Hz, 2H), 7.79 (dd, J = 4.5, 1.2 Hz, 1H)， 7.56 (q, J = 9.7 Hz, 1H), 7.50 (d, /= 8.1 Hz, 2H) , 7.17 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 7.6， 1.4 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6， 4.8 Hz, 1H), 4.88 (d, A of ABq, J= 14.7 Hz, 1H), 4.86 (m, 1H), 4.66 (d, B of ABq, J = 14.7 Hz, 1H) , 3.78 (s, 2H), 3.74 (m, 4H) , 3.68 (m, 1H), 3.54- 3.34 (m, 3H), 2.43 (m, 4H). 실시예 61. 2-((6-(4-(^B x ^/^ j-f 2, 4] ^ ^[4> 3- b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진 -證 (300 匪 z, CDCls) δ 8.13 (d, J = 9.7 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.79 (dd, J = 4.5, 1.2 Hz, 1H), 7.56 ( q, J = 9.7 Hz, 1H), 7.50 (d, / = 8.1 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 7.6, 1.4 Hz, 1H), 6.73 ( d, J = 8.6 Hz, 2H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (d, A of ABq, J = 14.7 Hz, 1H), 4.86 (m, 1H), 4.66 (d , B of ABq, J = 14.7 Hz, 1H), 3.78 (s, 2H), 3.74 (m, 4H), 3.68 (m, 1H), 3.54- 3.34 (m, 3H), 2.43 (m, 4H). Example 61. 2-((6- (4-(^ B x ^ / ^ jf 2, 4] ^ ^ [4 > 3 -b] pyridazin-3-yl) methyl) -3, 4-dihydro -2H-pyrido [3, 2-b] [1, 4] oxazine
Figure imgf000059_0001
Figure imgf000059_0001
ΡΜΒ 보호기 제거 반웅은 실시예 7과 동일한 방법으로 진행하여 2- ((6-(4- (몰폴리노메틸)페닐) -[l,2，4]트리아졸로[4,3-b]피리다진-3- 일)메틸)-3, 4-디히드로 -2Η-피리도 [3， 2-b] [1,4]옥사진  ΡΜΒ protecting group removal reaction was carried out in the same manner as in Example 7, 2-((6- (4- (morpholinomethyl) phenyl)-[l, 2,4] triazolo [4,3-b] pyridazine -3-yl) methyl) -3,4-dihydro-2nu-pyrido [3,2-b] [1,4] oxazine
트리플루오로아세트산염을 얻었다. Trifluoroacetic acid salt was obtained.
¾-NMR (300 MHz, CDC13) δ 10.75 (brs, 1Η), 8.27 (d, 9.7 Hz, 1H), 7.98 (d, J= 8.1 Hz, 2H) , 7.65 (d, J = 8.1 Hz, 2H), 7.64 (d, / = 9,7 Hz, 1H), 7.38 (d, J 6.0 Hz, 1H), 7.22 (d, / = 7.5 Hz, 1H), 6.64 (dd, J = 7,5, 4.8 Hz, 1H), 4.22(s, 2H), 3.86-3.79 (m, 2H), 3.70-3.63(m, 2H), 2.85(m, 4H)ᅳ 실시예 62. N-에틸 -3-(3-( (4-(4-메톡시벤질) -3 ,4-디히드로 -2H- 피리도 [3,2-b][l, 4]옥사진 -2-일)메틸) -[1,2, 4]트리아졸로 [4,3-b]피리다진- 6-일)벤자아마이드
Figure imgf000060_0001
¾-NMR (300 MHz, CDC1 3 ) δ 10.75 (brs, 1Η), 8.27 (d, 9.7 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H ), 7.64 (d, / = 9,7 Hz, 1H), 7.38 (d, J 6.0 Hz, 1H), 7.22 (d, / = 7.5 Hz, 1H), 6.64 (dd, J = 7,5, 4.8 Hz, 1H), 4.22 (s, 2H), 3.86-3.79 (m, 2H), 3.70-3.63 (m, 2H), 2.85 (m, 4H) Example 62. N-ethyl-3- (3- ((4- (4-methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine -2-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) benzaamide
Figure imgf000060_0001
실시예 33에서 얻은 3-(6-클로로피리다진 -3-일) 에틸벤자마이드와 실시예 18에서 얻은 2-(4-(4-메록시벤질) -3,4-다이하이드로-2^피리도[3,2- Λ][l,4]옥사진-2-일l)아세토하이드라지드를 실시예 34와 동일하게 반웅하여 ^에틸 -3-(3-((4-(4—메특시벤질) -3，4-다이하이드로-2^피리도[3，2- b][l，4]옥사진-2-일)메틸)-[l,2，4]트리아조로[4，3-b]피리다진-6- 일 )벤자마이드를 얻었다. 3- (6-chloropyridazin-3-yl) ethylbenzamide obtained in Example 33 and 2- (4- (4-methoxybenzyl) -3,4-dihydro-2 ^ pyridine obtained in Example 18. [3,2-Λ] [l, 4] oxazin-2-yll) acetohydrazide was reacted in the same manner as in Example 34 to give ^ ethyl-3- (3-((4- (4— Sibenzyl) -3,4-dihydro-2 ^ pyrido [3,2-b] [l, 4] oxazin-2-yl) methyl)-[l, 2,4] triazolo [4,3 -b] pyridazin-6-yl) benzamide.
-證 (300 MHz, CDCls) δ 8.32(s, 1H), 8.17(d, /= 9.7 Hz, 1H), 8.05 (d, J= 7.9 Hz, 1H), 7.91(d, J= 7.7 Hz, 1H), 7.75(dd, J= 4.9, 1.3Hz, 1H), 7.62(d, J= 9.7 Hz, 1H), 7.61(m, 1H) , 7.19(d, J= 8.5 Hz, 2H), 6.83(dd, J= 7.7, 1.3 Hz, 1H), 6.74(d, J= 8.5 Hz, 2H), 6.46(dd, 7.7 4.9 Hz, 1H), 6.41 (brs, 1H), 4.91(d, A of ABq, /= 14.7 Hz, 1H), 4.88(m, 1H), 4.67(d, B of ABq, J = 14.7 Hz, 1H), 3.74(s, 3H), 3.57- 3.35(m, 6H), 1.29(t, J= 7.2 Hz, 3H). 실시예 63. 3-(3-((3, 4-다이하이드로 -2H-피리도 [3 , 2-b][l, 4]옥사진- 2-일)메틸) -[ 1, 2, 4]트리아조로 [4, 3-b ]피리다진 -6-일) -N-에틸벤자마이드  證 (300 MHz, CDCls) δ 8.32 (s, 1H), 8.17 (d, / = 9.7 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H ), 7.75 (dd, J = 4.9, 1.3 Hz, 1H), 7.62 (d, J = 9.7 Hz, 1H), 7.61 (m, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.83 (dd , J = 7.7, 1.3 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 6.46 (dd, 7.7 4.9 Hz, 1H), 6.41 (brs, 1H), 4.91 (d, A of ABq, / = 14.7 Hz, 1H), 4.88 (m, 1H), 4.67 (d, B of ABq, J = 14.7 Hz, 1H), 3.74 (s, 3H), 3.57-3.35 (m, 6H), 1.29 (t, J = 7.2 Hz, 3H). Example 63. 3- (3-((3, 4-Dihydro-2H-pyrido [3, 2-b] [l, 4] oxazin-2-yl) methyl)-[1, 2, 4 ] Triazolo [4, 3-b] pyridazine-6-yl) -N-ethylbenzamide
Figure imgf000060_0002
Figure imgf000060_0002
^에틸 -3-(3-( (4-(4-메록시벤질) -3， 4-다이하이드로 -2^피리도 [3， 2- ώ][1,4]옥사진 -2-일)메틸) -[1,2，4]트리아조로 [4,3-A]피리다진 -6- 일)벤자마이드의 PMB 보호기 제거 반웅은 실시예 7과 동일한 방법으로 진행하여 2-((6— (4-(4-메틸피페라진 -1-일)메틸)페닐) -^ Ethyl-3- (3- ((4- (4-methoxybenzyl) -3, 4-dihydro-2 ^ pyrido [3, 2- ώ] [1,4] oxazin-2-yl) Methyl)-[1,2,4] triazolo [4,3-A] pyridazine-6- The PMB protecting group removal reaction of the 1) benzamide was carried out in the same manner as in Example 7 to obtain 2-((6— (4- (4- (4-methylpiperazin-1-yl) methyl) phenyl)-
[1，2，4]트리아졸로 [4,3-b]피리다진 -3—일)메틸) -3,4-디히드로 -2H- 피리도 [3,2-b][l,4]옥사진 트리플루오로아세트산염올 얻었다. [1,2,4] triazolo [4,3-b] pyridazine-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] jade Photo trifluoroacetic acid salt was obtained.
¾-醒 R (300 MHz, CDC13) δ 10.63 (s, 1H), 8.45 (s, 1H), 8.33 (d,¾- 醒 R (300 MHz, CDC1 3 ) δ 10.63 (s, 1H), 8.45 (s, 1H), 8.33 (d,
J = 9.6 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.74 (d, / = 9.6 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H) , 7.38 (d, J - 6.2 Hz, 1H), 7.21 (d, 7,7 Hz, 1H), 6.63 (t, / = 6.8 Hz, 1H), 6.36 (brs 1H), 4.87 (m, 1H), 3.86-3.54 (m, 6H), 1.30 (t, /= 7.2 Hz, 3H). 실시예 64. (3-(3-((4-(4-메톡시벤질) -3， 4-디히드로 -2H—피리도 [3， 2- b][ 1, 4]옥사진 -2-일)메틸 ) -[1 ' 2, 4]트리아졸로 [4, 3-b]피리다진 -6- 일)페닐) (4-메틸피페라진 -1-일)메타논 J = 9.6 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.74 (d, / = 9.6 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.38 (d, J-6.2 Hz, 1H), 7.21 (d, 7,7 Hz, 1H), 6.63 (t, / = 6.8 Hz, 1H), 6.36 (brs 1H), 4.87 ( m, 1H), 3.86-3.54 (m, 6H), 1.30 (t, / = 7.2 Hz, 3H). Example 64. (3- (3-((4- (4-methoxybenzyl) -3, 4-dihydro-2H—pyrido [3, 2-b] [1, 4] oxazine-2- Yl) methyl)-[1'2,4] triazolo [4,3-b] pyridazine-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone
Figure imgf000061_0001
Figure imgf000061_0001
실시예 62과 동일한 방법으로 진행하여 목적화합물 (3-(3-((4-(4- 메톡시벤질) -3 , 4-디히드로 -2H-피리도 [3 , 2-b] [1,4]옥사진 -2-일 )메틸) - [ 1 , 2， 4]트리아졸로 [4 , 3-b]피리다진 -6-일)페닐 ) (4-메틸피페라진 -1- 일)메타논 (48%)을 얻었다.  Proceed as in Example 62 to the target compound (3- (3-((4- (4-methoxybenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone (48%) was obtained.
¾匪 R (300 MHz, CDCI3) δ 8.17 (d, J= 9.7 Hz, 1H), 7.99 (m, 2H), 7.79 (d, J= 4.9 Hz, 1H), 7.59-7.56 (m, 3H) , 7.18 (d, J二 8.5 Hz, 2H), .89 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 7.6, .9 Hz, 1H), 4.89 (d, A of ABq, J = 14.7 Hz, 1H) , 4.87 (m, 1H), 4.67 (d, B of ABq, J = 14.7 Hz, 1H), 3.85 (m, 2H), 3.72 (s, 3H) , 3.70 (m, 1H), 3.56-3.35 (m, 5H), 2.53 (m, 2H), 2.38 (m, 2H) , 2.33 (s, 3H) . 실시예 65. (3-(3-( (3 , 4-디히드로 -2H-피리도 [3 , 2-b] [ 1， 4]옥사진 -2- 일)메틸) -[1,2, 4]트리아졸로 [4, 3-b]피리다진 -6-일)페닐) (4-메틸페라진 -1- 일)메타논 ¾ 匪 R (300 MHz, CDCI 3 ) δ 8.17 (d, J = 9.7 Hz, 1H), 7.99 (m, 2H), 7.79 (d, J = 4.9 Hz, 1H), 7.59-7.56 (m, 3H) , 7.18 (d, J 2 8.5 Hz, 2H), .89 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 7.6, .9 Hz, 1H), 4.89 (d, A of ABq, J = 14.7 Hz, 1H), 4.87 (m, 1H), 4.67 (d, B of ABq, J = 14.7 Hz, 1H), 3.85 (m, 2H), 3.72 (s, 3H), 3.70 (m, 1H), 3.56-3.35 (m, 5H), 2.53 (m, 2H), 2.38 (m, 2H), 2.33 (s, 3H). Example 65. (3- (3- ((3, 4-Dihydro-2H-pyrido [3, 2-b] [1, 4] oxazin-2-yl) methyl)-[1,2, 4] triazolo [4,3-b] pyridazin-6-yl) phenyl) (4-methylperazine-1-yl) methanone
Figure imgf000062_0001
Figure imgf000062_0001
PMB 보호기의 제거는 실시예 7과 동일하게 진행하여 (3-(3-((3，4- 디히드로 -2^피리도 [3,2-b] [1,4]옥사진 -2-일)메틸) -[1，2，4]트리아졸로 [4,3- 0]피리다진 -6-일)페닐) (4-메틸피페라진 -1-일)메타논을 얻었다.  Removal of the PMB protecting group was carried out in the same manner as in Example 7, except that (3- (3-((3,4-dihydro-2 ^ pyrido [3,2-b] [1,4] oxazin-2-yl) ) (Methyl)-[1,2,4] triazol gave [4,3-0] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone.
¾ NMR (300 MHz, CDC13) δ 10.55(brs, 1H) , 8.36(d, J= 9.7 Hz, 1H), 8.06(m, 2H), 7.66(m, 3H), 7.41(d, J= 6.2 Hz, 1H) , 7.24(d, J= 7.8 Hz, 1H)ᅳ 6.66(dd, J= 7.5， 4.9 Hz, 1H), 4.89(m, 1H), 3.86-3.53(m, 12H), 2.88(s, 3H). 실시예 66. (4-(3-((3，4-디히드로-2^피리도[3，2—1^][1，4]옥사진-2- 일 )메틸) -[1, 2, 4]트리아졸로 [4, 3-b]피리다진 -6-일)페닐) (4-메틸피페라진 -1ᅳ 일)메타논 ¾ NMR (300 MHz, CDC1 3 ) δ 10.55 (brs, 1H), 8.36 (d, J = 9.7 Hz, 1H), 8.06 (m, 2H), 7.66 (m, 3H), 7.41 (d, J = 6.2 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H) ᅳ 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 4.89 (m, 1H), 3.86-3.53 (m, 12H), 2.88 (s , 3H). Example 66. (4- (3-((3,4-Dihydro-2 ^ pyrido [3,2-1 ^] [1,4] oxazin-2-yl) methyl)-[1, 2 , 4] triazolo [4,3-b] pyridazine-6-yl) phenyl) (4-methylpiperazin-1xyl) methanone
Figure imgf000062_0002
Figure imgf000062_0002
실시예 62의 합성과 동일한 방법으로 진행하여 (4-(3— ((3，4- 디히드로 -2H-피리도 [3,2-b] [1,4]옥사진 -2-일)메틸) -[1,2, 4]트리아졸로 [4,3ᅳ b]피리다진 -6-일 )페닐) (4-메틸피페라진 -1-일 )메타논  Proceed in the same manner as in the synthesis of Example 62, to obtain (4- (3— ((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl )-[1,2,4] triazolo [4,3'b] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone
트리플루오로아세트산염을 얻었다. Trifluoroacetic acid salt was obtained.
¾ NMR (300 MHz, CDC13) δ 10.57 (brs, 1H), 8.60 (d, J = 9.7 Hz, 1H), 8.51 (d, / = 8.3 Hz, 2H), 8.49 (d, J = 8.3 Hz, 2H) , 8.04 (d, J = 9.7 Hz, 1H), 7.62 (d, J = 6.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6,69 (dd, / = 7.6， 4.8 Hz, 1H), 4.89 (m, 1H), 3.87-3.50 (m, 12H), 2.88 (s, 3H). 실시예 67. 4-(4-메톡시벤질) -2-((6-(1-메틸 -1H-인다졸 -3-일 )- [1,2,4]트리아졸로 [4, 3-b]피리다진 -3-일)메틸) -3， 4-디히드로 -2H- 피리도 [3, 2-b][l, 4]옥사진 ¾ NMR (300 MHz, CDC1 3 ) δ 10.57 (brs, 1H), 8.60 (d, J = 9.7 Hz, 1H), 8.51 (d, / = 8.3 Hz, 2H), 8.49 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 9.7 Hz, 1H), 7.62 (d, J = 6.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6,69 (dd, / = 7.6, 4.8 Hz, 1H), 4.89 (m, 1H), 3.87-3.50 (m, 12H), 2.88 (s, 3H). Example 67. 4- (4-methoxybenzyl) -2-((6- (1-methyl-1H-indazol-3-yl)-[1,2,4] triazolo [4, 3-b ] Pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazine
Figure imgf000063_0001
Figure imgf000063_0001
2-플루오로페닐아세토나이트릴 (80 mg, 0.54 mmol)을 디메틸포름아마이드 (5 mL)에 녹이고 포타슘 t-부록사이드 ( -BuOK, 30 mg, 1.1 mmol)를 OX：에서 가하고 30분 간 교반하였다. 실시예 6에서 얻은 2- ((6-클로로 -[1, 2,4] 트리아졸로 [4，3- ]피리다진 -3-일)메틸) -4-(4- 메록시벤질)-3，4-디히드로-2^피리도[3，2- [1，4]옥사진(0.23 g, 0.54 mmol)을 디메틸포름아마이드 (2 mL)에 녹여 반응용액에 적가하였다. 0°C에서 1시간 교반한 후 실온에서 12시간 교반한 다음 다시 0°C로 넁각한 후 과산화수소 (¾02， 5 mL)를 적가하고 실온에서 12시간 교반하였다. 반웅 후 에틸아세테이트로 회석하고 소금물로 세척한 다음 유기층을 무수 황산나트륨으로 건조하고 농축한 후 컬럼크로마토그래피 (60% EtOAc/Hexane)로 정제하여 (2-플루오로페닐 )(3-((4-(4-메특시벤질) -3，4- 디히드로 -2H—피리도 [3,2-b] [1，4]옥사진-2-일)메틸)- [1，2，4]트리아졸로 [4,3-b]피리다진 -6-일)메타논 (70 mg, 25%)을 얻었다. 2-fluorophenylacetonitrile (80 mg, 0.54 mmol) was dissolved in dimethylformamide (5 mL) and potassium t-butoxide (-BuOK, 30 mg, 1.1 mmol) was added in OX: and stirred for 30 minutes. . 2- ((6-chloro- [1,2,4] triazolo [4,3-] pyridazin-3-yl) methyl) -4- (4-methoxybenzyl) -3, obtained in Example 6 4-dihydro-2 ^ pyrido [3,2- [1,4] oxazine (0.23 g, 0.54 mmol) was dissolved in dimethylformamide (2 mL) and added dropwise to the reaction solution. After stirring for 1 hour at 0 ° C, and stirred for 12 hours at room temperature, and then stirred at 0 ° C again, hydrogen peroxide (¾0 2 , 5 mL) was added dropwise and stirred at room temperature for 12 hours. After reaction, distilled with ethyl acetate and washed with brine, the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (60% EtOAc / Hexane) to give (2-fluorophenyl) (3-((4- ( 4-Methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-2-yl) methyl)-[1,2,4] triazolo [ 4,3-b] pyridazine-6-yl) methanone (70 mg, 25%) was obtained.
¾證 (300 MHz, CDCls) δ 8.24 (d, J = 9.7 Hz, 1H), 7.78 (m, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.58 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.15 (d, / = 8.6 Hz, 2H), 7.01 (t, J = 9.4 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 6.77 (d, / = 8.6 Hz, 2H) , 6.49 (dd, /= 7.6, 4.8 Hz, 1H)， 4.83 (d, A of ABq, J - 14.8 Hz, 1H) , 4.74 (m, 1H), 4.66 (d, B of ABq, / = 14.8 Hz, 1H), 3.77 (s, 3H), 3.56-3.22 (m, 4H).  ¾ 證 (300 MHz, CDCls) δ 8.24 (d, J = 9.7 Hz, 1H), 7.78 (m, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.58 (m, 1H), 7.28 (d , J = 7.6 Hz, 1H), 7.15 (d, / = 8.6 Hz, 2H), 7.01 (t, J = 9.4 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 6.77 (d, / = 8.6 Hz, 2H), 6.49 (dd, / = 7.6, 4.8 Hz, 1H), 4.83 (d, A of ABq, J-14.8 Hz, 1H), 4.74 (m, 1H), 4.66 (d, B of ABq, / = 14.8 Hz, 1H), 3.77 (s, 3H), 3.56-3.22 (m, 4H).
(2-플루오로페닐 ) (3-( (4-(4—메록시벤질) -3， 4-디히드로 -2H- 피리도 [3,2-b] [1， 4]옥사진 -2-일)메틸) -[1，2，4]트리아졸로 [4,3-b]피리다진- 6-일)메타논 (20 mg, 0.04 麵 ol)과 메틸히드라진 (0.16 mL, 3.14 隱 ol)을 디메틸아세트아마이드 (1 mL)에 녹인 후 마이크로웨이브 기기를 사용해서 150 0C에서 15분간 반웅한다. 반응 후 에틸아세테이트로 희석하고 소금물로 세척한 다음 유기층을 무수 황산나트륨으로 건조하고 농축한 후 컬럼크로마토그래피 (EtOAc)로 정제하여 4-(4-메특시벤질) -2— ((6-(1-메틸- 1H-인다졸 -3-일 )- [ 1， 2， 4]트리아졸로 [4 , 3-b]피리다진 -3-일 )메틸) -3， 4- 디히드로 -2H-피리도 [3,2-b][l,4]옥사진 (11 mg, 55%)을 얻었다. (2-fluorophenyl) (3-((4- (4—methoxybenzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-2- 1) methyl)-[1,2,4] triazolo to [4,3-b] pyridazin-6-yl) methanone (20 mg, 0.04 μl) and methylhydrazine (0.16 mL, 3.14 μl ol) Dissolve in dimethylacetamide (1 mL) and react for 15 minutes at 150 0 C using a microwave instrument. After the reaction, dilute with ethyl acetate and brine The organic layer was washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EtOAc) to give 4- (4-methoxybenzyl) -2 — ((6- (1-methyl-1H-indazole-3-). Yl)-[1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3,2-b] [l, 4] oxazine (11 mg, 55%) was obtained.
¾ NMR (300 MHz, CDC13) δ 8.34(d, J = 9.7 Hz, 1H)ᅳ 8.09(m, 2H), 7.73 (d, / = 4.8 Hz, 1H), 7.47(m, 2H) , 7.29(m, 1H), 7.14(d, J = 8.6 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H) , 6.69(d, J二 8.6 Hz, 2H), 6.45(dd, J = 7.6， 4.8 Hz, 1H), 4.88(m, 1H), 4.80(d, A of ABq, J = 14.7 Hz, 1H), 4.67(d, B of ABq, J二 14.7 Hz, 1H), 4.16(s, 3H), 3.72(m, 1H), 3.70(s, 3H), 3.54(m 2H) , 3.39(m, 1H). 실시예 68.
Figure imgf000064_0001
¾ NMR (300 MHz, CDC1 3 ) δ 8.34 (d, J = 9.7 Hz, 1H) ᅳ 8.09 (m, 2H), 7.73 (d, / = 4.8 Hz, 1H), 7.47 (m, 2H), 7.29 ( m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.69 (d, J 二 8.6 Hz, 2H), 6.45 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (m, 1H), 4.80 (d, A of ABq, J = 14.7 Hz, 1H), 4.67 (d, B of ABq, J 二 14.7 Hz, 1H), 4.16 (s, 3H) , 3.72 (m, 1 H), 3.70 (s, 3 H), 3.54 (m 2 H), 3.39 (m, 1 H). Example 68.
Figure imgf000064_0001
b]피리다진 -3-일)메틸) -3, 4-디히드로 -2H-피리도 [3， 2-b][l, 4]옥사진
Figure imgf000064_0002
b] pyridazin-3-yl) methyl) -3,4-dihydro-2H-pyrido [3, 2-b] [l, 4] oxazine
Figure imgf000064_0002
PMB 보호기 제거 반응은 실시예 7과 동일한 방법으로 진행하여 2-((6- PMB protecting group removal reaction was carried out in the same manner as in Example 7 2-((6-
(1-메틸 -1H-인다졸 -3-일)— [1,2,4]트리아졸로 [4, 3-b]피리다진 -3-일)메틸) - 3 , 4-디히드로 -2H-피리도 [3 , 2-b] [ 1 , 4]옥사진 트리플루오로아세트산염을 얻었다, (1-methyl-1H-indazol-3-yl) — [1,2,4] triazolo [4,3-b] pyridazin-3-yl) methyl) -3,4-dihydro-2H- Pyrido [3,2-b] [1,4] oxazine trifluoroacetic acid salt was obtained,
¾-NMR (300 MHz, CDCI3) δ 10.72 (brs, 1H), 8.05 (d, J = 9.7 Hz, 1H), 7.99 (m, 2H), 7.69 (d, J= 9.7 Hz, 1H), 7.42 (d, J二 6.4 Hz, 1H), 7.42 (m 2H), 7.18 (d, J二 7.6 Hz, 1H), 6.60 (dd, / = 7.5, 4.8 Hz, 1H) , 4.89 (m, 1H), 4.17 (s, 3H), 3.60 (m, 1H), 3.51 (m, 2H) , 3.38 (m, 1H) . 실험예 1. c-Met 키나아제 억제활성 실험 ¾-NMR (300 MHz, CDCI 3 ) δ 10.72 (brs, 1H), 8.05 (d, J = 9.7 Hz, 1H), 7.99 (m, 2H), 7.69 (d, J = 9.7 Hz, 1H), 7.42 (d, J 二 6.4 Hz, 1H), 7.42 (m 2H), 7.18 (d, J 二 7.6 Hz, 1H), 6.60 (dd, / = 7.5, 4.8 Hz, 1H), 4.89 (m, 1H), 4.17 (s, 3 H), 3.60 (m, 1 H), 3.51 (m, 2 H), 3.38 (m, 1 H). Experimental Example 1. c-Met kinase inhibitory activity
본 발명에 따른 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 이상세포의 증식억제활성을 세포단계에서 측정하기 위하여 하기와 같은 실험을 수행하였다.  In order to determine the proliferation inhibitory activity of the abnormal cells of the pyrazolo pyridine derivative or a pharmaceutically acceptable salt thereof according to the present invention, the following experiment was performed.
c-Met 키나아제에 대한 저해활성을 시간분해형광도 (Time-resolved fluorescence, TRF)의 일종인 분리 증강된 란탄족플루오로 면역 분석 (Dissociat ion Enhanced Lanthanide Fluoro Immuno Assay, DELFIA; Perkin Elmer)을 이용하여 분석하였다. Time-resolved fluorescence of inhibitory activity against c-Met kinase Analysis was performed using Dissociat ion Enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), a type of fluorescence (TRF).
그레이너 96웰 V형 바닥 플레이트에 시험화합물로서 실시예 4~6, 8~12에서 제조된 화합물 10 mL을 가하고 c-Met 효소를 섞은 티로신 키나아제 버퍼 (20 mL)를 가한 후 상기 효소 및 시험화합물을 15분 동안 흔합하여 배양하였다. 여기에 ATP용액 (10 mL)을 가하여 상은에서 30분 동안 키나아제 반웅을 시킨후， 50 mM 에틸렌다이아민테트라아세트산 용액 (EDTAᅳ 40 mL)을 가하여 반웅을 중지시켰다.  10 mL of the compounds prepared in Examples 4 to 6 and 8 to 12 were added to a Grainer 96-well V-type bottom plate, and tyrosine kinase buffer (20 mL) mixed with c-Met enzyme was added. Was incubated for 15 minutes. ATP solution (10 mL) was added thereto, followed by kinase reaction for 30 minutes in silver, followed by 50 mM ethylenediaminetetraacetic acid solution (EDTAED 40 mL) to stop reaction.
스트랩트아비딘이 코팅된 플레이트에 반응물을 옮기고 진탕하에 배양하고 2시간 후 PBS-T 완층액 (PBS 0.05%트원 20)으로 3회 세척하였다. 유로품이 붙은 항-포스포타이로신 항체를 1:2， 500으로 회석시켜 웰 당 100 mL씩 가하고 진탕하에 배양하고 1시간 후， PBS-T 완충액 (PBS 0.05% 트휜 20)으로 5회 세척하였다.  The reaction was transferred to a strap-vidin-coated plate and incubated under shaking and washed three times with PBS-T complete solution (PBS 0.05% Twen 20) after 2 hours. Anti-phosphotyrosine antibody with flow cytometry was diluted 1: 2, 500, added 100 mL per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% TR20).
개선제 (enhancement solution, 100 mL)을 가하고 5분 동안 진탕배양한 후， 왈락 인비전 2103(Wallac Envision 2103) 기기로 '615/665 nm의 파장 범위에서 판독하였다, 상기 실험을 수행한 시험화합물의 IC50는 2개씩의 데이터 세트로 결정하였고 프리즘 (버전 5.01， 그래프패드) 소프트웨어를 이용하여 구하였다. Improver (enhancement solution, 100 mL) was added 5 minutes after shaking the culture, Wallac In-I 2103 (Wallac Envision 2103) unit to the 'was read at a wavelength range of 615/665 nm, of the test compound IC performing the experiment 50 was determined by two data sets and was obtained using Prism (version 5.01, GraphPad) software.
c-Met 키나아제 효소활성을 50%로 감소시키는 상기 화합물의 IC50 으로 하기 표 1에 나타내었다. The IC 50 of the compound that reduces c-Met kinase enzyme activity by 50% is shown in Table 1 below.
【표 1】 Table 1
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000065_0001
Figure imgf000066_0001
실시예 7， 9, 11， 13， 47, 49， 51， 55, 59, 65 및 68의 화합물은 c- Met에 대해 우수한 인 비트로 활성을 보이고 있다. 실험예 2. 암세포 증식억제 실험  The compounds of Examples 7, 9, 11, 13, 47, 49, 51, 55, 59, 65 and 68 show excellent in vitro activity against c-Met. Experimental Example 2. Cancer Cell Proliferation Inhibition Experiment
본 발명에 따른 신규 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 암세포 증식 억제능을 알아보기 위해 하기와 같은 실험을 수행하였다.  In order to determine the cancer cell proliferation inhibitory activity of the novel pyrazolo pyridine derivative or a pharmaceutically acceptable salt thereof according to the present invention, the following experiment was performed.
2-1. 실험 재료 2-1. Experimental material
세포배양액인 RPMI 1640 배지, FBS (fetal bovine serum) 및 트립신은 Gibco 사 (Grand Island, NY)로부터 구입하였으며, 탄산수소나트륨， 암포테리신 B 및 겐타마이신은 시그마케미컬 제품을 사용하였다. 또한， 세포독성 측정 실험에 사용한 시약인 SRB (sulforhodamine) B, 트리스마 염기 (Trisma base) 및 트리클로로아세트산 (TCA) 시약은 시그마케미컬사로부터 구입하였다. MTS 분석을 위해서는 CellTiter 96R AQueous Non-Radioactive Cell Proliferation Assay 제품을 프로메가 (Promega)사로부터 구입하였다. 또한， 세포배양을 위해 사용한 T-25 배양용기， 96-웰 (well) 폴레이트 및 기타 세포배양에 사용한 일회용 초자류는 팔콘사 (Lincoln Park, NJ) 제품을 사용하였다ᅳ . 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 gentamicin were used as sig-chemical products. In addition, SRB (sulforhodamine) B, Trisma base and trichloroacetic acid (TCA) reagents, which are reagents used in cytotoxicity measurement experiments, were purchased from Sigma Chemical. For MTS analysis, CellTiter 96 R AQueous Non-Radioactive Cell Proliferation Assay was purchased from Promega. In addition, T-25 culture vessels used for cell culture, 96-well folate, and disposable supernatants used for other cell cultures were manufactured by Lincoln Park (NJ).
세포독성 측정을 위한 엘라아자 리더기 (microplate reader)는 Molecular Devices사 (Sunnyvale, CA)의 E-max나 SpectraMax250 기종을 사용하였다. 2-2. 실험방법 As a microplate reader for measuring cytotoxicity, an E-max or SpectraMax250 type manufactured by Molecular Devices (Sunnyvale, Calif.) Was used. 2-2. Experiment method
실험에 사용한 약물은 시험에 원하는 농도까지 실험용 배지로서 희석하여 사용하였고, 최종 다이메틸설폭사이드 농도는 0.5% 이하가 되도록 하였다.  The drug used in the experiment was diluted as a test medium to the desired concentration in the test, and the final dimethyl sulfoxide concentration was adjusted to 0.5% or less.
실험에 사용한 암세포주는 모두 인체기원 암세포주들로서， 위암 세포주인 Hs746T, 및 MKN-45를 사용하였다. 배양액으로는 10% FBS (fetal bovine serum)가 첨가된 RPMI 1640 배지를 사용하여 37°C 및 5% 이산화탄소 인큐베이터에서 배양하였고， 3-4일에 한번씩 계대 유지하였다. The cancer cell lines used in the experiment were all human-derived cancer cell lines, and gastric cancer cell lines Hs746T and MKN-45 were used. Cultures were incubated in 37 ° C and 5% carbon dioxide incubator using RPMI 1640 medium added with 10% FBS (fetal bovine serum), and maintained once every 3-4 days.
96 웰 (well) 평평한 바닥 마이크로플레이트 (flat-bottom microplate)의 각 웰 (well)에 Hs746T는 5X103 cells을 분주하고， MKN-45는 1 104 eel Is를 분주하고， 세포가 바닥면에 부착하도톡 24시간 동안 배양한 후， 배양액을 제거하고， 여기에 본 발명 화합물이 각각 포함된 배양액을 가하고 72시간 동안 배양하였다. 상기 배양이 종료된 후， 세포독성 측정은 단백질 염색 시약인 SRB를 이용하여 측정하거나 MTS 분석법을 이용하여 측정하였다. In each well of a 96-well flat-bottom microplate, Hs746T dispenses 5X10 3 cells, MKN-45 dispenses 1 10 4 eel Is, and cells adhere to the bottom. After incubation for Hado Tok for 24 hours, the culture solution was removed, and the culture solution containing the compound of the present invention was added thereto and incubated for 72 hours. After the incubation was terminated, cytotoxicity was measured using SRB, a protein staining reagent, or MTS assay.
구체적으로, 본 발명의 화합물과의 배양이 종료된 후， 배양액올 제거하고 각 웰 (well)에 차가운 TCA 용액을 처리하고 4 °C에서 1시간 동안 방치하여 세포들을 고정시켰다. 상기 TCA 용액을 제거하고 실온에서 건조시킨 후, 1% 아세트산 용액에 0.4% SRB를 녹인 염색용액을 가하여 실온에서 30분 동안 방치하여 세포를 염색하였다. 세포와 결합하지 않은 여분의 SRB를 1% 아세트산 용액으로 세척하여 제거하고, 염색된 세포들에 H 10.3~10.5의 10 mM 트리스 완충용액 (Trisma base; unbuffered)을 가하여 SRB를 용출시켰다. 각 웰 (well)의 흡광도는 엘라이자 리더기 (microplate reader)를 이용하여 520 nm의 파장 범위에서 측정하였다. Specifically, after incubation with the compound of the present invention, the culture solution was removed, and treated with a cold TCA solution in each well, and left at 4 ° C for 1 hour to fix the cells. After removing the TCA solution and drying at room temperature, 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 not bound to the cells was removed by washing with 1% acetic acid solution, and SRB was eluted by adding 10 mM Tris buffer (unbuffered) of H 10.3-10.5 to H stained cells. The absorbance of each well was measured in a wavelength range of 520 nm using a microplate reader.
약물을 가하지 않은 웰 (well)(C)과 약물을 가한 각 웰 (well T) 및 약물을 처음 가할 때의 웰 (well Tz)의 0D값으로부터,  From 0D values of well (C) without drug, each well T with drug, and well Tz when the drug is first applied,
12^인 경우에는 [(T— Tz)/(C-Tz)]xi00의 수식에 의해 또는  For 12 ^, by the formula [(T— Tz) / (C-Tz)] xi00 or
12>丁인 경우에는 [(T-Tz)/(Tz)xi00 의 수식에 의해 약물의 세포독성을 계산하였다.  In the case of 12> 丁, the cytotoxicity of the drug was calculated by the formula [(T-Tz) / (Tz) xi00.
MTS 분석법을 이용한 암세포 증식억제 측정은 다음과 같이 실험하였다. 구체적으로ᅳ 본 발명의 화합물과의 배양이 종료된 후, Promega사의 Cel ITiter 96 AQueous Non-Radioact ive Cell Proliferation Assay 제품을 구성하고 있는 PMS 용액과 MTS 용액을 섞은 후 웰당 20 를 넣어주었다. 4시간 동안 배양기에 놓아둔 후 꺼내어 상온에서 10분간 방치하였다. Molecular Device사의 SpectraMax250 기종을 이용하여 490 nM에서의 흡광도를 측정한후 IC50 값을 계산하였다. Cancer cell proliferation inhibition measurement using MTS assay was performed as follows. Specifically after the incubation with the compound of the present invention, Promega's Cel ITiter 96 AQueous Non-Radioactive Cell Proliferation Assay product was mixed with PMS solution and MTS solution, and 20 per well was added. After leaving for 4 hours in the incubator was taken out and left for 10 minutes at room temperature. After measuring the absorbance at 490 nM using Molecular Device's SpectraMax250 model IC 50 value was calculated.
암세포 (Hs746T) 증식을 50¾로 억제하는 상기 화합물의 IC50는 하기 표 2에 나타내었다. The IC 50 of this compound that inhibits cancer cell (Hs746T) proliferation to 50¾ is shown in Table 2 below.
【표 2】 Table 2
각 화합물의 암세포 (Hs746T) 증식 억제 분석 [IC50(yM)] Inhibition of Cancer Cell (Hs746T) Proliferation of Each Compound [IC 50 (yM)]
Figure imgf000068_0001
표 2에 나타난 바와 같이， 암세포인 Hs746T에 대한 화합물의 IC50 값은 화학식 2(실시예 7)와 화학식 12(실시예 43)의 화합물이 0.1 μΜ의 낮은 값을 나타내었고, 화학식 7(실시예 17)과 화학식 26(실시예 68)은 각각 3.62 μΜ, 9.37 μΜ의 높은 값을 나타내었다, 이로부터 본 발명에 따른 신규 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 암세포 등의 증식을 억제하는 우수한 효과가 있음을 알 수 있다.
Figure imgf000068_0001
As shown in Table 2, the IC 50 value of the compound for cancer cells Hs746T showed a low value of 0.1 μΜ of the compounds of Formula 2 (Example 7) and Formula 12 (Example 43), and Formula 7 (Example 17) and Formula 26 (Example 68) showed high values of 3.62 μΜ and 9.37 μΜ, respectively, from which the novel pyrazolopyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention inhibit the proliferation of cancer cells and the like. It can be seen that there is an excellent effect.
하기에 본 발명의 조성물을 위한 제제예를 예시한다. 제제예 1 ： 약학적 제제의 제조  Examples of preparations for the compositions of the present invention are illustrated below. Formulation Example 1 Preparation of Pharmaceutical Formulation
1-1. 산제의 제조  1-1. Manufacture of powder
피라졸로 피리딘 유도체 2 g  2 g of pyrazolopyridine derivatives
유당 1 g  1 g lactose
상기의 성분을 흔합한 후， 기밀포에 층진하여 산제를 제조하였다.  After mixing the above components, it was laminated on an airtight cloth to prepare a powder.
1-2. 정제의 제조 1-2. Manufacture of tablets
피라졸로 피리딘 유도체 100 rag 옥수수전분 100 rag Pyrazolopyridine Derivatives 100 rag Corn starch 100 rag
유 당 100 rag  100 rag lactose
스테아린산 마그네슴 2 mg  Stearic acid magnes 2 mg
상기의 성분을 흔합한 후， 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.  After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
1-3. 캡술제의 제조 1-3. Preparation of Capsul
피라졸로 피리딘 유도체 100 nig  100 nig of pyrazolopyridine derivatives
옥수수전분 100 mg  Corn starch 100 mg
유 당 100 rag  100 rag lactose
스테아린산 마그네슘 2 rag  Magnesium Stearate 2rag
상기의 성분을 흔합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 층전하여 캡슐제를 제조하였다. 1-4. 주사액제의 제조  After the above ingredients were mixed, the capsules were prepared by layering the gelatine capsules according to a conventional method for preparing capsules. 1-4. Preparation of Injection
피라졸로 피리딘 유도체 10 g/i  10 g / i pyrazolopyridine derivative
묽은 염산 BP pH 3.5로 될 때까지  Dilute hydrochloric acid BP until pH 3.5
주사용 염화나트륨 BP 최대 1  Sodium Chloride BP for Injection up to 1
적당한 용적의 주사용 염화나트륨 BP 중에 본 발명에 따른 피라졸로 피리딘 유도체를 용해시키고， 생성된 용액의 pH를 묽은 염산 BP를 사용하여 pH 3.5로 조절하고, 주사용 염화나트륨 BP를 사용하여 용적을 조절하고 층분히 흔합하였다. 용액을 투명 유리로 된 5 타입 I 앰플 중에 층전시키고， 유리를 용해시킴으로써 공기의 상부 격자하에 봉입시키고, 120 °C에서 15 분 이상 오토클래이브시켜 살균하여 주사액제를 제조하였다. 이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며， 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다. Dissolve the pyrazolopyridine derivative according to the invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, adjust the volume with sodium chloride BP for injection and layer Mixed well. The solution was layered in a 5 type I ampoule made of transparent 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. Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims

【특허청구범위】  [Patent Claims]
【청구항 11  [Claim 11
하기의 화학식 1로 표시되는 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염:  Triazolo pyridazine derivatives represented by Formula 1 below or pharmaceutically acceptable salts thereof:
Figure imgf000070_0001
Figure imgf000070_0001
상기 화학식에서, A는 5각 -10각 고리의 아릴 또는 헤테로 아릴이고； Ri 내지 ¾는 각각 독립적으로 수소 또는 CrCs 알킬이며; R6는 수소, 하이드록시， 시아노， 할로겐, d-C4 알코올， 5각ᅳ 6각 고리의 헤테로사이클로알킬, 비치환되거나 5각— 6각 고리의 헤테로사이클로알킬로 치환된 d-Cs 알킬， 비치환되거나 5각 -6각 고리의 헤테로사이클로알킬로 치환된 알콕시， d-C5 알킬 에스터 , 비치환되거나 d-C5 알킬로 치환된 아민， -C(=0)NR7¾(R7및 Rs은 각각 독립적으로 수소 또는 (：厂(5 알킬이거나， R7 및 ¾이 고리로 연결된 5각 -6각 고리의 헤테로사이클로알킬이다)로 표시되는 아마이드이고; n은 0-5의 정수이다. In the above formula, A is a 5- or 10-membered aryl or hetero aryl; Ri to ¾ are each independently hydrogen or CrCs alkyl; R 6 is hydrogen, hydroxy, cyano, halogen, dC 4 alcohol, heterocycloalkyl of a pentagonal hexahexyl ring, d-Cs alkyl unsubstituted or substituted with a pentagonal—heterocycloalkyl of a hexagonal ring, non- Alkoxy, dC 5 alkyl esters, substituted or substituted by heterocycloalkyl of the pentagonal -hexagonal ring, amines unsubstituted or substituted with dC 5 alkyl, -C (= 0) NR 7 ¾ (R7 and Rs are each independently Hydrogen or an amide represented by (厂 ( 5 alkyl) or R 7 and ¾ are heterocycloalkyl of a pentagonal -hexagonal ring connected by a ring) n is an integer of 0-5.
【청구항 2] [Claim 2]
제 1 항에 있어서, 상기 화학식 1의 A는 페닐， 피라졸, 피리딘， 인돌 또는 인다졸이고; Ri내지 R5는 수소이며; Re는 수소, 하이드록시, 시아노, 할로겐， d-C2 알코을, 피페리딘， 피페라진， 몰폴린， 비치환되거나 피페리딘, 피페라진 또는 몰폴린으로 치환된 d-C3 알킬， 비치환되거나 피페리딘， 피페라진 또는 몰폴린으로 치환된 d-C2 알콕시, d-C3 알킬 에스터， d-C3 알킬로 치환된 아민， -C(=0)NR7 (R7및 ¾은 각각 독립적으로 수소 또는 d- C3 알킬이거나, R7 및 ¾이 고리로 연결된 피페라진이다)로 표시되는 아마이드이고; n은 1-3의 정수인 것을 특징으로 하는 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염. A compound according to claim 1, wherein A in Formula 1 is phenyl, pyrazole, pyridine, indole or indazole; Ri to R 5 are hydrogen; Re is hydrogen, hydroxy, cyano, halogen, dC 2 alcohol, piperidine, piperazine, morpholine, dC 3 alkyl unsubstituted or substituted with piperidine, piperazine or morpholine, unsubstituted or piperi DC 2 alkoxy substituted with dine, piperazine or morpholine, dC 3 alkyl ester, dC 3 alkyl substituted amine, -C (= 0) NR 7 (R 7 and ¾ each independently represent hydrogen or d-C 3 Alkyl, or an amide represented by R 7 and ¾ are piperazine linked by rings; triazolo pyridazine derivative or a pharmaceutically acceptable salt thereof, wherein n is an integer of 1-3.
【청구항 3】 [Claim 3]
제 1 항에 있어서, 상기 화학식 1로 표시되는 트리아졸로 피리다진 유도체는 하기의 화학식 2 내지 26으로 표시되는 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염:  The triazolo pyridazine derivative represented by Chemical Formula 1 is selected from the group consisting of compounds represented by the following Chemical Formulas 2 to 26, or a triazolo pyridazine derivative or a pharmaceutically acceptable salt thereof. :
화학식 2 화학식 3  Formula 2 Formula 3
Figure imgf000071_0001
화학식 10 화학식 11
Figure imgf000072_0001
Figure imgf000071_0001
Formula 10 Formula 11
Figure imgf000072_0001
화학식 12 화학식 13
Figure imgf000072_0002
Chemical Formula 12 Chemical Formula 13
Figure imgf000072_0002
화학식 14 화학식 15
Figure imgf000072_0003
Formula 14 Formula 15
Figure imgf000072_0003
화학식 16 화학식 17
Figure imgf000072_0004
Figure imgf000073_0001
Formula 16 Formula 17
Figure imgf000072_0004
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000073_0002
화학식 24 화학식 25
Figure imgf000073_0003
화학식 26 Chemical Formula 24 Chemical Formula 25
Figure imgf000073_0003
Formula 26
Figure imgf000074_0001
Figure imgf000074_0001
【청구항 4】  [Claim 4]
제 3 항에 있어서, 상기 트리아졸로 피리다진 유도체는 상기의 화학식 2 내지 5， 14 내지 16， 18， 20, 22 및 26으로 표시되는 화합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염 .  The triazolo pyridazine derivative according to claim 3, wherein the triazolo pyridazine derivative is selected from the group consisting of compounds represented by Formulas 2 to 5, 14 to 16, 18, 20, 22 and 26. Or pharmaceutically acceptable salts thereof.
【청구항 5】 [Claim 5]
제 1 항 내지 제 4 항 중 어느 한 항에 있어서， 상기 트리아졸로 피리다진 유도체의 약제학적 허용 가능한 염은 염산염 , 브름산염， 황산염 , 인산염， 구연산염， 아세트산염, 트리플루오로아세트산염, 젖산염, 주석산염， 말레인산염, 푸마린산염, 글루콘산염， 메탄설폰산염， 글리콘산염， 숙신산염, 4-를루엔설폰산염， 글루투론산염， 엠본산염, 글루탐산염， 또는 아스파트산염으로 구성된 군으로부터 선택되는 것을 특징으로 하는 트리아졸로 피리다진 유도체 또는 이의 약제학적 허용 가능한 염.  The pharmaceutically acceptable salt of the triazolo pyridazine derivative according to any one of claims 1 to 4 is hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tin Selected from the group consisting of acid salts, maleic acid salts, fumaric acid salts, gluconate salts, methane sulfonate salts, glyconate salts, succinate salts, 4-luenesulfonate salts, gluturonate salts, embon salts, glutamate salts, or aspartates Triazolo pyridazine derivatives or pharmaceutically acceptable salts thereof.
【청구항 6】 [Claim 6]
제 1 항 내지 제 4 항 중 어느 한 항의 트리아졸로 피리다진 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 c-Met 티로신 키나아제 활성 억제용 약제학적 조성물.  A pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising the triazolo pyridazine derivative of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
【청구항 7】 [Claim 7]
(a) 제 1 항 내지 제 4 항 중 어느 한 항의 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물; 및 (b) 약제학적으로 허용되는 담체를 포함하는 이상증식성 질환 (hyper proliferative disorder)의 예방 또는 치료용 약제학적 조성물ᅳ (a) the triazolo pyridazine derivative of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or solvate thereof; And (b) a pharmaceutical composition for the prophylaxis or treatment of a hyperproliferative disorder comprising a pharmaceutically acceptable carrier.
【청구항 8】 [Claim 8]
제 7 항에 있어서, 상기 이상증식성 질환 (hyper proliferative disorder)은 암， 당뇨병성 망막증， 미숙아 망막증， 각막 이식 거부, 신생혈관성 녹내장 홍색증， 증식성 망막증, 건선， 류마티스 관절염, 골관절염， 자가면역 질환, 크론씨병， 재발협착증， 아테롬성 동맥경화, 장관 접착， 궤양, 간경병증， 사구체신염， 당뇨병성 신장병증, 악성 신경화증， 혈전성 미소혈관증， 기관 이식 거부 및 신사구체병증으로 구성된 군으로부터 선택되는 것을 특징으로 하는 조성물.  8. The method of claim 7, wherein the hyperproliferative disorder is cancer, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, neovascular glaucoma erythematosis, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neurosis, thrombotic microangiopathy, organ transplant rejection and renal glomerulopathy Composition.
【청구항 9】 [Claim 9]
제 8 항에 있어서， 상기 암은 폐암， 위암， 췌장암, 대장암， 난소암, 신장 세포암， 전립선암 또는 뇌종양인 것을 특징으로 하는 조성물.  The composition of claim 8, wherein the cancer is lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer, or brain tumor.
【청구항 10] [Claim 10]
(a) 제 1 항 내지 제 4 항 중 어느 한 항의 트리아졸로 피리다진 유도체， 이의 약제학적 허용 가능한 염 또는 이의 용매화물; 및 (b) 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물의 약제학적 유효량을 이를 필요로 하는 객체 (subject)에 투여하는 단계를 포함하는 c- Met 티로신 키나아제 활성을 억제하는 방법 .  (a) the triazolo pyridazine derivative of any one of claims 1-4, a pharmaceutically acceptable salt thereof, or solvate thereof; And (b) administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
【청구항 11] [Claim 11]
제 1 항 내지 제 4 항 중 어느 한 항의 트리아졸로 피리다진 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 약제학적 조성물의 약제학적 유효량을 이를 필요로 하는 객체에 투여하는 단계를 포함하는 이상증식성 질환 (hyper proliferative disorder)을 예방 또는 치료하는 방법.  A method of administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising the triazolo pyridazine derivative of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Method for preventing or treating hyperproliferative disorder comprising a.
【청구항 12] [Claim 12]
제 11 항에 있어서， 상기 이상증식성 질환 (hyper proliferative disorder)은 암, 당뇨병성 망막증， 미숙아 망막증, 각막 이식 거부， 신생혈관성 녹내장， 홍색증， 증식성 망막증, 건선, 류마티스 관절염, 골관절염， 자가면역 질환, 크론씨병， 재발협착증, 아테롬성 동맥경화， 장관 접착， 궤양, 간경병증， 사구체신염， 당뇨병성 신장병증， 악성 신경화증, 혈전성 미소혈관증， 기관 이식 거부 및 신사구체병증으로 구성된 군으로부터 선택되는 것을 특징으로 하는 방법 . The method of claim 11, wherein the hyperproliferative disorder is cancer, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, neovascular glaucoma, erythematosis, proliferative retinopathy, psoriasis, rheumatoid arthritis, Osteoarthritis, Autoimmune Disease, Crohn's Disease, Restenosis, Atherosclerosis, Intestinal Adhesion, Ulcer, Liver Cirrhosis, Glomerulonephritis, Diabetic Nephropathy, Malignant Neurosis, Thrombotic Microangiopathy, Organ Transplant Rejection and Renal Glomerulopathy Characterized in that it is selected from.
【청구항 13] [Claim 13]
제 12 항에 있어서， 상기 암은 폐암, 위암， 췌장암ᅳ 대장암, 난소암, 신장 세포암， 전립선암 또는 뇌종양인 것을 특징으로 하는 방법 .  The method of claim 12, wherein the cancer is lung cancer, gastric cancer, pancreatic cancer or colorectal cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.
PCT/KR2013/001443 2012-03-05 2013-02-22 Novel triazolo pyridazine derivative and use therefor WO2013133556A1 (en)

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