WO2012077932A2 - Novel pyrazole pyridine derivative or pharmaceutically acceptable salts thereof, method for producing same, and pharmaceutical composition including same - Google Patents

Novel pyrazole pyridine derivative or pharmaceutically acceptable salts thereof, method for producing same, and pharmaceutical composition including same Download PDF

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WO2012077932A2
WO2012077932A2 PCT/KR2011/009224 KR2011009224W WO2012077932A2 WO 2012077932 A2 WO2012077932 A2 WO 2012077932A2 KR 2011009224 W KR2011009224 W KR 2011009224W WO 2012077932 A2 WO2012077932 A2 WO 2012077932A2
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pyrazolo
compound represented
formula
pyridine
amino
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PCT/KR2011/009224
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Korean (ko)
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WO2012077932A3 (en
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김명화
구일회
천광우
류동규
최정훈
김영하
조보영
박지선
이한창
김강전
김승현
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제일약품주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

  • Novel pyrazolopyridine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition comprising the same
  • the present invention relates to a novel pyrazolo pyridine derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition comprising the same.
  • Glycogen synthase kinase-3 (GSK-3) is a highly expressed serine / threonine protein kinase in the brain, consisting of the ⁇ and ⁇ isoforms encoded by different genes (Wood gett JR., EMBO J., 9 (8), 2431-2438, 1990).
  • GSK-3 ⁇ and GSK-3P having molecular weights of 51 and 47 kDa, respectively, have 85% sequence equivalents and share 97% sequence similarity in the kinase catalyst domain (Ali A., et al., Chem Rev., 101, 2527-2540, 2001).
  • GSK-3 was originally identified as an enzyme that inhibits activation by directly phosphorylating glycogen synthase (gS) involved in glycogen production (Embi N., et al., Eur J Biochem., 107, 519- 527, 1980; Hemmin gs BA., Et al., Eur J Biochem., 119, 443-451, 1981).
  • gS glycogen synthase
  • microtubule-related protein Tau as a structural protein
  • ⁇ -catenin as a transcription factor
  • AP-l activator protein -l
  • CREB activated T-cell nuclear factor (NFAT) cyclic AMP reaction element binding Protein
  • HSF-l heat shock factor -l
  • c-Jun c_Myc
  • NFK B NFK B
  • Inhibition of GSK-3 may be effective in the treatment of insulin resistance and in the treatment of type 2 diabetes (Kaidanovich 0., et al, Expert Opin Ther Tar gets, 6, 555-561, 2002).
  • Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia due to lack of insulin action and can be divided into insulin-dependent type 1 diabetes and insulin-independent type 2 diabetes.
  • Type 1 diabetes is caused by insulin deficiency due to the destruction of pancreatic ⁇ cells.
  • Type 2 diabetes is caused by decreased insulin secretion and insulin resistance. In general, type 1 diabetes is associated with decreased or almost insignificant levels of insulin, so treatment is by injection of an alternate dose of insulin.
  • GSK-3 phosphorylates the insulin receptor substrate -KIRS-1), which impairs insulin action and attenuates intracellular insulin effects by inhibiting glycogen synthase activity (Eldar-Finkelman ⁇ ., Et al., PNAS, 94, 9660-9664, 1997). Furthermore, type 2 diabetes It has also been reported that GSK-3 is overexpressed in the muscles of diseased patients (Nikoulina SE., Et al., Diabetes, 49 (2), 263-271, 2000). Therefore, GSK-3 inhibitors are useful for the treatment of diabetes that increases insulin activity.
  • GSK-3 activity is also associated with Alzheimer's disease.
  • Alzheimer's disease is a degenerative brain disease and is a representative disease that causes dementia in the elderly.
  • the disease consists mainly of the accumulation of ⁇ -amyloid peptide ( ⁇ ), an abnormal product of the amyloid precursor protein (APP), and the formation of paired helical filaments (PHFs), composed mostly of hyperphosphorylated tau protein.
  • ⁇ ⁇ -amyloid peptide
  • APP amyloid precursor protein
  • PHFs paired helical filaments
  • tau is highly expressed in the central and peripheral nervous system and is a protein that enhances the safety of microtubules, which is present in large quantities in axons of neurons and provides structural support for forming axons and dendritic compartments. It consists of six protein isomers. do.
  • the tau isomer is formed from another mRNA junction in a single gene and has a molecular weight ranging from 50 to 70 kDa. Phosphorylation at abnormal locations of tau by GSK-3 has been shown to promote filaments (PHF), which form neurofibrillary tan gles (Han ger DP., Et al., Neurosci Lett., 147).
  • PPF neurofibrillary tan gles
  • Bipolar disorder is characterized by mania and depression.
  • Lithium which has been used as a therapeutic agent for this disease, has been found to be a GSK-3 inhibitor (Klein PS., Et al, PNAS, 93, 8455-8459, 1996; Stambolic V., et al., Curr Biol., 6) 12), 1664-1668, 1996; Phi el CJ., Et al., Annu Rev Pharmacol Toxicol., 41, 789-813, 2001).
  • Valprophosphate a commonly used bipolar disorder treatment, is also known to be an effective GSK-3 inhibitor (Chen g., Et al., J Neurochemistry, 72, 1327-1330, 1999).
  • the mechanism by this GSK-3 inhibitor is to increase the survival of abnormally high levels of excited neurons induced by the neurotransmitter glutamate (Nonaka S., et al., PNAS 95, 2642-2647, 1998).
  • Glutamate toxicity of neurons induced by glutamate is believed to be a major cause of neurodegeneration associated with acute injury such as cerebral ischemia, traumatic brain injury and bacterial infection.
  • excessive glutamate signaling is believed to be a factor in chronic neurological damage in diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • GSK-3 phosphorylates NF-AT and escapes from the nucleus. Promotes early blocking of activation of immune response genes by NF-AT (Beals CR., Et al., Science, 275, 1930-1934, 1997).
  • GSK-3 inhibitors are believed to prolong and enhance the immunostimulatory effects of certain cytokines, which may enhance the potential of these cytokines for tumor immunotherapy or indeed for general immunotherapy.
  • GSK-3 is a tumor that is induced by breast cancer, colon cancer, thyroid cancer, T- or B-cell leukemia and several viruses (Eastman Q., et al., Curr Opin Cell Biol., 11, 233-240, 1999). Shakoori A., et al., Cancer Sci., 98 (9), 1388-1393, 2007; unnimalaiyaan M., et al., Mol Cancer Ther., 6 (3), 1151-1158, 2007; Holmes T , et al., Curr Med Chen]., 15 (15), 1493-1499, 2008; Manoukian AS., et al., Adv Cancer Res. 84, 203-229, 2002), cardiac hypertrophy (Badorff C.
  • Lithium which is used as a therapeutic agent for manic or bipolar disorder mentioned above, is known to inhibit other targets such as inosi as monophosphatase (IMPase) and inosi as polyphosphate phosphatase (IPPase) as nonspecific inhibitors for GSK-3.
  • IMPase monophosphatase
  • IPPase polyphosphate phosphatase
  • Nypta NP-12, NP031112
  • SA previously Neuropharma, SA
  • Nypta is a thiadiazolidinone (TDZD) derivative that is an uncompetitive GSK-3 inhibitor to ATP.
  • NP103 another GSK-3 inhibitor developed by Noscira, S.A, is under preclinical development as a treatment for Alzheimer's disease.
  • Competitive GSK-3 inhibitors for ATP include SB216763 and SB_415286 developed by glaxoSmithKline (Cross DAE., Et al., J Neurochemistry, 77, 94-102, 2001) for the treatment of diabetes and stroke, CHIR98023 and CHIR9902K for Chiron.
  • GSK-3 inhibitors are ongoing, but there is an urgent need for the development of effective and GSK-3 selective inhibitors with good pharmaceutical properties related to ADME (administration, distribution, metabolism, secretion). Accordingly, the present inventors have been studying pyrazolopyridine derivatives while developing a low molecular weight GSK-3 inhibitor which can be used for the treatment of various diseases caused by the excess activity of glycogen synthase kinase-3 (GSK-3). ⁇ , and confirmed that the compound exhibits excellent GSK-3 inhibitory activity, completing the present invention.
  • GSK-3 glycogen synthase kinase-3
  • Another object of the present invention is to provide a method for preparing a pyrazolo pyridine derivative.
  • Another object of the present invention is a pharmaceutical composition for preventing or treating a disease related to GSK-3
  • the present invention also provides a method for preparing a pyrazolo pyridine derivative represented by the formula (1).
  • the present invention provides a pharmaceutical composition for preventing or treating a disease related to GSK-3P (glycogen synthase kinase-3 ⁇ ) containing pyrazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • GSK-3P glycosylase-3P
  • novel pyrazolopyridine derivatives of the present invention inhibit GSK-3P, thereby dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology It can be usefully used to prevent or treat related diseases.
  • Example 1 is a graph showing the GSK-3P enzyme inhibitory effect of the compound of Example 1 according to the present invention. .
  • Alkyl is a saturated, straight or pulverized hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, in particular 1 to 8 or 1 to 6 or 1 to 4 carbon atoms, for example methyl, Ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-nuclear, 2, 2-dimethyl-butyl or n-octyl groups.
  • Heteroarylalkyls are those in which one or more (preferably 1, 2, 3 or 4) carbon atoms are replaced with oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atoms (preferably oxygen, sulfur or nitrogen) Aralkyl groups as defined above, ie groups containing aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups as defined above.
  • the heteroaralkyl group is one or two aromatic ring systems (1 or 2 rings) containing 5 or 6 to 10 carbon atoms, and one or two alkyl, alkenyl containing 1 or 2 to 6 carbon atoms And / or alkynyl groups, and / or 1, 2, 3 or 4 or cycloalkyl groups containing such carbon atoms replaced with 5 or 6 ring carbon atoms, oxygen, sulfur or nitrogen atoms.
  • Examples include arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, Heteroaryl alkenyl, Heteroaryl alkynyl, Heteroaryl heteroalkyl, Heteroarylcycloalkyl, Heteroarylcycloalkenyl, Heteroaryl heterocycloalkyl, Heteroaryl heterocycloalkenyl, Heteroarylalkyl Cycloalkyl Heteroaryl alkyl heterocyclo Alkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroal
  • Aryl represents an aromatic group having one or more rings containing 6 to 14 ring carbon atoms, preferably 6 to 10 (particularly 6) carbon atoms.
  • aryl (or Ar) denotes a group in which one or more hydrogen atoms are replaced with fluorine, chlorine, bromine or iodine atoms or with OH, SH, NH2, or N02 groups. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups.
  • Heteroaryl represents an aromatic group having one or more rings, contains 5 to 14 ring atoms, preferably 5 to 10 (particularly 5 or 6) ring atoms, and one or more (preferably 1, Formed by a ring system containing 2, 3 or 4 oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N).
  • heteroaryl represents a group in which one or more hydrogen atoms are replaced with fluorine, chlorine bromine or iodine atoms or with OH, SH, NH 2 , or NO 2 groups.
  • Examples include 4-pyridyl, 2-imidazolyl, 3-phenyl-pyryl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyrida Genyl, quinolinyl, furinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuryl, 3 ⁇ pyrazolyl and isoquinolinyl groups.
  • the present invention is a pyrazolo pyridine derivative represented by the following formula (1) and
  • A is nitrogen (N) or carbon (C);
  • R 1 is hydrogen; The one selected from the group consisting of an unsubstituted or an amine, and OR 5 is substituted by a substituent on C 5 - 10 aryl; 5-10 membered heteroaryl containing one or more nitrogen (N) atoms in the ring; D- 4 straight or branched chain alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of -NR 6 R 7 and -0H; -C00R 8 or -C0R 8 ;
  • R 5 is hydrogen, d- 4 linear alkyl
  • R 6 and R 7 are each hydrogen or d- 4 straight or branched alkyl
  • R 8 is hydrogen, N3 ⁇ 4, unsubstituted or NR3 ⁇ 4 7 d- 4 linear or branched alkyl; 5 eu 8-membered heteroaryl d- 4 alkyl or C 5 - 10 aryl;
  • R 2 is hydrogen, NR3 ⁇ 4 7 or; Substituted C is unsubstituted or one or more OR 5 5 - 10 aryl;
  • R 3 is hydrogen, 0 rS or — (CH 2 ) n —NR 3 7 ; Or is;
  • n 0 to 15;
  • R 10 is NR 6 R 7 ; -(CH 2 ) n -C00R 5 ; -(C) n -NR 3 7 ; C 5 - 12 aryl; 5-12 membered heteroaryl; And 5 ⁇ 12 membered heterocycloalkyl, - (CH 2) n -C 5 - 12 aryl, - (C3 ⁇ 4) n -5 ⁇ 12 -membered heteroaryl, - (CH 2) n -5 ⁇ 12 -membered heterocycloalkyl;
  • the aryl, heteroaryl or heterocycloalkyl is unsubstituted or d- 4 linear or branched alkyl, OR 5 , NR 6 R 7 ,-(CH 2 ) n -NR 6 R 7 , C00R 5 , halogen, N0 2 , CN, PMB,
  • R 1 Is hydrogen; Phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of amines and OR 5 ; Pyridine,-(CH 2 ) n -NR 6 R 7 ,-(CH 2 ) n -0H, -C00R 8 or -COR 8 ;
  • R 5 is H, CH 3 , ⁇ ⁇ or ⁇ ;
  • R 6 and R 7 are each H or CH 3 ;
  • R 8 is H, NH 2j N (C3 ⁇ 4) 2 , methyl, ethyl, Phenyl again ego;
  • n provides 1 or 2 pyrazolo pyridine derivatives and pharmaceutically acceptable salts thereof.
  • R 2 Is hydrogen, N3 ⁇ 4, NH (CH 3 ), N (CH 3 ) 2 Or; Pyrazolo pyridine derivatives which are unsubstituted or substituted with OH, 0CH 3 , and pharmaceutically acceptable salts thereof.
  • R 3 is hydrogen, or
  • the silver provides 0 to 5 pyrazolo pyridine derivatives and pharmaceutically acceptable salts thereof.
  • R 4 is NH 2 , -NH- (CH 2 ) n- ,
  • N is 0 to 4.
  • R 10 is unsubstituted or. Methyl, ethyl, propyl, —OH, —OMe, ⁇ NH 2 , —N0 2 , —N (C3 ⁇ 4) 2 , —CH 2 N (CH 3 ) 2) -(CH 2 ) 2 N (CH 3 ) 2 , -0 (CH 2 ) 2 N (CH 3 ) 2) -COOH, -COOMe,-(CH 3 ) 2 C00H, -C0NH 2 , -CN, -F, -CI, -PMB, -S000H, -S000CH 2 CH 3 , -S000 (CH 2 ) 2 CH 3 , — S000 (CH 2 ) 5 C3 ⁇ 4,
  • O ⁇ ⁇ ⁇ / HO ⁇ / R 1 is hydrogen
  • R 2 is hydrogen, NH 2 , NHCH 3) It is 1 type selected from consisting of;
  • 6- (4-hydroxyphenyl) -3- (pyridin-1-yl) -1 ⁇ pyrazolo is one selected from the group consisting of [3,4-pyridine.
  • the derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydrochloric acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid lactic acid, maleic acid gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid.
  • These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate Nate, Suberic, Sebacate, Fumarate, Maleate, Butine-1,4-Diate, Nucleic Acid-1,6-Diate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxy Benzoate, Meoxybenzoate, Phthalate, Terephthalate Benzenesulfonate, toluenesulfonate, chlorobenz
  • Acid addition salt according to the present invention is a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent, for example methane, ethanol, acetone, methylene chloride, acetonitrile and the like, and adding an organic or inorganic acid It can be prepared by filtration, drying, or by distillation under reduced pressure of the solvent and excess acid and dried or crystallized in an organic solvent.
  • an organic solvent for example methane, ethanol, acetone, methylene chloride, acetonitrile and the like
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts for example, compounds in excess of alkali metal It is dissolved in a cargo or alkaline earth metal hydroxide solution, and is obtained by filtering the insoluble compound salt and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only pyrazolo pyridine derivatives represented by the general formula (1) and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, stereoisomers and the like that can be prepared therefrom.
  • the present invention also provides a method for preparing a pyrazolo pyridine derivative represented by the formula (1).
  • step 2 Dehydrating the compound represented by Chemical Formula 3 prepared in Step 1 to obtain a compound represented by Chemical Formula 4 (step 2);
  • step 3 Performing a condensation reaction with the compoundol 2-aminomalononitrile represented by Chemical Formula 4 prepared in Step 2 to obtain a compound represented by Chemical Formula 5 (step 3); Reducing the compound represented by Chemical Formula 5 prepared in Step 3 with phosphorus trichloride to obtain a compound represented by Chemical Formula 6 (step 4);
  • Step 8 A process for preparing a compound represented by Chemical Formula la by performing a reaction for removing a protecting group of the compound represented by Chemical Formula 10 (Step 8):
  • A, R 5 , R 10 are as defined in Formula 1, and as a P protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxy Benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • Step 1 is a step of preparing a compound represented by Chemical Formula 3 by oxidizing a ketone compound represented by Chemical Formula 2 using selenium oxide, which may be easily obtained commercially or prepared by a conventionally known method.
  • organic solvent that can be used a solvent that does not adversely affect reaction can be used, and preferably dioxane and water can be used in combination.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of the room temperature to the solvent.
  • step 2 is a step of preparing a compound represented by Formula 4 by performing a dehydration reaction using hydroxyamine and sodium acetate to the compound represented by Formula 3 prepared in step 1.
  • the usable solvent may be reacted in water without using an organic solvent.
  • reaction temperature is not particularly limited, but the boiling point range of the room temperature to the solvent It can be performed within the stomach.
  • step 3 is a step of condensing the compound represented by Formula 4 prepared in the second step with 2-aminomalononitrile to obtain a compound represented by Formula 5.
  • the usable organic solvent may be reacted using methane, ethanol, 2-propane, isobutanol or butane, etc., which does not adversely affect the reaction, and preferably 2-propanol may be used. have.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of the room temperature to the solvent.
  • step 4 is a step of obtaining a compound represented by the formula (6) by reducing the compound represented by the formula (5) prepared in the third step with phosphorus trichloride.
  • organic solvent that can be used, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not adversely affect reaction, can be used, and preferably tetrahydrofuran can be used. .
  • reaction temperature is not particularly limited, but may be performed in a boiling point range of room temperature to the solvent.
  • step 5 is added to the compound represented by the chemical machination 6 prepared in the fourth step and the catalytic amount of copper chloride (II) and subjected to a sandmeyer reaction using isoamyl nitrite to formula (7) It is a step of obtaining the displayed compound.
  • the usable organic solvent may be subjected to reaction using dichloromethane, chloroform, acetonitrile, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, which do not adversely affect reaction.
  • acetonitrile can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of the room temperature to the solvent.
  • step 6 is a step of obtaining a compound represented by the formula (8) by performing a cyclization reaction of the compound represented by the formula (7) prepared in step 5 with a hydrazine hydrate protected with a protecting group.
  • the usable organic solvent may be reacted with methane, a solvent which does not adversely affect the reaction, using ethanol, acetonitrile, pyridine, tetrahydrofuran or dimethylformamide, preferably ethanol.
  • methane a solvent which does not adversely affect the reaction
  • ethanol acetonitrile
  • pyridine a solvent which does not adversely affect the reaction
  • tetrahydrofuran or dimethylformamide preferably ethanol.
  • reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
  • Step 7 is a step of obtaining a compound represented by Chemical Formula 10 by reacting the compound represented by Chemical Formula 8 prepared in Step 6 with the compound represented by Chemical Formula 9.
  • Step 7 is amidation reaction ion with the carbonyl chloride compound represented by the formula (9) prepared by using a cheonyl chloride or oxalyl chloride prepared in step 6 To prepare a compound represented by Formula 10.
  • the reaction of step 7 may be performed without using a base, but generally, pyridine, triethylamine, diethylisopropylamine, N-methylmorpholine, or the like, which may be used for the amidation reaction, may be used. Can be used, preferably using DMF.
  • dichloromethane chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not affect the reaction, can be used, and preferably dichloromethane can be used. .
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 8 is a step of preparing a compound represented by the formula la by performing a deprotection reaction of the compound represented by the formula (10) prepared in step 7.
  • hydrochloric acid sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, or the like can be used, and preferably trifluoroacetic acid can be used.
  • usable solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, which do not adversely affect reaction. Can be used, preferably may not be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the compound represented by Chemical Formula 10 may be dissolved in trifluoroacetic acid, stirred to perform reaction, and after completion of reaction, the reaction product may be filtered under reduced pressure to obtain a compound represented by Chemical Formula la.
  • another method for preparing a derivative of Formula 1 according to the present invention is obtained by adding ethyl chloroformate to the cyanoacetate compound represented by Formula 11 to obtain a compound represented by Formula 12, as shown in Reaction Formula 2 below. Step (step 1);
  • step 2 Performing a methylation reaction on the compound represented by Chemical Formula 12 prepared in Step 1 to obtain a compound represented by Chemical Formula 13 (step 2);
  • step 6 Reacting the compound represented by Chemical Formula 16 and the compound represented by Chemical Formula 9 prepared in Step 5 to obtain a compound represented by Chemical Formula 17 (step 6); And a step (step 7) of obtaining a compound represented by the formula lb by performing a reaction of removing the protecting group of the compound represented by the formula (17) prepared in step 6 above:
  • A, R 1 and R 5 in Scheme 2 are as defined in Formula 1, and as a P protecting group, a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc) P-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • a P protecting group a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc) P-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)
  • Step 1 is a step of obtaining a compound represented by Formula 12 by adding a base to the cyanoacetate compound represented by Formula 11, and then adding ethylchloroformate.
  • sodium hydride sodium alcoholate, potassium carbonate, diisopropylamine, triethylamine, n-butyllithium or potassium t-butoxide may be used, preferably sodium Eroxide can be used.
  • the solvent that can be used methane which is a solvent which does not adversely affect the reaction, ethane, tetrahydrofuran, diethyl ether or the like can be used, and preferably ethanol can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 2 is a step of obtaining a compound represented by the formula (13) by performing a methylation reaction to the compound represented by the formula (12) prepared in step 1.
  • Solvents that can be used include dichloromethane, chloroform, tetrahydrofuran, diethyl ether or dimethylformamide, which do not adversely affect reaction, and ⁇ dimethylformamide may be preferably used.
  • reaction temperature is not particularly limited, but the phase may be carried out within the boiling point range of the solvent.
  • step 3 is a step of obtaining a compound represented by Chemical Formula 14 by condensation reaction of 2-cyanoacetamide with a compound represented by Chemical Formula 13 prepared in Step 2 in the presence of a base.
  • Examples of the base that can be used include sodium hydride, sodium alcoholate, potassium carbonate, diisopropylamine, triethylamine, n-butyllithium or potassium t-butoxide, and preferably sodium Eroxide can be used.
  • the solvent may be methanol, ethanol, tetrahydrofuran, diethyl ether, or the like, which does not adversely affect the reaction.
  • ethane may be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 4 is a step of obtaining a compound represented by the formula (15) by performing a halogenated reaction to the compound represented by the formula (14) prepared in step 3.
  • phosphorus trichloride phosphorus pentachloride, phosphoryl chloride, olsalyl chloride, thionyl chloride, and the like may be used.
  • phosphorus trichloride may be used.
  • a solvent which can be used methane which does not adversely affect a reaction
  • methane which does not adversely affect a reaction ethane, tetrahydrofuran, diethyl ether, dimethylformamide, etc. can be used, Preferably it is not used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • phosphorus trichloride is added to the compound represented by Chemical Formula 15 prepared in the third step, the reaction mixture is stirred under reflux at 110 ° C, the reaction is terminated, and after the addition of ice water, The solid may be filtered to obtain a compound represented by Formula 16.
  • the steps 5 to 7 may be performed by the same method as the method for obtaining the compound represented by the formula la of the above formulas 6 to 7 to obtain the compound represented by the formula lb.
  • another method for preparing a derivative of Formula 1 according to the present invention is as shown in the following formula 3, wherein the compound represented by the formula a is obtained by using a triphosgene to obtain a compound represented by the formula a '( Step A);
  • step 2 Performing a reaction to remove the protecting group of the compound represented by Chemical Formula 18 to obtain a compound represented by Chemical Formula lc (step 2)
  • R 1 , R 2 and R 10 are as defined in Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc), p ⁇ methoxy benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc), p ⁇ methoxy benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • Step A is a step of condensing the compound represented by Chemical Formula a with triphosgene under a base and a solvent to obtain an isocyanate compound represented by Chemical Formula a '.
  • usable bases include triethylamine, diisopropylethylamine and the like, and preferably triethylamine can be used.
  • dichloromethane chloroform, dimethylformamide, or the like, which does not adversely affect the reaction
  • dichloromethane can be used as the solvent that can be used, and preferably dichloromethane can be used.
  • step 1 is a step of obtaining a compound represented by the formula (18) by performing a urea reaction with the isocyanate compound represented by the formula (a ') and the compound represented by the formula (8) or (16).
  • a base which can be generally used, such as pyridine, triethylamine, diethylisopropylamine or N-methylmorpholine, preferably pyridine Can be used.
  • usable solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, which do not adversely affect reaction. It is possible to use, preferably dichloromethane.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 2 may be carried out in the same manner as the method of obtaining the compound represented by the formula la in the step 8 of Scheme 1 to obtain a compound represented by the formula (lc).
  • Method for preparing a derivative of Formula 1 according to the present invention is to obtain a compound represented by the formula (19) by introducing a protecting group to the compound represented by the formula (15) prepared in Scheme 2 as shown in One) ;
  • a preparation method comprising the step (step 4) of obtaining a compound represented by Chemical Formula Id by performing a reaction to remove the protecting group of the compound represented by Chemical Formula 22 prepared in Step 3 above:
  • R 10 is selected from the group consisting of pyridine, benzyl and cyclopentane
  • P is a protecting group, benzyloxycarbonyl group (Cbz) , t-butoxycarbonyl group (t-Boc), P-methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc).
  • benzyloxycarbonyl group Cbz
  • t-Boc t-butoxycarbonyl group
  • PMB P-methoxy benzyl group
  • Fmoc 9-fluorenyl methoxycarbonyl group
  • Step 1 is a step of obtaining a compound represented by the formula (19) by introducing a protective group to the compound represented by the formula (15) prepared in Scheme 2.
  • a benzyloxycarbonyl group (Cbz), t-subspecific carbonyl group (t-Boc), P-methoxybenzyl group (PMB), or 9-fluorenyl methoxycarbonyl group (Fmoc) can be used. And preferably t-butoxycarbonyl group (t-Boc).
  • an organic solvent that can be used may be a solvent that does not adversely affect the reaction of methanol, ethanol, acetonitrile, pyridine, tetrahydrofuran or dimethylformamide, and the like, preferably dichloromethane.
  • the reaction temperature is not particularly limited, but may be performed in a range of room temperature to the boiling point of the solvent.
  • step 2 is a step of obtaining a compound represented by the formula (20) by reacting with the compound represented by the formula (19) prepared in step 1 and the hydrazine hydrate protected with a protecting group represented by the formula (8) It can be obtained by performing the same method as the method for obtaining the compound.
  • Step 3 is a step of obtaining a compound represented by Chemical Schematic 22 by performing a reducing amino reaction with the compound represented by Formula 20 prepared in Step 2 and the aldehyde compound represented by Formula 21.
  • sodium cyanoborohydride, sodium borohydride or triacetic borohydride and the like can be used as acetic acid, preferably sodium cyanoborohydride.
  • step 4 is a step of obtaining a compound represented by the formula Id by performing a reaction to remove the protecting group of the compound represented by the formula (22) prepared in step 3 to obtain a formula la of step 8 of the reaction formula 1
  • the compound represented by Chemical Formula Id may be obtained by the same method as described above.
  • Another method for preparing a derivative of Formula 1 according to the present invention includes the steps of performing a reduction reaction on a compound represented by Formula 17 to obtain a compound represented by Formula 23, as shown in Step 5 below (Step 1);
  • Step 4 Deprotection reaction of the compound represented by Formula 25 prepared in Step 3 to obtain a compound represented by Formula l e (Step 4):
  • R 6 , R 7 and R 10 are as defined in Formula 1, R 5 ' is selected from the group consisting of H, ethyl, (CH 2 ) 3 N (C3 ⁇ 4) 2 , toluene and benzene
  • P is a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethamic carbonyl group (Fmoc) as a protecting group) .
  • P is a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethamic carbonyl group (Fmoc) as a protecting group
  • Step 1 is a step of obtaining a compound represented by the chemical process 23 by performing a reduction reaction on the compound represented by Formula 17 prepared in Step 6 of the reaction formula 2.
  • a reducing agent for performing the reduction reaction sodium borohydride, trialuminum hydride, lithium aluminum hydride, borane or lithium tri-addendum aluminum hydride may be used, preferably lithium aluminum hydride. Can be used.
  • the solvent which can be used ethanol, isopropanol, ethyl ether, tetrahydrofuran, diethylene glycol, acetonitrile, ⁇ , ⁇ -dimethylacetamide, etc., which does not adversely affect reaction, can be used. Methanol can be used.
  • the reaction temperature is not particularly limited, but may be carried out at room temperature to the boiling point of the solvent.
  • step 2 is a compound represented by the formula (23) prepared in step 1 It is a step of obtaining a compound represented by Chemical Formula 24 by performing an oxidation reaction of water.
  • the oxidation reaction may be pyridinium chlorochromate, Dess-Martin oxidation or Swern oxidation, and as a usable solvent, dichloro does not adversely affect the reaction.
  • Methane, chloroform, tetrahydrofuran diethyl ether, toluene or dimethylformamide can be used, and preferably dichloromethane can be used.
  • reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
  • Step 3 is a step of obtaining a compound represented by Chemical Formula 22 of Scheme 4 by performing a reductive amination reaction on the compound represented by Chemical Formula 24 prepared in Step 2 to obtain a compound represented by Chemical Formula 25.
  • the compound represented by the formula (25) can be obtained by performing the same reaction as.
  • Another method for preparing a derivative of Formula 1 according to the present invention comprises the steps of obtaining a compound represented by Formula 26 by introducing a protecting group into a compound represented by Formula 15, as shown in Scheme 6 below (Step 1);
  • step 2 Performing a cyclization reaction with the hydrazine hydrate protected with a protecting group by the compound represented by Chemical Formula 26 prepared in Step 1 to obtain a compound represented by Chemical Formula 27 (step 2);
  • Step 6 A process for preparing a compound represented by Chemical Formula if (Step 6) by performing a deprotection reaction on the compound represented by Chemical Formula 30 prepared in Step 5 (Step 6):
  • R 5 ' is selected from the group consisting of H, ethyl, (C3 ⁇ 4) 3 N (C3 ⁇ 4) 2 , toluene and benzene
  • P is As an expiration group, it is a benzyloxycarbonyl group (Cbz), t- butyloxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB), or 9-fluorenyl methoxycarbonyl group (Fmoc).
  • Step 1 is a step of obtaining a compound represented by the formula (26) by introducing a protecting group to the compound represented by the formula (15) prepared in step 4 of the reaction formula 2, represented by the formula (19) in step 1 of the reaction
  • the compound represented by the formula (26) can be obtained by the same method as the method for obtaining the compound.
  • the step 2 is a step of obtaining a compound represented by the formula (27) by performing a cyclization reaction with the hydrazine hydrate protected with a protecting group to the compound represented by the formula (26) prepared in step 1, the step of the formula 4
  • the compound represented by the formula (27) can be obtained by performing the same method as the method for obtaining the compound represented by the formula (20).
  • Step 3 is a step of obtaining a compound represented by Formula 28 by reacting the compound represented by Formula 27 and the compound represented by Formula 9 prepared in Step 2, wherein the compound represented by Formula 17 in Step 6
  • the compound represented by Chemical Formula 28 may be obtained by performing the same method as the method for obtaining the compound represented by.
  • step 4 is a step of obtaining a compound represented by the formula (29) by hydrolysis of the compound represented by the formula (28) prepared in step 3.
  • Bases that can be used include potassium hydroxide, sodium hydroxide or potassium hydroxide, and preferably potassium hydroxide.
  • water, methanol, ethane, isopropanol, ethyl ether, tetrahydrofuranium diethylene glycol, acetonitrile, etc. which do not adversely affect the reaction can be used, and preferably water and ethanol are mixed, Can be used.
  • reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
  • step 5 is a step of obtaining a compound represented by the formula (30) by performing a coupling reaction (coupling react ion) with the compound represented by the formula (29) prepared in step 4.
  • the coupling reaction is a coupling reagent 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (l- (3-dimethylaminopropyl) —3-ethylcarbodi imide, EDC), 1-hydride Hydroxybenzotriazole hydrate (l-hydroxylbenzotriazole, HOBt) or 1,3-dicyclonuxyl carbodiimide (l, 3_dicyclohexyl carbodi imide, DCC) and the like can be used, preferably 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide (1— (3-dimethylaminopropyl) -3 ethylcarbodiiniide, EIX :) can be used.
  • the coupling reaction can be carried out without using a base, but 4-dimethylaminopyridine, pyridine, triethylamine, diethylisopropylamine, N-methylmo, which are general bases that can be used for the amide reaction reaction. Pauline or dimethylphenylamine and the like can be used, and preferably pyridin-3-yl-methanol can be used.
  • acetonitrile, dimethylformamide, dichloromethane, and the like which do not adversely affect the reaction, may be used as the solvent, and dimethylformamide may be preferably used.
  • reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
  • the compound represented by Chemical Formula 29 prepared in Step 3 is dissolved in dimethyl formamide (DMF), pyridin-3-yl-methane is added after adding EDC, HOBt, DIPEA, and stirred at room temperature, After completion of the reaction, column chromatography may be performed to obtain a compound represented by Chemical Formula 30.
  • performing a deprotection reaction of the compound represented by Formula 30 prepared in step 5 to obtain a compound represented by Formula H a method of obtaining a compound represented by the formula la in step 8 of the reaction formula 1 The same reaction can be performed to obtain a compound represented by the formula If.
  • Another method for preparing a derivative of Formula 1 according to the present invention is to combine the amine compound and the compound represented by the formula (29) Carrying out to obtain a compound represented by formula (31) (step 1); And
  • Step 2 A process for preparing a compound represented by Chemical Formula lg by performing a deprotection reaction on the compound represented by Chemical Formula 31 prepared in Step 1 (Step 2):
  • R 6 , R 7 and R 10 in Scheme 7 are as defined in Chemical Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p- Methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
  • P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p- Methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
  • the step 1 is a step of performing a coupling reaction between the compound represented by formula 29 and the amine compound prepared in step 4 of the reaction formula 6 to obtain a compound represented by formula 31, step 5 of the reaction formula 6 By performing the step of obtaining a compound represented by the formula in 30 to obtain a compound represented by the formula (31), but is not limited thereto.
  • step 2 is a step of obtaining a compound represented by the formula lg by performing a deprotection reaction of the compound represented by the formula (31) prepared in step 1 in the same manner as the method for obtaining the formula la in the step 8 of the semi-formula 1 It can be carried out by the method to obtain a compound represented by the formula (lg), but is not limited thereto.
  • Another method of preparing a derivative of Formula 1 according to the present invention includes the steps of obtaining a compound represented by Chemical Formula 33 by reacting a compound represented by Chemical Formula 16 with a compound represented by Chemical Formula 32, Step 1);
  • Step 2 Performing a N-alkylation reaction of the compound represented by Formula 33 and the amine compound prepared in Step 1 to obtain a compound represented by Formula 34 (step 2); And deprotecting the compound represented by Chemical Formula 34 prepared in Step 2 to obtain a compound represented by Chemical Formula lh (Step 3).
  • R 6 and R 7 are the same as defined in Chemical Formula 1, and R 5 is selected from the group consisting of H, ethyl, (CH 2 ) 3 N (CH 3 ) 2 , toluene and benzene.
  • P is a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc) as a protecting group. ).
  • Step 1 is a step of obtaining a compound represented by Formula 33 by reacting the compound represented by Formula 16 and the compound represented by Formula 32 prepared in Step 5 of Banung Formula 2, wherein Formula 6 is used in Step 6 of Banung Formula 2.
  • the compound represented by Chemical Formula 33 may be obtained by the same method as the method of obtaining the compound represented by 17, but is not limited thereto.
  • step 2 is a step of obtaining a compound represented by the formula (34) by performing an N-alkylation reaction with the compound represented by the formula (33) prepared in step 1 and the amine compound.
  • methane, ethane, acetonitrile, pyridine, tetrahydrofuran or dimethylformamide, etc., which do not adversely affect the reaction can be used, and preferably dimethylformamide can be used.
  • reaction temperature is not particularly limited, but may be performed in a boiling point range of room temperature to the solvent.
  • step 3 is a step of performing a deprotection reaction of the compound represented by the formula (34) prepared in step 2 to obtain a compound represented by the formula lh, which is represented by the formula la in step 8 of the reaction formula 1
  • the compound represented by Chemical Formula lh may be obtained by performing the same process, but is not limited thereto.
  • Another method of preparing a derivative of Formula 1 according to the present invention includes the steps of obtaining a compound represented by Formula 36 by reacting a compound represented by Formula 27 with a compound represented by Formula 35, as shown in Scheme 9 below (Step 1 );
  • step 2 Reacting the compound represented by Chemical Formula 36 and the compound represented by Chemical Formula 37 prepared in Step 1 to obtain a compound represented by Chemical Formula 38 (step 2);
  • Step 4 A process for preparing a compound represented by Chemical Formula li by performing a deprotection reaction of the compound represented by Chemical Formula 39 prepared in Step 3 (Step 4):
  • Step 1 is a step of reacting the compound represented by Formula 27 prepared in Step 2 of Scheme 6 with the compound represented by Formula 35 to obtain a compound represented by Formula 36.
  • the compound represented by Chemical Formula 36 may be obtained by the same method as the method for obtaining the compound represented by 28, but is not limited thereto.
  • step 2 is a step of obtaining a compound represented by the formula 38 by reacting the compound represented by the formula (36) and the compound represented by the formula 37 prepared in step 1, the formula in step 7 of the reaction formula 1
  • the compound represented by Chemical Formula 38 may be obtained by the same method as the method of obtaining the compound represented by 10, but is not limited thereto.
  • Step 3 is a step of obtaining a compound represented by Formula 39 by reacting the compound represented by Formula 38 and the amine compound prepared in Step 2, wherein the compound represented by Formula 33 in Step 2 of Reaction Scheme 8 is obtained.
  • the compound represented by Chemical Formula 39 may be obtained by the same method as the method of obtaining the compound, but is not limited thereto.
  • step 4 is a step of performing a deprotection reaction of the compound represented by the formula (39) prepared in step 3 to obtain a compound represented by the formula li to the compound represented by the formula la in step 8 of the reaction
  • the compound represented by Chemical Formula li may be obtained by the same method as the obtaining method, but is not limited thereto.
  • Another method for preparing a derivative of Formula 1 according to the present invention comprises the steps of obtaining an compound represented by Formula 41 by adding an acid to the compound represented by Formula 40, as shown in the following formula (Step 1);
  • step 2 Performing a 0-alkylation reaction of the compound represented by Chemical Formula 41 and the compound represented by Chemical Formula 42 prepared in Step 1 to obtain a compound represented by Chemical Formula 43 (step 2);
  • Step 5 Deprotection reaction of the compound represented by Formula 45 prepared in step 4 to obtain a compound represented by the formula (lj) (Step 5):
  • R 1 is as defined in Formula 1, R 5 ' is a methyl group, R 10' is morpholine or pyridine, P is a protecting group, benzyloxycarbonyl group (Cbz), t- Subspecific carbonyl group (t— Boc), p-methoxybenzyl group (PMB) or 9-polorenyl methoxycarbonyl group (Fmoc)).
  • P is a protecting group, benzyloxycarbonyl group (Cbz), t- Subspecific carbonyl group (t— Boc), p-methoxybenzyl group (PMB) or 9-polorenyl methoxycarbonyl group (Fmoc)).
  • Step 1 is a step of obtaining a compound represented by the formula 41 by adding an acid to the compound represented by the formula (40).
  • step 2 is a step of obtaining a compound represented by the formula 43 by performing 0-alkylation reaction of the compound represented by the formula 41 and the compound represented by the formula 42 prepared in step 1, the step of the formula 8
  • the compound represented by the chemical formula 43 may be obtained by performing the same method as the method for obtaining the compound represented by the chemical formula 34 in 2, but is not limited thereto.
  • step 3 is a step of obtaining a compound represented by the formula (44) by hydrolyzing the compound represented by the formula (43) prepared in step 2, to obtain a compound represented by the formula (29) in step 4 of the reaction formula 6
  • the compound represented by Chemical Formula 44 may be obtained by the same method as the method, but is not limited thereto.
  • the step 4 is a step of obtaining a compound represented by the formula 45 by reacting the compound represented by the formula (44) prepared in step 3 with the compound represented by the formula (20), Formula 10 in step 7 of the reaction formula 1
  • the compound represented by Chemical Formula 45 may be obtained by the same method as the method of obtaining the compound represented by, but is not limited thereto.
  • step 5 is a step of deprotecting the compound represented by Formula 45 prepared in Step 4 to obtain a compound represented by Formula lj, the compound represented by Formula la in Step 8 of Scheme 1
  • the compound represented by the formula lj may be obtained by the same method as the method for obtaining the compound, but is not limited thereto.
  • another manufacturing method of a derivative of the general formula (I) according to the present invention is to banung formula 11, "step carried out with a compound represented by Formula 46 can selenium oxide and banung for obtaining a compound represented by the formula 47 (step 1 );
  • Step 2 Reacting the compound represented by Chemical Formula 47 and the compound represented by Chemical Formula 20 prepared in Step 1 to obtain a compound represented by Chemical Formula 48 (step 2); And deprotecting the compound represented by Chemical Formula 48 prepared in Step 2 to obtain a compound represented by Chemical Formula lk (Step 3).
  • A, R 1 and R 10 in the reaction formula 11 is as defined in Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p—meth Oxybenzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
  • P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p—meth Oxybenzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
  • Step 1 is a step of obtaining a compound represented by the formula 47 by performing a reaction with the compound ol selenium oxide represented by the formula (46).
  • Pyridine, dimethylformamide, acetonitrile, and the like may be used as the solvent, and pyridine may be preferably used.
  • Step 2 is a step of obtaining a compound represented by Formula 48 by reacting the compound represented by Formula 47 and the compound represented by Formula 20 prepared in Step 1, wherein from step 7 of Scheme 1 to Formula 10 Reaction may be carried out in the same manner as the method for obtaining the compound, to obtain the compound represented by Chemical Formula 48, but is not limited thereto.
  • step 3 is a step of deprotecting the compound represented by Formula 48 prepared in Step 2 to obtain a compound represented by Formula lk, and the compound represented by Formula la in Step 8 of Scheme 1
  • the reaction may be performed in the same manner as to obtain the compound represented by Chemical Formula lk, but is not limited thereto.
  • Another method for preparing a derivative of Formula 1 according to the present invention is to obtain a compound represented by Formula 50 by reacting the compound represented by Formula 49 with the compound represented by Formula 20, as shown in Scheme 12 below (Step 1 );
  • Step 3 A process for preparing a compound represented by Chemical Formula 11 by performing deprotection reaction of the compound represented by Chemical Formula 51 prepared in Step 2 (Step 3):
  • R 10 is selected from the group consisting of H and d- 6 linear alkyl
  • P is a protecting group
  • t- Appendix is a carbonyl group (t-Boc), a P-methoxybenzyl group (PMB) or a 9-fluorenyl methoxy carbonyl group (Fmoc)).
  • t-Boc benzyloxycarbonyl group
  • PMB P-methoxybenzyl group
  • Fmoc 9-fluorenyl methoxy carbonyl group
  • Step 1 is a step of obtaining a compound represented by the formula (50) by reacting the compound represented by the formula (49) and the compound represented by the formula (20), a method of obtaining a compound represented by the formula (10) in step 7 of the reaction formula 1
  • the reaction may be performed in the same manner as described above to obtain a compound represented by Chemical Formula 50, but is not limited thereto.
  • Step 2 is a step of coupling the compound and the alcohol represented by Formula 50 prepared in Step 1 to obtain a compound represented by Formula 51 to the compound represented by Formula 30 in Step 5 of Scheme 6
  • the reaction can be carried out in the same manner as in the obtaining method to obtain a compound represented by Chemical Formula 51, but is not limited thereto.
  • Step 3 is a step of performing a deprotection reaction of the compound represented by Formula 51 prepared in Step 2 to obtain a compound represented by Formula 11, the compound represented by Formula la in Step 8 of the reaction formula 1
  • the compound represented by the formula (11) can be obtained by the same method as the method of obtaining the compound, but is not limited thereto.
  • Another method for preparing a derivative of Formula 1 according to the present invention is to obtain a compound represented by Formula 52 by performing a urea reaction between a compound represented by Formula 16 and an amine compound as shown in Reaction Formula 13 below (Step 1 );
  • Step 3 Deprotection reaction of the compound represented by Formula 53 prepared in Step 2 to obtain a compound represented by Formula lm (Step 3):
  • R 1 and n are as defined in Formula 1, R 10 ' is dimethylamine or morpholine, P is a protecting group, benzyloxycarbonyl group (Cbz), t-addition Nyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • P is a protecting group, benzyloxycarbonyl group (Cbz), t-addition Nyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • Step 1 is a step of performing a urea reaction of the compound represented by the formula (16) and the amine compound prepared in step 1 of Scheme 2 to obtain a compound represented by the formula 52, to the formula 18 in step 1 of the reaction formula 3
  • the reaction represented by Chemical Formula 52 may be obtained by the same method as the method for obtaining the compound, but is not limited thereto.
  • step 2 is a step of obtaining a compound represented by formula 53 by hydrolyzing the compound represented by formula 52 prepared in step 1, the same method as the method of obtaining a compound represented by formula 29 in step 4 of Scheme 6
  • the reaction may be performed to obtain a compound represented by Chemical Formula 53, but is not limited thereto.
  • step 3 is a step of performing a deprotection reaction of the compound represented by Formula 53 prepared in Step 2 to obtain a compound represented by Formula lm.
  • Compound represented by Formula la in Step 8 of Banung Formula 1 The compound represented by the formula lm may be obtained by the same method as the method of obtaining the compound, but is not limited thereto.
  • Another method for preparing a derivative of Formula 1 according to the present invention as shown in the following Scheme 14, by performing a coupling reaction between the compound represented by the formula lb and the compound represented by the formula 54 to obtain a compound represented by the formula (55) Step (step 1); And Further comprising the step (step 2) of performing a deprotection reaction of the compound represented by formula 55 prepared in step 1 to obtain a compound represented by formula In:
  • R 1 , R 9 and R 10 are the same as defined in Chemical Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc), p ⁇ me Methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
  • P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc), p ⁇ me Methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
  • Step 1 is a step of performing a coupling reaction between the compound represented by Formula lb and the compound represented by Formula 54 prepared in Step 7 of Reaction Formula 2 to obtain a compound represented by Formula 55.
  • the compound represented by Chemical Formula 55 may be obtained by performing the same method as the method of obtaining the compound represented by Chemical Formula 30 in step 5, but is not limited thereto.
  • Step 2 is a step of obtaining a compound represented by the formula In by performing a deprotection reaction of the compound represented by Formula 55 prepared in Step 1, the compound represented by the formula la in step 8 of Scheme 1
  • the compound represented by the formula In may be obtained by the same method as the obtaining method, but is not limited thereto.
  • Another method of preparing a derivative of Formula 1 according to the present invention includes the steps of obtaining a compound represented by Formula lo by reacting a compound represented by Formula lb with a compound represented by Formula 56, as shown in Reaction Formula 15 below. Manufacturing method further comprising step 1):
  • Step 1 is a step of obtaining a compound represented by formula lo by reacting the compound represented by Formula lb prepared in Step 7 of Reaction Formula 2 with the compound represented by Formula 56.
  • the compound represented by the formula lo may be obtained by the same method as the method of obtaining the compound represented by 30, but is not limited thereto.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease related to GSK-313 (glycogen synthase kinase-3 ⁇ ) containing a pyrazolo pyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
  • 3 (glycogen synthase kinase— 3) related diseases include dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary tangle Diseases associated with pathology.
  • the pyrazolopyridine derivative represented by the formula (1) according to the present invention shows an excellent IC 50 value of less than 0.1 ⁇ as a result of GSK-3P (glycogen synthase kinase -3 ⁇ ) enzyme inhibition experiment, GSK-3
  • the pyrazolopyridine derivative represented by Formula 1 according to the present invention has an inhibitory effect on the GSK-3P (glycogen synthase kinase-3 ⁇ ) enzyme, which is induced by GSK-3P, Alzheimer's disease, Parkinson's disease, and frontal It can be usefully used to prevent or treat diseases associated with the Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complications, HIV dementia or neurofibrillary pathology.
  • a pharmaceutical composition containing a derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Water may be formulated and administered in various oral or parenteral dosage forms as described below, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc.
  • lubricants e.g. silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcell rose and / or polyvinylpyridine, and optionally starch, agar, alginic acid or its sodium Disintegrants or boiling mixtures such as salts and / or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcell rose and / or polyvinylpyridine, and optionally starch, agar, alginic acid or its sodium Disintegrants or boiling mixtures such as salts and / or absorbents, colorants, flavors, and sweeteners.
  • compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered orally, and parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the pyrazolo pyridine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a vulcanizing agent to prepare a solution or suspension, and the salt or vial unit It may be prepared in a dosage form.
  • the composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, condition and degree of disease of the patient, and preferably 0.01 to 200 rag / In the amount of kg / day can be administered by oral or parenteral route by a predetermined time interval divided by several times a day, preferably once to three times a day, according to the judgment of the doctor or pharmacist.
  • Step 1 Preparation of l- [2- (4—methoxybenzyloxy) phenyl] ethanone
  • Step 2 2,2-dihydroxy Preparation of -l- [2- (4-methoxybenzyloxy) phenyl] ethanone
  • the compound represented by the formula (c-1) prepared in Step 1 (20.0 g, 78.03 'ol) was prepared in 1> 4 -dioxane ( 3 6 was dissolved in a mixed solution of water (1.5), and the reaction mixture was stirred up to 60 ° C.
  • Step 1 Preparation of Sodium) -2-Cyano-3-ethoxy-3-oxoprop-1-ene—1-erlate
  • Ethyl 2-cyanoacetate (100.0 g, 884.01 mmol) was dissolved in ethanol, and then an aqueous solution of sodium ethoxide (2M solution, 486) was slowly added, followed by the addition of ethyl formate (214 2652.05 ⁇ l) and stirred at room temperature for 12 hours. After completion of the reaction, the resulting solid was filtered to obtain a compound represented by Chemical Formula c-2 (100.9 g, reaction yield: 70%, white solid).
  • 3 ⁇ 4 400 400 (400 ⁇ z, DMSO-ok): ⁇ 8.61 (s, 1H), 7.12 (d, ⁇ , 2H), 6.83 (d, J ⁇ .6Hz, 2H), 5.78 (s, 2H), 5.05 (s, 2H), 4.27 (q, J ⁇ 7.2 Hz, 2H), 3.70 (s, 3H), 1.32 (t, J-6.6 Hz, 3H)
  • Step 1 Preparation of ethyl 6—amino—1- (4-methoxybenzyl) -3- (nicotinamido) -1-pyrazolo [3,4-Z>] pyridine-5-carboxylate
  • the compound represented by Chemical Formula 37A (29 mg, 0.09 ⁇ l) prepared in Step 2 was dissolved in 3.7 M hydrochloric acid (2 mi, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After the completion of the semi-ungung, the reaction was filtered under reduced pressure to obtain a compound represented by the formula (19.4 mg, half-water rate: 61%, brown solid).
  • Step 1 Synthesis of [3,4-A] pyridine-5-carboxylate with ethyl l- (4-methoxybenzyl) -6- (methylamino) -3- (nicotinamido) 1-pyrazol
  • Example 37 After dissolving the compound represented by the formula (37) prepared in Example 37 (100.0 mg, 0.44 mmol) in toluene (10), sodium hydroxide dissolved in water at 50% concentration with dimethyl sulfate (4.6 ⁇ , 0.49 ⁇ ol) (50 mg, 1.25 ⁇ l ol) and tetrabutylammonium bromide (14 mg, 0.04 ⁇ l ol) were slowly added and stirred for 48 hours.
  • dimethyl sulfate 4 ⁇ , 0.49 ⁇ ol
  • tetrabutylammonium bromide 14 mg, 0.04 ⁇ l ol
  • Step 1 Preparation of Ethyl 2-butoxycarbonylamino) -6-chloro-5-cyanonicotinate
  • the compound represented by Chemical Formula c-4 (1.04 g, 5.77, ol) prepared in Step 1 was dissolved in methanol (30), and then 10% -palladium (104 mg, 10 wt3 ⁇ 4) was added thereto, followed by 30 minutes under hydrogen gas.
  • the finished reaction mixture was removed with palladium through a celite filter and the solvent was concentrated under reduced pressure to obtain a compound represented by Chemical Formula a-4 (802 mg, reaction yield: 93 ⁇ 4, yellow liquid) without purification.
  • Step 1 l- ⁇ 4-[(dimethylamino) methyl] phenyl ⁇ -3— [l- (4-methoxybenzyl) -5 (4—methoxyphenyl) -L pyrazolo [4, 3-Z >] Synthesis of Pyrazin-3-yl] urea
  • the compound represented by Chemical Formula 95A-a prepared in Step 2 (34 mg, 0.06 ′ ol) was dissolved in trifluoroacetic acid (5), and stirred at 100 ° C. for 5 days. After cooling to room temperature, the reaction was terminated with a cold saturated aqueous sodium bicarbonate solution, and the reaction product was filtered under reduced pressure to obtain a compound represented by the formula (95A) (10 mg, water repellency: 36.5%, brown solid).
  • the compound represented by Chemical Formula 95A (9 mg, 0.02 Korean ol) prepared in step 3 was dissolved in 3.7 M hydrochloric acid (2 pi ⁇ , 1,4-dioxane solution), and stirred at room temperature for 12 hours. After the reaction was completed, the reaction product was filtered under reduced pressure to obtain a compound of Formula 95 (8 mg, reaction rate: 83 ⁇ 4, brown solid).
  • Step 1 Preparation of () -4- [3- (1,3-dioxolan-2-yl) prop-1-enyl] pyridine
  • the compound represented by Chemical Formula 96A (35 mg, 0.06 ⁇ l) prepared in step 1 was dissolved in 3.7 M hydrochloric acid (2,1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 96 (11.2 mg, reaction yield: 483 ⁇ 4, ivory solid).
  • the compound represented by the formula 106A-a prepared in Step 1 (1.0 g, 2.10 mmol) was dissolved in ethanol (20) and water (2 m ⁇ , and then potassium hydroxide (590 mg, 10.50 mmol) was added thereto, and 80 The mixture was stirred at reflux for 2 hours at ° C. After completion of reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, the aqueous layer was acidified with 1 hydrochloric acid solution, and extracted again with ethyl acetate. After drying with magnesium, the solvent was concentrated under reduced pressure to obtain a compound represented by Chemical Formula 106A-b (450 mg, reaction yield: 47%, white solid).
  • the compound represented by Chemical Formula 106A-b prepared in Step 2 (100 mg, 0.22 mmol) was dissolved in cydimethylformamide (3), and then pyridin-3-yl-methanol (0.03 ml, 0.33 ⁇ ol) and 1- Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC, 86 mg, 0.44 mmol) and 1-hydroxy-benzotriazole hydrate (HOBt, 61 mg, 0.44 mmol), and Isopropylethylamine (0.16 ml, 0.89 mmol) was added, followed by stirring at room temperature for 12 hours After completion of reaction, the mixture was extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure.
  • EDC Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride
  • the compound represented by Chemical Formula 106A-C prepared in Step 3 (35 mg, 0.06 ⁇ l) was dissolved in trifluoroacetic acid (3 i), and then placed in a shielded tube for 2 hours at 90 ° C. Stirred. After cooling to room temperature, the mixture was concentrated under reduced pressure. Ethyl acetate was added and the resulting solid was filtered and washed again with ethyl acetate to obtain the compound represented by the chemical formula 106A (20 mg, reaction yield: 82%, white solid).
  • the compound represented by Chemical Formula 106A prepared in Step 4 (20 mg, 0.04 ⁇ ol) was dissolved in 1> 4 -dioxane Q ⁇ £), and 3 / 7M hydrochloric acid 1,4-dioxane solution (1 was added thereto). After stirring for 24 hours, the solvent was concentrated under reduced pressure, and ethyl acetate and diethyl ether were added to the residue, which was then stirred for 30 minutes, filtered, and washed with diethyl ether to obtain a compound represented by Chemical Formula 106 ( 17 mg, reaction yield: 79%, green solid).
  • the compound represented by Formula 112A-b prepared in Step 1 (100 mg, 0.19 mmol) was dissolved in -dimethylformamide (3), and then dimethylamine (145 /, 0.29 ⁇ l) and 1-ethyl-3- ( 3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC, 56 mg, 0.28 ⁇ l ol) and dimethylaminopyridine (4.7 mg, 0.04 ⁇ l ol) were added and stirred at room temperature for 24 hours.
  • EDC 1-ethyl-3- ( 3-dimethylaminopropyl) -carbodiimide hydrochloride
  • dimethylaminopyridine 4.7 mg, 0.04 ⁇ l ol
  • the compound represented by Chemical Formula 112A prepared in Step 3 (16 mg, 0.05 mmol) was dissolved in 3.7M hydrochloric acid (2 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 112 (6.3 mg, reaction yield: 35%, brown solid).
  • Step 1 ethyl secondary carbonylamino) -3- [4- (2—chloroethyl) benzamido] -1- (4—methoxybenzyl) -Ly-pyrazolo [3,4-b] pyridine- Preparation of 5-carboxylate
  • the compound represented by the formula 113A (36 mg, 0.06 mmol) prepared in the step 2 was represented by the formula 113 using the reactions of Steps 2 to 3 of Example 37 (15 mg, the semi-water yield: 58%, ivory color) Solid).
  • the compound represented by the formula (119A) prepared in the step 2 (32 mg, 0.06 ⁇ l) was represented by the formula (119) by the method of Steps 2 to 3 of Example 37 (10.2 mg, the semi-shallow rate: 44%, gray Solid)
  • Step 1 Ethyl 6-amino-1- (4-methoxybenzyl) -3- (4- (pyridin-3-ylmethoxy) benzamido) —pyrazolo [3, -Mpyridine-5-carboxylate Produce
  • reaction mixture was extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was concentrated under reduced pressure, and then washed with ethyl ether.
  • the compound represented by (120 mg, half-water yield: 74%, white solid) was obtained.
  • the compound represented by Chemical Formula 121A-a prepared in Step 1 120 mg, 0.21 ⁇ ol) ol was dissolved in ethanol (10) and water (1.5), followed by addition of potassium hydroxide (76 mg, 1.35 ⁇ ol) 80 It was stirred at reflux for 2 hours at ° C. After completion of reaction, the mixture was cooled to room temperature, extracted with ethyl acetate, the aqueous layer was acidified with 1 hydrochloric acid solution, and extracted again with ethyl acetate. The organic solvent layer was dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure to obtain a compound represented by Chemical Formula 121A-b (82 mg, half-water yield: 74 3 ⁇ 4, white solid).
  • the compound represented by Chemical Formula 121A-b prepared in Step 2 (80.0 mg, 0.13 ⁇ l) was dissolved in dimethylformamide (3), and then pyridin-3-yl methanol (0.02 m ⁇ , 0.19 mmol) and 1- Ethyl— 3— (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC, 58 mg, 0.30 mmol) and 1-hydroxy-benzotriazole hydrate (HOBt, 41 mg, 0.30 mmol), and diisopropyl Ethylamine (0.11 0.61 Pa ol) was added, followed by stirring at room temperature for 12 hours.
  • EDC 1- Ethyl— 3— (3-dimethylaminopropyl) -carbodiimide hydrochloride
  • HOBt 1-hydroxy-benzotriazole hydrate
  • the compound represented by Chemical Formula 121A-C prepared in Step 3 (20 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (3 mO, and then put in a shielded tube, followed by stirring at 90 ° C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure, ethyl acetate was added, and the produced solid was filtered and washed again with ethyl acetate (12 mg, reaction yield: 75%, white solid).
  • the compound represented by Chemical Formula 121A (12 mg, 0.02 mmol) prepared in Step 4 was dissolved in 1! 4 -dioxane ⁇ ⁇ , and then 3.7 M hydrochloric acid (2 1,4-dioxane solution) was added. After stirring for 24 hours, the solvent was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, which was then concentrated under reduced pressure, stirred for 30 minutes, filtered and washed with diethyl ether to obtain the compound represented by Chemical Formula 121 (9.0 mg, reaction yield: 653 ⁇ 4, green solid). Got it.
  • Step 1 Ethyl 6- (butoxycarbonylamino) -3- [3- (nuxyloxysulfonyl) benzamido] 1- (4-methoxybenzyl) — L—pyrazole [3, 4->] Preparation of Pyridine-5-carboxylate
  • the compound represented by Formula 136A-a prepared in Step 1 (26 mg, 0.05 mmol) was dissolved in ethanol (7 m «, followed by addition of water (1.2 m « and potassium hydroxide (6.3 mg, 0.16). ⁇ ol) and then stirred at 80 ° C for 2 hours. Water (5 m £) and ethyl acetate (10) were added and extracted with water. Acidified with LV hydrochloric acid and extracted with ethyl acetate. Washed with brine, dried over anhydrous sodium sulfate, filtered and dried to obtain the compound represented by the chemical formula 136A-b (20 mg, reaction yield: 80%, white solid).
  • Step 1 Preparation of ethyl 6-amino-1- (2- ( ⁇ butoxycarbonylamino) acetyl) -3- (nicotinamido) pyrazolo [3, 4->] pyridine-5-carboxylate
  • Example 37 The compound represented by the formula (37A) prepared in step 2 (50 mg, 0.15 ⁇ l) was dissolved in ⁇ dimethyldimethylformamide (5, and then 1-ethyl-3— (3-dimethylaminopropyl) -carr Bodyimide hydrochloride (EDC, 39 mg, 0.20 mmol), 1-hydroxy-benzotriazole hydrate (27 mg, 0.20 ⁇ l ol) and cdimethylethylenediamine (22 ⁇ g, 0.20 ⁇ l ol) were added and 15 hours The reaction was terminated with a saturated aqueous sodium bicarbonate solution, extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and a small amount of diethyl ether was added to the residue. Filtration under reduced pressure gave a compound represented by Chemical Formula 137A (12.3 mg, reaction yield: 22%, ivory solid).
  • EDC 1-ethyl-3— (3
  • Step 1 Preparation of [3,4->] pyridine-1,5-dicarboxylate with 5-ethyl 1-phenyl 6-amino-3- (nicotinamido) pyrazolo
  • step 1 The compound (45 mg, 0.10 mg ol) prepared in step 1 was dissolved in 3.7M hydrochloric acid (2 ml, 1,4-dioxane solution) and stirred for 12 hours at silver. After completion of the reaction, the reaction mixture was filtered under reduced pressure to obtain the title compound (34 mg, semi-water yield: 34%, gray solid).
  • Step 1 Preparation of ethyl 6-amino-1 — (3— (dimethylamino) propyl) -3- (nicotinamido) lazolo [3, 4-b] pyridine-5-carboxylate
  • Example 37 The compound represented by Chemical Formula 37A (100 mg, 0.31 mmol) prepared in Step 1 was dissolved in ⁇ -dimethylformamide (2), and then 3 ⁇ chloropropyl (dimethyl) amine (41 mg, 0.34 mmol) was used. Calcium carbonate (128 mg, 0.93 ⁇ l) was added slowly and then stirred at 70 ° C. for 5 hours. After completion of reaction, water and dichloromethane were added to the reaction mixture, and the separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure and washed with ethyl acetate (41 mg, reaction yield). : 33%, brown solid). NMR (400 MHz, DMSO- ⁇ ); ⁇ 11.38 (s, 1 H), 9.16 (s, 1 H), 8.94 (s, 1 H),
  • Step 1 Preparation of 6- (4-methoxyphenyl) -2-oxo-1,2-dihydropyridine-3-carbonitrile 4-methoxyacetophenone (1.0 g, 6.66 'ol) To vV, V-dimethylformamide dimethyl acetal (4.4 ⁇ , 33.30 ⁇ ol) was added at room temperature, followed by stirring under reflux for 12 hours. After completion of reaction, the reaction was cooled to room temperature and concentrated under reduced pressure.
  • Example 152 The compound represented by Chemical Formula 152 (13 mg, 0.04 ⁇ l) obtained in Example 152 was dissolved in dichloromethane (2 and 1M borontribromide dichloromethane solution (0.2) and stirred at room temperature for 12 hours. The reaction mixture was terminated and neutralized with an aqueous solution of sodium hydroxide, and the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 153 (9 mg, reaction yield: 76%, yellow solid).
  • GSK-3P enzyme inhibitory activity of the compounds prepared in the above examples was obtained from recombinant human GSK-3P (Cat No. 14-306) and phosphorylated GSK-3 substrate (GS2, Cat No. 12-241) purchased from Upstate. ) Was assayed as follows with reference to the manufacturer's protocol.
  • GSK-3P enzyme (lng / well), 6.67 uM phospho-glycogen synthase peptide, in various concentrations of Example compounds at a final concentration of 1% DMS0 in Corning's 96 well round bottom plate (Cat No. 3365) at room temperature.
  • Reaction buffer containing 2 (GS2, YRRMVPPSPSLSRHSSPHQ (pS) EDEEE) (12 mM MOPS (pH 7.0), ImM DTT, ImM EDTA, 100 mM MgCl 2 ] and enzyme buffer (2 mM MOPS (pH 7.0), O .OlmM EDTA, 0.001% Brij-35, 0.5% glycerol, O.lmg BSA, 0.01% 2-mercaptoethanol] was preliminarily reacted for 10 minutes at 30 ° C. After 10 minutes, 0.2 uCi ( 33 P_ATP] and labeling Uncoated luM ATP was added and reacted for 30 minutes at 30 ° C.
  • the reaction was then terminated by adding 3% phosphoric acid to the plate Amount of phosphorylation formed by GSK-3I3 enzyme ⁇ cell harvester (IN0TECH Co., Ltd.) , Model name IH— 110) 3 ml of scintillation cocktail on a Liquid Scintillation counter (Wallac, Model 1409), then delivered to P81 cation exchange filter paper (Whatman, Cat No. 3698-915), washed four times with 0.5% phosphoric acid and finally with acetone. (PerkinElmer, Cat No. 1205-440).
  • the derivatives of the present invention inhibit GSK-3JP to prevent or prevent dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam's Parkinson's dementia complications, HIV dementia or neurofibrillary pathology. It can be usefully used for treatment.
  • H4IIE H4IIE (ATCC, CRL154) cells were seeded in 96 well tissue culture plates at 100,000 cells / well in 0.1 cell culture medium (DMEM medium / 10% dialyzed fetal bovine serum) per well at 37 ° C, 5% C0 2 Incubated for 3 hours under the culture conditions. After 3 hours, washed once with 0.1 PBS (phosphate buffered water) and exchanged with 0.1 glucose producing medium (DMEM medium without glucose and serum, containing 20 mM sodium lactate and 2 mM sodium pyruvate). Then incubated for 21 hours.
  • DMEM medium phosphate buffered water
  • the cells were exchanged for 90 ⁇ fresh glucose producing medium, and the compounds diluted at each concentration were dissolved in glucose producing medium, added 10 ⁇ each, and incubated for 24 hours.
  • the supernatant 10 ⁇ and the 1 ⁇ 2plex Red reaction solution (Amplex Red Glucose Assay Kit; Invitrogen) were mixed and reacted in a 384 well plate for 30 minutes at room temperature, followed by fluorescence (Ex 560 nm, Em 615 nm). , Turku, Finland).
  • fluorescence Ex 560 nm, Em 615 nm). , Turku, Finland.
  • the concentration of compound (IC 50 ) that inhibits glucose producing activity to 50% of DMS0 alone was determined by fitting to the sigmoidal curve for the graphed data.
  • a comparative experiment was performed using SB415286 (Sigma), which is commercially available as described above, as a control.
  • the experimental results are shown in Table 13 below (where M represents IC 50 's ⁇ 5.0yM, A represents IC 50 's ⁇ 10yM and B represents IC 50 's> 10yM).
  • M represents IC 50 's ⁇ 5.0yM
  • A represents IC 50 's ⁇ 10yM
  • B represents IC 50 's> 10yM
  • the derivatives of the present invention inhibit GSK-3I3 to prevent diseases associated with dementia, Alzheimer's disease, Parkinson's disease, Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complications, HIV dementia or neurofibrillary pathology. Or may be usefully used for treatment.
  • the pyrazolo pyridine derivative represented by Formula 1 according to the present invention According to the purpose, it can be formulated in various forms. Below is the chemical formula according to the invention

Abstract

The present invention relates to a novel pyrazole pyridine derivative or pharmaceutically acceptable salts thereof, to a method for producing same, and to a pharmaceutical composition including same. The novel pyrazole pyridine derivative of the present invention inhibits GSK-3β, and can be effectively used to prevent or treat disorders related to dementia, Alzheimer's disease, Parkinson's disease, frontotemporal dementia parkinsonism, Guam Parkinson-dementia complex, HIV dementia, or neurofibrillary tangle pathology.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
신규한 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용가능한 염， 이의 제조방법 및 이를 포함하는 약학적 조성물  Novel pyrazolopyridine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition comprising the same
【기술분야】 Technical Field
본 발명은 신규한 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용가능한 염， 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다.  The present invention relates to a novel pyrazolo pyridine derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition comprising the same.
【배경기술】 Background Art
글리코겐 합성효소 키나아제 -3(GSK-3)은 뇌에서 고도로 발현되는 세린 /트레 오닌 단백질 키나아제로， 각각 상이한 유전자에 의해 코딩되는 α 및 β 이성체형 으로 구성된다 (Wood gett JR., EMBO J. , 9(8)， 2431-2438, 1990). 분자량이 각각 51 및 47 kDa인 GSK-3 α 및 GSK-3P는 85% 서열 동등성을 갖고， 키나제 촉매 도 메인내에서 97% 서열 유사성을 공유한다 (Ali A. , et al .， Chem Rev., 101, 2527-2540, 2001).  Glycogen synthase kinase-3 (GSK-3) is a highly expressed serine / threonine protein kinase in the brain, consisting of the α and β isoforms encoded by different genes (Wood gett JR., EMBO J., 9 (8), 2431-2438, 1990). GSK-3 α and GSK-3P having molecular weights of 51 and 47 kDa, respectively, have 85% sequence equivalents and share 97% sequence similarity in the kinase catalyst domain (Ali A., et al., Chem Rev., 101, 2527-2540, 2001).
GSK-3는 원래 글리코겐 생성에 관여하는 글리코겐 합성효소 (glyco gen synthase, gS)를 직접 인산화시켜서 활성화를 억제하는 효소로서 확인되었다 (Embi N. , et al . , Eur J Biochem. , 107, 519-527, 1980； Hemmin gs BA. , et al. , Eur J Biochem. , 119, 443-451, 1981).  GSK-3 was originally identified as an enzyme that inhibits activation by directly phosphorylating glycogen synthase (gS) involved in glycogen production (Embi N., et al., Eur J Biochem., 107, 519- 527, 1980; Hemmin gs BA., Et al., Eur J Biochem., 119, 443-451, 1981).
이후， 글리코겐 합성효소 이외에도 다수의 조절 단백질을 인산화하여 이의 활성을 조정하는 것으로 알려져 있다 (Wood gett JR. , et al . , Biochem Soc Trans. , 21， 905-907, 1993； grimes CA. , et al . , Pro g Neurobiol. , 65， 391-426, 2001； Ali A., Chem Rev. , 101， 2527-2540, 2001). 이들 중， 대사 단백질 및 신호전달 단 백질로서 아밀로이드 전구 단백질 (APP), 번역개시 인자 eIF-2B, ATP 시트레이트 리 아제 (ATP citrate lyase), 액신 (Axin), 및 인술린 수용체 기질 -l(IRS-l)이 있고 구 조 단백질로서 미소관 -관련 단백질 타우 (Tau)가 속하고 전사인자로서 β-카테닌 (β -catenin), 활성인자 단백질 -l(AP-l), 시클릭 AMP 반웅 원소 결합 단백질 (CREB 활성화된 T—세포의 핵인자 (NFAT), 열 충격 인자 -l(HSF-l), c-Jun, c_Myc, 및 NFK B가 포함되어 있다 (Eldar-Finkelman H. , Trends Mol Med. , 8(3), 126-132, 2002) . 이러한 다양한 표적들은 세포 대사, 증식, 분화 및 생존의 조절에 있어서 GSK-3과 연관되어 있다.  Since then, in addition to glycogen synthase, phosphorylation of a number of regulatory proteins is known to modulate their activity (Wood gett JR., Et al., Biochem Soc Trans., 21, 905-907, 1993; grimes CA., et al. , Pro g Neurobiol., 65, 391-426, 2001; Ali A., Chem Rev., 101, 2527-2540, 2001). Among these, amyloid precursor protein (APP), translation initiation factor eIF-2B, ATP citrate lyase, Axin, and insulin receptor substrate -l (IRS) as metabolic and signaling proteins. -l) and belong to microtubule-related protein Tau as a structural protein, β-catenin as a transcription factor, activator protein -l (AP-l), cyclic AMP reaction element binding Protein (CREB activated T-cell nuclear factor (NFAT), heat shock factor -l (HSF-l), c-Jun, c_Myc, and NFK B (Eldar-Finkelman H., Trends Mol Med. , 8 (3), 126-132, 2002) These various targets are associated with GSK-3 in the regulation of cell metabolism, proliferation, differentiation and survival.
GSK-3의 억제는 인슐린 저항성 치료 및 제 2형 당뇨병의 치료에 효과를 발휘 할 수 있다 (Kaidanovich 0.， et al , Expert Opin Ther Tar gets, 6， 555-561, 2002). 당뇨병은 인술린 작용의 부족에 의한 만성 고혈당증을 특징으로 하는 대사 이상 질환으로 크게 인슐린 .의존성의 제 1형 당뇨병과 인슐린 비의존성의 제 2형 당 뇨병으로 나눌 수 있다. 제 1형 당뇨병은 췌장 β세포의의 파괴로 인슐린이 결핍되 어 생기는 병이고 제 2형 당뇨병은 인슐린 분비 저하와 인슐린 저항성으로 발생한 다. 일반적으로 제 1형 당뇨병은 감소 또는 거의 존재하지 않는 수준의 인술린과 연 관되어 있으므로 대체 용량의 인슐린을 주사로 투여하여 치료한다. GSK-3의 활성 으로 인슐린 수용체 기질 -KIRS-1) 세린 잔기를 인산화하여 인슐린 작용을 손상시 키며 글리코겐 합성효소의 활성을 억제시킴으로써 세포내 인슬린 영향을 약화 시킨 다 (Eldar-Finkelman Η.， et al .， PNAS, 94, 9660-9664, 1997) . 더욱이 게 2형 당뇨 병 환자의 근육에서 GSK-3이 과발현 된다는 보고도 있다 (Nikoulina SE., et al . , Diabetes, 49(2)， 263-271, 2000) . 따라서ᅳ GSK-3억제는 인슐린 활성을 증가시키 는 당뇨병 치료에 유용하다. Inhibition of GSK-3 may be effective in the treatment of insulin resistance and in the treatment of type 2 diabetes (Kaidanovich 0., et al, Expert Opin Ther Tar gets, 6, 555-561, 2002). Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia due to lack of insulin action and can be divided into insulin-dependent type 1 diabetes and insulin-independent type 2 diabetes. Type 1 diabetes is caused by insulin deficiency due to the destruction of pancreatic β cells. Type 2 diabetes is caused by decreased insulin secretion and insulin resistance. In general, type 1 diabetes is associated with decreased or almost insignificant levels of insulin, so treatment is by injection of an alternate dose of insulin. The activity of GSK-3 phosphorylates the insulin receptor substrate -KIRS-1), which impairs insulin action and attenuates intracellular insulin effects by inhibiting glycogen synthase activity (Eldar-Finkelman Η., Et al., PNAS, 94, 9660-9664, 1997). Furthermore, type 2 diabetes It has also been reported that GSK-3 is overexpressed in the muscles of diseased patients (Nikoulina SE., Et al., Diabetes, 49 (2), 263-271, 2000). Therefore, GSK-3 inhibitors are useful for the treatment of diabetes that increases insulin activity.
GSK-3 활성은 알츠하이머 질환과도 관련되어 있다. 알츠하이머병이란 퇴행 성 뇌질환으로 노인에게 주로 나타나는 치매를 일으키는 대표적인 질환이다. 이 질 환은 아밀로이드 전구물질 단백질 (APP)의 비정상적인 산물인 β-아밀로이드 펩티드 (Αβ)의 축적과 과인산화된 타우 (tau) 단백질로 대부분 구성되어 짝지어진 나선형 필라멘트 (paired helical filament, PHF)의 형성을 특징으로 한다. 타우는 중추 및 말초신경계에서 크게 발현되며 특히 뉴런의 축색돌기에 다량 존재하여 축색 및 수 상돌기 구획을 형성하기 위한 구조적인 지지체를 제공하는 미세관의 안전성을 향상 시키는 단백질로 6개의 단백질 이성체로 구성된다. 타우 이성질체는 단일 유전자 에서 또다른 mRNA 접합으로부터 형성되어， 50 내지 70kDa 범위의 분자량을 갖는다. GSK-3에 의한 타우의 비정상적인 위치에서의 인산화는 신경섬유 다발 (Neurofibrillary tan gles)을 형성하는 필라멘트 (PHF)를 촉진하는 것으로 나타났 다 (Han ger DP. , et al. , Neurosci Lett. , 147(1)， 58-62, 1992； Mandelkow EM. , et al. , FEES.314(3), 315-321, 1992; Loves tone S.， et al .， Curr Biol. , 4(12)， 1077-1086, 1994； Mulot SF. , et al . , Biochem Soc Trans. , 23(1), 45S, 1995； Baum L. , et al .， Mol Chem Neuropathol. , 29, 253-261, 1996). 추가적인 증거로 GSK-3를 특이적으로 과발현시킨 형질전환 마우스에서， 현저히 증가된 타우의 과인 산화 및 비정상적인 형태의 신경세포가 발견되었다 (Lucas JJ., et al . , ΕΜΒΟ J. , 20, 27-39, 2001) . 따라서， GSK-3의 억제는 타우의 과인산화를 방지하여 신경섬유 다발의 형성을 완화 또는 제어함으로써 알츠하이머 질환을 치료할 수 있다.  GSK-3 activity is also associated with Alzheimer's disease. Alzheimer's disease is a degenerative brain disease and is a representative disease that causes dementia in the elderly. The disease consists mainly of the accumulation of β-amyloid peptide (Αβ), an abnormal product of the amyloid precursor protein (APP), and the formation of paired helical filaments (PHFs), composed mostly of hyperphosphorylated tau protein. It features. Tau is highly expressed in the central and peripheral nervous system and is a protein that enhances the safety of microtubules, which is present in large quantities in axons of neurons and provides structural support for forming axons and dendritic compartments. It consists of six protein isomers. do. The tau isomer is formed from another mRNA junction in a single gene and has a molecular weight ranging from 50 to 70 kDa. Phosphorylation at abnormal locations of tau by GSK-3 has been shown to promote filaments (PHF), which form neurofibrillary tan gles (Han ger DP., Et al., Neurosci Lett., 147). (1), 58-62, 1992; Mandelkow EM., Et al., FEES.314 (3), 315-321, 1992; Loves tone S., et al., Curr Biol., 4 (12), 1077 -1086, 1994; Mulot SF., Et al., Biochem Soc Trans., 23 (1), 45S, 1995; Baum L., et al., Mol Chem Neuropathol., 29, 253-261, 1996). As additional evidence, a significantly increased tau overphosphorylation and abnormal types of neurons were found in transgenic mice that specifically overexpress GSK-3 (Lucas JJ., Et al., ΕΜΒΟ J., 20, 27- 39, 2001). Therefore, inhibition of GSK-3 can treat Alzheimer's disease by preventing hyperphosphorylation of tau to mitigate or control the formation of nerve fiber bundles.
양극성 장애 (Bipolar disorder)는 조증 상태 및 우울증 상태를 특징으로 한 다. 이 질환의 치료제로 사용되어 왔던 리튬은 GSK-3 억제제인 것으로 밝혀졌다( Klein PS. , et al, PNAS, 93, 8455-8459, 1996； Stambolic V. , et al. , Curr Biol., 6(12)， 1664-1668, 1996； Phi el CJ. , et al . , Annu Rev Pharmacol Toxicol. , 41， 789-813, 2001).  Bipolar disorder is characterized by mania and depression. Lithium, which has been used as a therapeutic agent for this disease, has been found to be a GSK-3 inhibitor (Klein PS., Et al, PNAS, 93, 8455-8459, 1996; Stambolic V., et al., Curr Biol., 6) 12), 1664-1668, 1996; Phi el CJ., Et al., Annu Rev Pharmacol Toxicol., 41, 789-813, 2001).
리튬에 의한 영향으로 글리코겐 합성의 활성화 (Chen g K. , et al .， Mol Cell Biochem. , 56(2), 183-189, 1983), β-카테닌의의 안정화 및 축적 (Stambolic V. , et al., Curr Biol., 6(12), 1664-1668, 1996)， 신경세포사의 보호 (Bijur gN.， et al., JBC, 275(11), 7583-7590, 2000]가 보고된 바 있다.  Activation of glycogen synthesis under the influence of lithium (Chen g K., et al., Mol Cell Biochem., 56 (2), 183-189, 1983), stabilization and accumulation of β-catenin (Stambolic V., et. al., Curr Biol., 6 (12), 1664-1668, 1996), protection of neuronal cell death (Bijur gN., et al., JBC, 275 (11), 7583-7590, 2000). .
또한， 통상적으로 사용되는 양극성 장애 치료제인 발프로인산이 효과적인 GSK-3 억제제인 것으로 알려졌다 (Chen g. , et al . , J Neurochemistry, 72， 1327-1330, 1999). 이러한 GSK-3 억제제에 의한 메카니즘은 신경전달 물질인 글루 타메이트에 의해 유도된 비정상적으로 높은 수준의 흥분된 신경세포의 생존을 증가 시키는 것이다 (Nonaka S.， et al . , PNAS 95, 2642-2647, 1998).  Valprophosphate, a commonly used bipolar disorder treatment, is also known to be an effective GSK-3 inhibitor (Chen g., Et al., J Neurochemistry, 72, 1327-1330, 1999). The mechanism by this GSK-3 inhibitor is to increase the survival of abnormally high levels of excited neurons induced by the neurotransmitter glutamate (Nonaka S., et al., PNAS 95, 2642-2647, 1998).
글루타메이트에 의해 유도된 신경세포의 홍분독성은 뇌허혈， 외상성 뇌손상 및 세균성 감염에서와 같은 급성 손상과 관련되어 있는 신경변성의 주된 원인인 것 으로 여겨지고 있다. 또한， 과도한 글루타메이트 신호화는 알츠하이머병， 헌팅톤 병, 파킨슨병， 에이즈관련 치매， 근위축성 측삭 경화증 (ALS) 및 다발성 경화증 (MS) 과 같은 질환에서 나타나는 만성적 신경손상의 한 요인인 것으로 여겨진다 (Thomas l, J Am ger i at r Soc. , 43(11), 1279-1289, 1995) . 따라서， GSK-3 억제제는 이 들 및 다른 신경변성 장애에서 유용한 치료제가 될 것이다. GSK-3은 또한 면역반응 활성화와도 관련이 있다. 전사인자 NF-AT를 탈인산화 하여 핵으로의 이동을 촉진하여 초기의 면역반웅 유전자의 전사를 활성화시키는 칼 시뉴린의 효과와는 반대로 GSK-3은 NF-AT를 인산화하여 핵으로부터 빠져나오는 것 을 촉진하여 NF-AT에 의한 면역반응 유전자의 활성화를 초기에 차단하게 된다 ( Beals CR., et al. , Science, 275, 1930-1934, 1997). 따라서， GSK-3 억제제는 어 떤 시토카인의 면역자극 효과를 연장 및 강화한다고 여겨지며, 그러한 효과는 종양 면역치료나 또는 실제로 일반적인 면역치료법에 대한 이들 시토카인의 잠재력을 증 진 시킬수 있다. Glutamate toxicity of neurons induced by glutamate is believed to be a major cause of neurodegeneration associated with acute injury such as cerebral ischemia, traumatic brain injury and bacterial infection. In addition, excessive glutamate signaling is believed to be a factor in chronic neurological damage in diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). l, J Am ger i at r Soc., 43 (11), 1279-1289, 1995). Thus, GSK-3 inhibitors will be useful therapeutics in these and other neurodegenerative disorders. GSK-3 is also associated with immune response activation. Contrary to the effect of calcineurin, which dephosphorylates the transcription factor NF-AT and promotes its migration to the nucleus, activating the transcription of early immune response genes, GSK-3 phosphorylates NF-AT and escapes from the nucleus. Promotes early blocking of activation of immune response genes by NF-AT (Beals CR., Et al., Science, 275, 1930-1934, 1997). Thus, GSK-3 inhibitors are believed to prolong and enhance the immunostimulatory effects of certain cytokines, which may enhance the potential of these cytokines for tumor immunotherapy or indeed for general immunotherapy.
그 외에도， GSK-3는 유방암， 대장암, 갑상선암， T또는 B세포 백혈병 및 여 러 바이러스에 의해 유도된 종양 (Eastman Q., et al. , Curr Opin Cell Biol. , 11， 233-240, 1999； Shakoori A. , et al . , Cancer Sci. , 98(9)， 1388-1393, 2007； unnimalaiyaan M.， et al., Mol Cancer Ther. , 6(3), 1151-1158， 2007； Holmes T., et al., Curr Med Chen]., 15(15)， 1493-1499, 2008； Manoukian AS. , et al. , Adv Cancer Res. 84, 203-229, 2002), 심장 비대증 (Badorff C. , et al. , J Clin Invest, 109, 373-381, 2002； Haq S. , et al . , J Cell Biol. , 151， 11그 129， 2000; Ton g H.( et al .， Circulation Res. , 90， 377-379, 2002)， 모발 손실 (Fuchs E.， et al., Develop Cell, 1, 13-25, 2001) 및 비만 (Orena SJ. , et al. , JBC, 275, 15765-15772, 2000) 을 비롯한 많은 질환의 치료에서 중요한 잠재성을 갖는다. In addition, GSK-3 is a tumor that is induced by breast cancer, colon cancer, thyroid cancer, T- or B-cell leukemia and several viruses (Eastman Q., et al., Curr Opin Cell Biol., 11, 233-240, 1999). Shakoori A., et al., Cancer Sci., 98 (9), 1388-1393, 2007; unnimalaiyaan M., et al., Mol Cancer Ther., 6 (3), 1151-1158, 2007; Holmes T , et al., Curr Med Chen]., 15 (15), 1493-1499, 2008; Manoukian AS., et al., Adv Cancer Res. 84, 203-229, 2002), cardiac hypertrophy (Badorff C. , et al., J Clin Invest, 109, 373-381, 2002; Haq S., et al., J Cell Biol., 151, 11 he 129, 2000; Ton g H. ( et al., Circulation Res. , 90, 377-379, 2002), hair loss (Fuchs E., et al., Develop Cell, 1, 13-25, 2001) and obesity (Orena SJ., Et al., JBC, 275, 15765-15772 , 2000) have important potential in the treatment of many diseases, including.
상기 언급된 조증 또는 양극성 장애 질환 치료제로서 사용되고 있는 리튬은 GSK-3에 대해 비특이적인 억제제로 이노시를 모노포스파타제 (IMPase) 및 이노시를 폴리포스페이트 포스파타제 (IPPase)와 같은 다른 표적도 억제하는 것으로 알려져 있다 (Williams RSB. , et al. , Trends in Pharmacol Sci. , 21, 61-64, 2000) . 최근 GSK-3를 특이적으로 억제시키는 많은 다양한 구조의 억제제 중에서 Noscira, S.A(formerly Neuropharma , S.A.)에서 개발한 Nypta(NP-12, NP031112)가 알츠하이머병 또는 신경퇴행성 질환 치료제로 임상 2상 개발 중에 있다. Nypta(NP-12)는 티아디아졸리디논 (TDZD) 유도체로서 ATP에 비경쟁적인 GSK—3 억제 제이다. Noscira, S.A에서 개발한 다른 GSK-3 억제제로서 NP103은 알츠하이머병 치료제로 전임상 개발 중에 있다. ATP에 경쟁적인 GSK-3 억제제로는 glaxoSmithKline사에서 개발한 SB216763 및 SB_415286(Cross DAE. , et al. , J Neurochemistry, 77, 94-102， 2001]이 당뇨병과 뇌졸중 치료제로， Chiron사의 CHIR98023 및 CHIR9902K미국특허출원 US20020156087; Cline gW. , et al . , Diabetes, 51, 2903-2910, 2002]이 당뇨병 치료제로， CNRS의 Aloisine A(Mapelli M. , et al. , J Med Chew. , 48, 671-679, 2005]와 Alsterpaul lone(Leost M. , et al., Eur J Biochew. , 267， 5983-5994, 2000]은 항암제로 전임상 개발되고 있다. 그 외에 AstraZeneca사의 AR-A014418(Bhat R. , et al .， JBC, 278(46), 45937-45945, 2003) 이 우울증 치료제로， Vertex사의 VX608이 뇌졸중 치료제로， Sanofi-Aventis사의 SAR502250이 당뇨병과 알츠하이머병 치료제로 개발되었으나 전 임상 단계에서 중단된 상태이다.  Lithium, which is used as a therapeutic agent for manic or bipolar disorder mentioned above, is known to inhibit other targets such as inosi as monophosphatase (IMPase) and inosi as polyphosphate phosphatase (IPPase) as nonspecific inhibitors for GSK-3. (Williams RSB., Et al., Trends in Pharmacol Sci., 21, 61-64, 2000). Recently, Nypta (NP-12, NP031112), developed by Noscira, SA (formerly Neuropharma, SA), among the various inhibitors that specifically inhibit GSK-3, is currently in Phase II clinical trials for the treatment of Alzheimer's disease or neurodegenerative diseases. have. Nypta (NP-12) is a thiadiazolidinone (TDZD) derivative that is an uncompetitive GSK-3 inhibitor to ATP. NP103, another GSK-3 inhibitor developed by Noscira, S.A, is under preclinical development as a treatment for Alzheimer's disease. Competitive GSK-3 inhibitors for ATP include SB216763 and SB_415286 developed by glaxoSmithKline (Cross DAE., Et al., J Neurochemistry, 77, 94-102, 2001) for the treatment of diabetes and stroke, CHIR98023 and CHIR9902K for Chiron. U.S. Patent Application US20020156087; Cline gW., Et al., Diabetes, 51, 2903-2910, 2002] for the treatment of diabetes mellitus, CNRS Aloisine A (Mapelli M., et al., J Med Chew., 48, 671- 679, 2005] and Alsterpaul lone (Leost M., et al., Eur J Biochew., 267, 5983-5994, 2000) are being developed preclinically as anticancer agents, and AR-A014418 from AstraZeneca (Bhat R., et. al., JBC, 278 (46), 45937-45945, 2003) Depressive drugs, Vertex's VX608 for strokes, Sanofi-Aventis SAR502250 for diabetes and Alzheimer's disease, but have been discontinued at all clinical stages to be.
현재까지 GSK-3 억제제 개발은 꾸준히 진행되고 있으나 ADME (투여， 분배， 대사, 분비)와 관련된 양호한 제약학적 성질을 갖는 효과적이고 GSK-3 선택적인 억제제의 개발이 절실하게 요망되고 있다. 이에 본 발명자들은 글리코겐 합성효소 키나아제 -3(GSK-3)의 과잉 활성에 의 하여 유발되는 각종 질환의 치료에 사용할 수 있는 저분자의 GSK-3 억제제를 개발 하기 위하여 연구하던 중, 피라졸로 피리딘 유도체를 제 φ하였으며， 상기 화합물이 우수한 GSK-3 저해 활성을 나타내는 것을 확인하고 본 발명을 완성하였다. To date, the development of GSK-3 inhibitors is ongoing, but there is an urgent need for the development of effective and GSK-3 selective inhibitors with good pharmaceutical properties related to ADME (administration, distribution, metabolism, secretion). Accordingly, the present inventors have been studying pyrazolopyridine derivatives while developing a low molecular weight GSK-3 inhibitor which can be used for the treatment of various diseases caused by the excess activity of glycogen synthase kinase-3 (GSK-3). Φ, and confirmed that the compound exhibits excellent GSK-3 inhibitory activity, completing the present invention.
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
본 발명의 목적은 신규한 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염을 제공하는 것이다.  It is an object of the present invention to provide novel pyrazolopyridine derivatives and their pharmaceutically acceptable salts.
본 발명의 다른 목적은 피라졸로 피리딘 유도체의 제조방법을 제공하는 것이 다.  Another object of the present invention is to provide a method for preparing a pyrazolo pyridine derivative.
본 발명의 또 따른 목적은 피라졸로 피리딘 유도체 또는 이의 약학적으로 허 용 가능한 염을 유효성분으로 함유하는 GSK-3|3(글리코겐 합성 효소 카이네이즈 -3 β) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.  Another object of the present invention is a pharmaceutical composition for preventing or treating a disease related to GSK-3 | 3 (glycogen synthase kinase-3 β) containing pyrazolo pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
【기술적 해결방법】 Technical Solution
상기 목적을 달성하기 위하여 하기 화학식 1로 표시되는 피라졸로 피리딘 유 도체 및 이의 약학적으로 허용 가능한 염을 제공한다:  In order to achieve the above object is provided a pyrazolo pyridine derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof:
[화학식 1]  [Formula 1]
Figure imgf000006_0001
Figure imgf000006_0001
(상기 Α 및 R1 내지 R4는 본 명세서 내에서 정의한 바와 같다). (A and R 1 to R 4 are as defined in the present specification).
또한， 본 발명은 상기 화학식 1로 표시되는 피라졸로 피리딘 유도체의 제조 방법을 제공한다.  The present invention also provides a method for preparing a pyrazolo pyridine derivative represented by the formula (1).
나아가， 본 발명은 화학식 1로 표시되는 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 GSK-3P (글리코겐 합성 효소 카이네이즈 -3β) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.  Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease related to GSK-3P (glycogen synthase kinase-3β) containing pyrazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
【유리한 효과】 Advantageous Effects
본 발명의 신규한 피라졸로 피리딘 유도체는 GSK-3P를 억제함으로써， 치매， 알츠하이머 병， 파킨슨 병， 전두측두 (Frontotemporal) 치매 파킨슨 유형， 괌 (Guam) 파킨슨 치매 복합증， HIV 치매 또는 신경섬유 얽힘 병리학과 관련된 질환을 예방 또는 치료하는데 유용하게 사용될 수 있다.  The novel pyrazolopyridine derivatives of the present invention inhibit GSK-3P, thereby dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology It can be usefully used to prevent or treat related diseases.
【도면의 간단한 설명】 [Brief Description of Drawings]
도 1은 본 발명에 따른 실시예 1의 화합물의 GSK-3P 효소 저해효과를 나타 내는 그래프이다. .  1 is a graph showing the GSK-3P enzyme inhibitory effect of the compound of Example 1 according to the present invention. .
【발명을 실시를 위한 최선의 형태】 이하， 본 발명의 치환기를 설명한다. [The best form for carrying out invention] Hereinafter, the substituent of this invention is demonstrated.
알킬은 1 내지 20의 탄소 원자， 바람직하게는 1 내지 12의 탄소 원자, 특히 1 내지 8 또는 1 내지 6 또는 1 내지 4의 탄소 원자를 함유하는 포화， 직쇄 또는 분쇄 탄화수소기， 예를 들어 메틸， 에틸， 프로필， 이소프로필， 이소부틸, tert-부 틸， n-핵실, 2, 2-디메틸 -부틸 또는 n-옥틸기를 나타낸다. 헤테로아릴알킬은 하나 또는 그 이상 (바람직하게 1, 2, 3 또는 4)의 탄소 원 자가 산소， 질소, 실리콘, 셀레늄， 인, 보론 또는 황 원자 (바람직하게 산소， 황 또 는 질소)로 대체되는 상기 정의된 대로 아르알킬기, 즉 상기 정의된 대로 아릴 또 는 헤테로아릴 및 또한 알킬, 알케닐， 알키닐 및 /또는 헤테로알킬 및 /또는 시클로 알킬 및 /또는 헤테로시클로알킬기를 함유한 기를 나타낸다. 바람직하게 헤테로아르 알킬기는 5 또는 6 내지 10 탄소 원자를 함유하는 하나 또는 두개의 방향족 고리계 (1 또는 2 고리)， 및 1 또는 2 내지 6 탄소 원자를 함유하는 하나 또는 두개의 알 킬， 알케닐 및 /또는 알키닐기， 및 /또는 5 또는 6 고리 탄소 원자， 산소， 황 또는 질소 원자로 대체된 1， 2， 3 또는 4 또는 이러한 탄소 원자를 함유하는 시클로알킬 기를 함유한다.  Alkyl is a saturated, straight or pulverized hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, in particular 1 to 8 or 1 to 6 or 1 to 4 carbon atoms, for example methyl, Ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-nuclear, 2, 2-dimethyl-butyl or n-octyl groups. Heteroarylalkyls are those in which one or more (preferably 1, 2, 3 or 4) carbon atoms are replaced with oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atoms (preferably oxygen, sulfur or nitrogen) Aralkyl groups as defined above, ie groups containing aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups as defined above. Preferably the heteroaralkyl group is one or two aromatic ring systems (1 or 2 rings) containing 5 or 6 to 10 carbon atoms, and one or two alkyl, alkenyl containing 1 or 2 to 6 carbon atoms And / or alkynyl groups, and / or 1, 2, 3 or 4 or cycloalkyl groups containing such carbon atoms replaced with 5 or 6 ring carbon atoms, oxygen, sulfur or nitrogen atoms.
예로는 아릴헤테로알킬， 아릴헤테로시클로알킬， 아릴헤테로시클로알케닐, 아 릴알킬헤테로시클로알킬， 아릴알케닐헤테로시클로알킬 , 아릴알키닐헤테로시클로알 킬， 아릴알킬헤테로시클로알케닐, 헤테로아릴알킬， 헤테로아릴알케닐， 헤테로아릴 알키닐， 헤테로아릴헤테로알킬， 헤테로아릴시클로알킬， 헤테로아릴시클로알케닐， 헤테로아릴헤테로시클로알킬 , 헤테로아릴헤테로시클로알케닐， 헤테로아릴알킬시클 로알킬 헤테로아릴알킬헤테로시클로알케닐， 헤테로아릴헤테로알킬시클로알킬, 헤 테로아릴해테로알킬시클로알케닐 및 헤테로아릴헤테로알킬헤테로시클로알킬기， 포 화 또는 모노-ᅳ 디- 또는 트리—불포화 시클릭기이다. 특별한 예로는 테트라히드로 이소퀴놀일-， 벤조일-, 2- 또는 3-에틸인돌일-， 4—메틸—피리디노-, 2-， 3- 또는 4- 메톡시페닐-， 4-에톡시페닐-, 2-, 3- 또는 4-카복시페닐-알킬기이다. 아릴은 6 내지 14의 고리 탄소 원자, 바람직하게 6 내지 10(특히 6)의 탄소 원자를 함유하는 하나 또는 그 이상의 고리를 갖는 방향족 기를 나타낸다. 게다가， 아릴 (또는 Ar)은 하나 또는 그 이상의 수소 원자가 불소， 염소, 브롬 또는 요오드 원자 또는 OH, SH, NH2, 또는 N02 기로 대체되는 기를 나타낸다. 예로는 페닐, 나 프틸, 비페닐， 2-플루오로페닐， 아닐리닐， 3-니트로페닐 또는 4-히드톡시페닐기이 다. Examples include arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, Heteroaryl alkenyl, Heteroaryl alkynyl, Heteroaryl heteroalkyl, Heteroarylcycloalkyl, Heteroarylcycloalkenyl, Heteroaryl heterocycloalkyl, Heteroaryl heterocycloalkenyl, Heteroarylalkyl Cycloalkyl Heteroaryl alkyl heterocyclo Alkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, saturated or mono-di- or tri-unsaturated cyclic groups. Specific examples are tetrahydro isoquinolyl-, benzoyl-, 2- or 3-ethylindolyl-, 4—methyl-pyridino-, 2-, 3- or 4-methoxyphenyl-, 4 -ethoxyphenyl- , A 2- , 3- or 4-carboxyphenyl-alkyl group. Aryl represents an aromatic group having one or more rings containing 6 to 14 ring carbon atoms, preferably 6 to 10 (particularly 6) carbon atoms. In addition, aryl (or Ar) denotes a group in which one or more hydrogen atoms are replaced with fluorine, chlorine, bromine or iodine atoms or with OH, SH, NH2, or N02 groups. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups.
헤테로아릴은 하나 또는 그 이상의 고리를 갖는 방향족 기를 나타내고, 5 내 지 14의 고리 원자, 바람직하게 5 내지 10(특히 5 또는 6)의 고리 원자를 함유하 고, 하나 또는 그 이상 (바람직하게 1， 2, 3 또는 4)의 산소， 질소, 인 또는 황 고 리 원자 (바람직하게 0， S 또는 N)를 함유하는 고리계에 의해 형성된다. 게다가， 헤 테로아릴은 하나 또는 그 이상의 수소 원자가 불소， 염소 브롬 또는 요오드 원자 또는 OH, SH, NH2, 또는 N02 기로 대체되는 기를 나타낸다. 예로는 4-피리딜， 2-이 미다졸일， 3-페닐-피를일， 티아졸일， 옥사졸일， 트리아졸일， 테트라졸일， 이속사졸 일， 인다졸일， 인돌일， 벤즈이미다졸일, 피리다지닐， 퀴놀리닐， 푸리닐， 카바졸일， 아크리디닐， 피리미디닐， 2，3'-비퓨릴, 3ᅳ피라졸일 및 이소퀴놀리닐기이다. 헤테로시클로알킬은 하나 또는 그 이상 (바람직하게 1， 2 또는 3)의 고리 탄 소 원자가 산소, 질소， 실리콘， 셀레늄, 인 또는 황 원자 (바람직하게 산소, 황 또 는 질소)로 대체되는 상기 정의된 대로 시클로알킬기를 나타낸다. 바람직하게， 헤 테로시클로알킬기는 3 내지 10 (특히， 3， 4， 5, 6 또는 7)의 고리 원자를 함유하는 1 또는 2 고리를 갖는다. 게다가, 헤테로시클로알킬은 하나 또는 그 이상의 수소 원자가 불소， 염소， 브롬 또는 요오드 원자 또는 0H, =0， SH, =S, NH2, =NH 또는 N02 기를 나타낸다. 예로는 피페리딜， 모폴리닐， 유로트로피닐， 피를리디닐, 테트 라히드로티오페닐， 테트라히드로피라닐， 테트라히드로퓨릴， 옥사시클로프로필 아 자시클로프로필 또는 2-피라졸리닐기 및 또한 락탐， 락톤， 시클릭 이미드 및 시클 릭 안하이드라이드이다. 이하， 본 발명을 상세히 설명한다. 본 발명은 하기 화학식 1로 표시되는 피라졸로 피리딘 유도체 및 Heteroaryl represents an aromatic group having one or more rings, contains 5 to 14 ring atoms, preferably 5 to 10 (particularly 5 or 6) ring atoms, and one or more (preferably 1, Formed by a ring system containing 2, 3 or 4 oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N). In addition, heteroaryl represents a group in which one or more hydrogen atoms are replaced with fluorine, chlorine bromine or iodine atoms or with OH, SH, NH 2 , or NO 2 groups. Examples include 4-pyridyl, 2-imidazolyl, 3-phenyl-pyryl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyrida Genyl, quinolinyl, furinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuryl, 3 ᅳ pyrazolyl and isoquinolinyl groups. Heterocycloalkyl is defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably oxygen, sulfur or nitrogen). As shown, a cycloalkyl group is shown. Preferably, the heterocycloalkyl group has 1 or 2 rings containing 3 to 10 (particularly 3, 4, 5, 6 or 7) ring atoms. In addition, heterocycloalkyl refers to one or more hydrogen atoms having a fluorine, chlorine, bromine or iodine atom or a 0H, = 0, SH, = S, NH2, = NH or N02 group. Examples include piperidyl, morpholinyl, eurotropinyl, pyridinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, oxcyclopropyl azacyclopropyl or 2-pyrazolinyl groups and also lactams. , Lactones, cyclic imides and cyclic anhydrides. Hereinafter, the present invention will be described in detail. The present invention is a pyrazolo pyridine derivative represented by the following formula (1) and
적으로 허용 가능한 염을 제공한다: Provides acceptable salts by way of example:
【화학식 11  Formula 11
Figure imgf000008_0001
Figure imgf000008_0001
상기 화학식 1에서，  In Chemical Formula 1,
A는 질소 (N) 또는 탄소 (C)이고;  A is nitrogen (N) or carbon (C);
R1은 수소; 비치환 또는 아민 및 OR5로 이루어지는 군으로부터 선택되는 1 이 상의 치환기로 치환된 C5-10 아릴; 고리 내 질소 (N) 원자를 1 이상 포함하는 5~10 원 헤테로아릴; 비치환 또는 -NR6R7 및 -0H로 이루어지는 군으로부터 선택되는 1 이상 의 치환기로 치환된 d-4 직쇄 또는 측쇄 알킬 ; -C00R8또는 -C0R8이고; R 1 is hydrogen; The one selected from the group consisting of an unsubstituted or an amine, and OR 5 is substituted by a substituent on C 5 - 10 aryl; 5-10 membered heteroaryl containing one or more nitrogen (N) atoms in the ring; D- 4 straight or branched chain alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of -NR 6 R 7 and -0H; -C00R 8 or -C0R 8 ;
이때， 상기 R5는 수소, d-4 직쇄 알킬，
Figure imgf000008_0002
In this case, R 5 is hydrogen, d- 4 linear alkyl,
Figure imgf000008_0002
고; High;
R6 및 R7은 각각 수소 또는 d-4 직쇄 또는 측쇄 알킬이고; R 6 and R 7 are each hydrogen or d- 4 straight or branched alkyl;
R8은 수소， N¾, 비치환 또는 NR¾7로 치환된 d-4 직쇄 또는 측쇄 알킬; 5ᅳ 8 원 헤테로아릴 d-4알킬 또는 C5-10 아릴이고; R 8 is hydrogen, N¾, unsubstituted or NR¾ 7 d- 4 linear or branched alkyl; 5 eu 8-membered heteroaryl d- 4 alkyl or C 5 - 10 aryl;
R2는 수소， NR¾7 또는; 비치환 또는 1 이상의 OR5로 치환된 C5-10 아릴이고; R 2 is hydrogen, NR¾ 7 or; Substituted C is unsubstituted or one or more OR 5 5 - 10 aryl;
R3는 수소, 0 rS 또는 -(CH2)n-NR¾7이고;
Figure imgf000009_0001
또는 이고; R 3 is hydrogen, 0 rS or — (CH 2 ) n —NR 3 7 ;
Figure imgf000009_0001
Or is;
n은 0 내지 15이고;  n is 0 to 15;
Figure imgf000009_0002
Figure imgf000009_0002
이때， R10은 NR6R7; -(CH2)n-C00R5; -(C )n-NR¾7; C5-12아릴; 5~12원 헤테로아 릴; 5~12원 헤테로사이클로알킬이고， -(CH2)n-C5-12아릴 ，- (C¾)n-5~12원 헤테로아릴， -(CH2)n-5~12원 헤테로사이클로알킬; In this case, R 10 is NR 6 R 7 ; -(CH 2 ) n -C00R 5 ; -(C) n -NR 3 7 ; C 5 - 12 aryl; 5-12 membered heteroaryl; And 5 ~ 12 membered heterocycloalkyl, - (CH 2) n -C 5 - 12 aryl, - (C¾) n -5 ~ 12 -membered heteroaryl, - (CH 2) n -5 ~ 12 -membered heterocycloalkyl;
이때， 상기 아릴, 헤테로아릴 또는 헤테로사이클로알킬은 비치환 또는 d-4 직쇄 또는 측쇄 알킬， OR5, NR6R7, -(CH2)n-NR6R7, C00R5, 할로겐， N02, CN, PMB, In this case, the aryl, heteroaryl or heterocycloalkyl is unsubstituted or d- 4 linear or branched alkyl, OR 5 , NR 6 R 7 ,-(CH 2 ) n -NR 6 R 7 , C00R 5 , halogen, N0 2 , CN, PMB,
Figure imgf000009_0003
Figure imgf000010_0001
로 이루어지는 군으로부 터 선택되는 하나 이상의 치환기로 치환될 수 있고， 상기 헤테로아릴 또는 헤테로 사이클로알킬은 고리내 N또는 0를 1이상포함한다. 또한， 본 발명은 상기 화학식 1에서 R1은 수소; 비치환 또는 아민 및 OR5로 이루어지는 군으로부터 선택되는 1이상의 치환기로 치환된 페닐; 피리딘， -(CH2)n-NR6R7, -(CH2)n-0H, -C00R8또는 -COR8이고;
Figure imgf000009_0003
Figure imgf000010_0001
It may be substituted with one or more substituents selected from the group consisting of, wherein the heteroaryl or hetero cycloalkyl includes one or more N or 0 in the ring. In addition, the present invention in the general formula 1 R 1 Is hydrogen; Phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of amines and OR 5 ; Pyridine,-(CH 2 ) n -NR 6 R 7 ,-(CH 2 ) n -0H, -C00R 8 or -COR 8 ;
N. N.
이때， 상기 R5는 H, CH3, ^ ^^ 또는 \ 이고; Wherein R 5 is H, CH 3 , ^ ^^ or \;
상기 R6 및 R7은 각각 H또는 CH3이고; 상기 R8은 H, NH2j N(C¾)2, 메틸， 에틸,
Figure imgf000010_0002
， 페닐 또
Figure imgf000010_0003
이고; R 6 and R 7 are each H or CH 3 ; R 8 is H, NH 2j N (C¾) 2 , methyl, ethyl,
Figure imgf000010_0002
Phenyl again
Figure imgf000010_0003
ego;
n은 1 또는 2인 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염을 제공한다. 나아가， 본 발명은 상기 화학식 1에서 R2는 수소 , N¾, NH(CH3) , N(CH3)2 또는; 비치환 또는 OH, 0CH3로 치환된 페닐인 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염을 제공한다. n provides 1 or 2 pyrazolo pyridine derivatives and pharmaceutically acceptable salts thereof. Further, the present invention in the formula 1 R 2 Is hydrogen, N¾, NH (CH 3 ), N (CH 3 ) 2 Or; Pyrazolo pyridine derivatives which are unsubstituted or substituted with OH, 0CH 3 , and pharmaceutically acceptable salts thereof.
또한， 본 발명은 상기 화학식 1에서 R3는 수소，
Figure imgf000010_0004
또는 In addition, the present invention in the general formula 1 R 3 is hydrogen,
Figure imgf000010_0004
or
-(CH2)m-NR6R7이고, 이때， m은 1 내지 7이고; -(CH 2 ) m -NR 6 R 7, wherein m is 1 to 7;
Figure imgf000010_0005
Figure imgf000011_0001
이고;
Figure imgf000010_0005
Figure imgf000011_0001
ego;
이때, 상기 은 0 내지 5인 피라졸로 피리딘 유도체 및 이의 약학적으로 허 용 가능한 염을 제공한다.  In this case, the silver provides 0 to 5 pyrazolo pyridine derivatives and pharmaceutically acceptable salts thereof.
나아가， R4는 NH2, -NH-(CH2)n- ,
Figure imgf000011_0002
Furthermore, R 4 is NH 2 , -NH- (CH 2 ) n- ,
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0003
이때， n은 0 ~ 4이고;  N is 0 to 4;
상기 R10은 비치환 또는. 메틸， 에틸, 프로필, —OH, -OMe, ᅳ NH2, -N02, -N(C¾)2, -CH2N(CH3)2) -(CH2)2N(CH3)2, -0(CH2)2N(CH3)2) -COOH, -COOMe, -(CH3)2C00H, -C0NH2, -CN, -F, -CI, -PMB, -S000H, -S000CH2CH3, -S000(CH2)2CH3, — S000(CH2)5C¾, R 10 is unsubstituted or. Methyl, ethyl, propyl, —OH, —OMe, ᅳ NH 2 , —N0 2 , —N (C¾) 2 , —CH 2 N (CH 3 ) 2) -(CH 2 ) 2 N (CH 3 ) 2 , -0 (CH 2 ) 2 N (CH 3 ) 2) -COOH, -COOMe,-(CH 3 ) 2 C00H, -C0NH 2 , -CN, -F, -CI, -PMB, -S000H, -S000CH 2 CH 3 , -S000 (CH 2 ) 2 CH 3 , — S000 (CH 2 ) 5 C¾,
Figure imgf000011_0004
Figure imgf000011_0005
또는 로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환된; 페닐， 피리딘, 피페라진， 피페리딘, 이소인돌린， 벤즈이미다졸，
Figure imgf000011_0004
Figure imgf000011_0005
Or substituted with one or more substituents selected from the group consisting of; Phenyl, pyridine, piperazine, piperidine, isoindolin, benzimidazole,
나프탈렌，
Figure imgf000011_0006
인 피라졸로 피리딘 유도체 및 0 의 약학적으로 허용 가능한 염을 제공한다. 바람직하게， O ᄋ ᄋ 人 /
Figure imgf000012_0001
HO人 / 상기 R1은 수소, naphthalene,
Figure imgf000011_0006
Inpyrazolo pyridine derivatives and zero pharmaceutically acceptable salts. Preferably, O ᄋ ᄋ 人 /
Figure imgf000012_0001
HO人 / R 1 is hydrogen,
Figure imgf000012_0002
으로 이루어지는 군으로부터 선택되는 1종이고;
Figure imgf000012_0002
It is 1 type chosen from the group which consists of;
R2는 수소， NH2, NHCH3)
Figure imgf000012_0003
으로 이루어지 으로부터 선택되는 1종이고; R 2 is hydrogen, NH 2 , NHCH 3)
Figure imgf000012_0003
It is 1 type selected from consisting of;
Figure imgf000012_0004
Figure imgf000012_0004
Figure imgf000012_0005
으로 이루어지는 군으로부터 선택되는 1종이고; 11
Figure imgf000012_0005
It is 1 type chosen from the group which consists of; 11
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000013_0001
Figure imgf000014_0001
Zl Zl
^ΖΖ600/ΐΐΟΖΗΜ/Χ3<Ι Z 6LLmiOZ OAV ^ ΖΖ600 / ΐΐΟΖΗΜ / Χ3 <Ι Z 6LLmiOZ OAV
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000015_0002
로 이루어진 군으로부터 선택되는 1종이다. 더욱 바람직하게， 본 발명의 상기 화학식 1의 유도체는，
Figure imgf000015_0002
It is 1 type chosen from the group which consists of. More preferably, the derivative of Formula 1 of the present invention,
(1) 3-히드록시 -V-[5-(2-히드록시페닐 )-L7-피라졸로 [3 , 4-?]피라진ᅳ 3-일 ]벤즈 아미드；  (1) 3-hydroxy-V- [5- (2-hydroxyphenyl) -L7-pyrazolo [3,4-?] Pyrazin-3-yl] benzamide;
(2) 4-니트로— 7\ 5-페닐 -1 ―피라졸로 [4 , 3-b]피라진 -3-일 )벤즈아미드； (2) 4-nitro-7 \ 5-phenyl-1 -pyrazolo [4,3-b] pyrazin-3-yl) benzamide;
(3) vV-[5-(4-메톡시페닐) -1 -피라졸로 [3,4-b]피라진 -3—일]니코틴아미드 하이 드로클로라이드; (3) vV- [5- (4-methoxyphenyl) -1-pyrazolo [3,4-b] pyrazin-3-yl] nicotinamide hydrochloride;
(4) 그[5-(4—메특시페닐) -L 피라졸로 [3,4-?]피라진 -3-일] -4-니트로벤즈아미  (4) Gly [5- (4-methoxyphenyl) -L pyrazolo [3,4-?] Pyrazin-3-yl] -4-nitrobenzami
(5) 4-플루오로 -ΛΚ 5- ( 4—메톡시페닐 ) -1 ^피라졸로 [3 , 4 피라진—3-일]벤즈아 미드； (5) 4-fluoro-ΛΚ 5- (4—methoxyphenyl) -1 ^ pyrazolo [3,4 pyrazin-3-yl] benzamide;
(6) Λ45-(4-메록시페닐 피라졸로 [3 ,4- ]피라진 -3-일]벤즈아미드； (6) Λ45- (4-methoxyphenyl pyrazolo [3,4-] pyrazin-3-yl] benzamide;
(7) 4-메록시 -Λ 5_(4-메록시페닐 )-L¾L피라졸로 [3,4-Ζ?]피라진 -3—일]벤즈아미 (7) 4-Methoxy-Λ 5_ (4-methoxyphenyl) -L¾Lpyrazolo [3,4-,?] pyrazine-3-yl] benzami
(8) Λ45-(4-메톡시페닐 )-1^피라졸로 [4,3-?]피라진 -3-일]이소니코틴아미드；(8) Λ45- (4-methoxyphenyl) -1 ^ pyrazolo [4,3-?] Pyrazin-3-yl] isonicotinamide;
(9) 3- (디메틸아미노) -Λ45-(4-메톡시페닐 피라졸로 [3， 4-/?]피라진 -3-일 ] 프로판아미드 하이드로클로라이드; (9) 3- (dimethylamino) -Λ45- (4-methoxyphenyl pyrazolo [3,4-/?] Pyrazin-3-yl] propanamide hydrochloride;
( 10) yV-[5-(4-메특시페닐 )-1 -피라졸로 [3， 4 피라진 -3-일 ] -4-메틸벤즈아미  (10) yV- [5- (4-methoxyphenyl) -1 -pyrazolo [3,4 pyrazin-3-yl] -4-methylbenzami
(11) 4-시아노 -Ι 5- ( 4—메록시페닐) - 1 -피라졸로 [ 3， 4 피라진 -3-일]벤즈아 미드; (11) 4-cyano-Ι 5- (4-hydroxyphenyl) -1-pyrazolo [3,4 pyrazin-3-yl] benzamide;
( 12) 5-(4-메록시페닐 )-1 Γ -피라졸로 [3， 4- 피라진 -3-일 ]테레프탈아미드；(12) 5- (4-methoxyphenyl) -1 Γ -pyrazolo [3,4-pyrazin-3-yl] terephthalamide;
( 13) 3-메록시 -Λ45-(4-메록시페닐 )-1^피라졸로 [3 A~b\피라진ᅳ 3-일 ]벤즈아 미드; (13) 3-Methoxy-Λ45- (4-Methoxyphenyl) -1 ^ pyrazolo [3 A to b \ pyrazinyl 3-yl] benzia American drama;
(14) 4- (디메틸아미노) - -[5-(4-메특시페닐 )-1그피라졸로 [3， 4- 피라진 -3- 일]벤즈아미드;  (14) 4- (dimethylamino)-[5- (4-methoxyphenyl) -1gpyrazolo [3,4-pyrazin-3-yl] benzamide;
(15) Λ 5-페닐 피라졸로 [3,4-A]피라진 -3-일)니코틴아미드 하이드로클로 라이드; .  (15) Λ 5-phenyl pyrazolo [3,4-A] pyrazin-3-yl) nicotinamide hydrochloride; .
(16) Λ45-(3-히드록시페닐 )-1^피라졸로 [3，4- 피라진 -3-일]니코틴아미드 하이드로클로라이드;  (16) Λ45- (3-hydroxyphenyl) -1 ^ pyrazolo [3,4-pyrazin-3-yl] nicotinamide hydrochloride;
( 17) Λ 5-(4-메록시페닐) -1^피라졸로 [3 ,4-b]피라진 -3-일 ]벤젠술폰아미드； (17) Λ 5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] benzenesulfonamide;
(18) y\ 5-(4-메특시페닐) -l 피라졸로 [3,4-¾피라진 -3—일]피페라진 -1-카복 사아미드 하이드로클로라이드; (18) y \ 5- (4-methoxyphenyl) -1 pyrazolo [3,4-¾pyrazine-3-yl] piperazin-1-carboxamide hydrochloride;
(19) ΛΗ5-(4-메특시페닐 )-L 피라졸로 [3，4- ]피라진 -3-일] -4-메틸피페라진 -1-카복사아미드 하이드로클로라이드;  (19) ΛΗ5- (4-methoxyphenyl) -L pyrazolo [3,4-] pyrazin-3-yl] -4-methylpiperazin-1-carboxamide hydrochloride;
(20) Λ 5-{3-[2- (디메틸아미노)에특시 ]페닐 }-1^피라졸로 [3 , -b피라진—3- 일)니코틴아미드;  (20) Λ 5- {3- [2- (dimethylamino) specific] phenyl} -1 ^ pyrazolo [3, -bpyrazin—3-yl) nicotinamide;
(21) 3-시아노 -\ 5-(4-메톡시페닐 )-1 "피라졸로 [3， 4-b]피라진— 3-일 ]벤즈아 미드;  (21) 3-cyano- \ 5- (4-methoxyphenyl) -1 "pyrazolo [3, 4-b] pyrazine- 3-yl] benzamide;
(22) ΛΗ5-(4-메특시페닐) -1^피라졸로 [3,4-b]피라진 -3-일]— 2-페닐아세트아 미드；  (22) ΛΗ5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] — 2-phenylacetamide;
( 23 ) 4-히드록시 -Λ 5- ( 4ᅳ메톡시페닐 )-1 -피라졸로 [ 3， 4 - 피라진 -3-일 ]벤즈 아미드； (23) 4-hydroxy-Λ 5- ( 4 ᅳ methoxyphenyl) -1-pyrazolo [3,4-pyrazin-3-yl] benzamide;
(24) 3-히드톡시 -그[5-(4-메톡시페닐 )-1 ^피라졸로 [3， 4-6]피라진— 3-일 ]벤즈 아미드；  (24) 3-hydroxythoxy-g [5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-6] pyrazine- 3-yl] benzamide;
(25) 4-히드록시 -Λ45-(4-히드록시페닐 )-LY-피라졸로 [3， 피라진 -3—일 ]벤 즈아미드；  (25) 4-hydroxy-Λ45- (4-hydroxyphenyl) -LY-pyrazolo [3, pyrazin-3-yl] benzamide;
(26) 3-히드톡시 -ΛΚ5-(4-히드록시페닐 )-1 -피라졸로 [3， 4-b]피라진 -3-일]벤 즈아미드;  (26) 3-hydroxythoxy-ΛΚ5- (4-hydroxyphenyl) -1-pyrazolo [3,4-b] pyrazin-3-yl] benzamide;
(27) V-[5-(2-히드톡시페닐 )-1 -피라졸로 [3 ,4~b]피라진 -3-일]니코틴아미드 하이드로클로라이드; (27) V- [5- (2-hydroxythoxyphenyl) -1 -pyrazolo [3,4 - b] pyrazin-3-yl] nicotinamide hydrochloride;
(28) -[5- (피리딘 -3_일)-1 -피라졸로 [3，4- 피라진 -3-일]니코틴아미드 디하 이드로클로라이드;  (28)-[5- (pyridin-3_yl) -1 -pyrazolo [3,4-pyrazin-3-yl] nicotinamide dihydrochloride;
(29) 4-아미노 -Η:5-(2-히드록시페닐) -L 피라졸로 [3， 4-b]피라진 -3-일]벤즈 아미드 하이드로클로라이드;  (29) 4-amino-Η: 5- (2-hydroxyphenyl) -L pyrazolo [3, 4-b] pyrazin-3-yl] benz amide hydrochloride;
(30) 4-[5-(2-히드록시페닐)-1^피라졸로[3,4-6]피라진-3-일카바모일]벤조익 액시드;  (30) 4- [5- (2-hydroxyphenyl) -1 ^ pyrazolo [3,4-6] pyrazin-3-ylcarbamoyl] benzoic acid;
(31) 4—히드록시 -Λ45-(2-히드록시페닐 )-1^피라졸로 [3， 4— 피라진 -3-일 ]벤 즈아미드;  (31) 4—hydroxy-Λ45- (2-hydroxyphenyl) -1 ^ pyrazolo [3, 4—pyrazin-3-yl] benzamide;
(32) 3_[5-(2-히드록시페닐 )-1^피라졸로 [3，4- 피라진 -3-일카바모일]벤조익 액시드;  (32) 3_ [5- (2-hydroxyphenyl) -1 ^ pyrazolo [3,4-pyrazin-3-ylcarbamoyl] benzoic acid;
(33) 메틸 3-[5-(2-히드록시페닐) -I 피라졸로 [3,4-?]피라진 -3-일카바모일] 벤조에이트;  (33) methyl 3- [5- (2-hydroxyphenyl) -I pyrazolo [3,4-?] Pyrazine-3-ylcarbamoyl] benzoate;
(34) 3-아미노 -Λ45-(2-히드록시페닐 )-L 피라졸로 [3，4- ]피라진 -3-일 ]벤즈 아미드 하이드로클로라이드;  (34) 3-amino-Λ45- (2-hydroxyphenyl) -L pyrazolo [3,4-] pyrazin-3-yl] benzamide hydrochloride;
(35) 소듐 2-[3-(3-옥시도벤즈아미도) -1 -피라졸로 [3，4- 피라진 -5-일]페놀 레이트; (35) Sodium 2- [3- (3-Oxydobenzamido) -1-pyrazolo [3,4-pyrazin-5-yl] phenol Rate;
(36) Λ45-(2-메록시페닐) 피라졸로 [3,4-Z>]피라진 -3-일]니코틴아미드 하 이드로클로라이드;  (36) Λ45- (2-methoxyphenyl) pyrazolo [3,4-Z>] pyrazin-3-yl] nicotinamide hydrochloride;
(37) 에틸 6-아미노 -3- (니코틴아미도) -L7-피라졸로 [3,4 피리딘 -5—카복실레 이트 하이드로클로라이드;  (37) ethyl 6-amino-3- (nicotinamido) -L7-pyrazolo [3,4 pyridine-5—carboxylate hydrochloride;
(38) 6-아미노 -3— (니코틴아미도) -1 -피라졸로 [3，4- ]피리진 -5-카복사아미드 하이드로클로라이드;  (38) 6-amino-3— (nicotinamido) -1-pyrazolo [3,4-] pyrazine-5-carboxamide hydrochloride;
(39) Λ 6-아미노 -5-페닐— 1^피라졸로 [3，4- ]피라진 -3-일)니코틴아미드 하이 드로클로라이드;  (39) Λ 6-amino-5-phenyl—1 ^ pyrazolo [3,4-] pyrazin-3-yl) nicotinamide hydrochloride;
(40) 에틸 6-아미노 -3- (이소니코틴아미도) 피라졸로 [3，4- ]피리딘 5ᅳ카복 실레이트 하이드로클로라이드;  (40) ethyl 6-amino-3- (isonicotinamido) pyrazolo [3,4-] pyridine 5′carboxylate hydrochloride;
(41) 에틸 6-아미노 -3-(3-시아노벤즈아미도) -1 -피라졸로 [3，4- 피리딘 -5-카 복실레이트;  (41) ethyl 6-amino-3- (3-cyanobenzamido) -1-pyrazolo [3,4-pyridine-5-carboxylate;
(42) 에틸 6-아미노 -3-(3-카바모일벤즈아미도 피라졸로 [3,4-Λ]피리딘 -5- 카복실레이트; .  (42) ethyl 6-amino-3- (3-carbamoylbenzamido pyrazolo [3,4-Λ] pyridine-5-carboxylate;
(43) 에틸 6-아미노 -3-(3-니트로벤즈아미도) 피라졸로 [3,4—?]피리딘 -5-카 복실레이트;  (43) ethyl 6-amino-3- (3-nitrobenzamido) pyrazolo [3,4 —?] Pyridine-5-carboxylate;
(44) 에틸 6-아미노 -3-(3-아미노벤즈아미도) 피라졸로 [3,4-?]피리딘 -5-카 복실레이트 하이드로클로라이드;  (44) ethyl 6-amino-3- (3-aminobenzamido) pyrazolo [3,4-?] Pyridine-5-carboxylate hydrochloride;
(45) 에틸 6-아미노 -3-(3-히드톡시벤즈아미도 )-1 -피라졸로 [3,4-b]피리딘 -5- 카복실레이트;  (45) ethyl 6-amino-3- (3-hydroxymethoxybenzamido) -1 -pyrazolo [3,4-b] pyridine-5-carboxylate;
(46) 에틸 6-아미노 -3- (벤조 [ί] [1,3]디옥솔 -5-카복사아미도 )-1 -피라졸로 [3, 4 -?]피리딘 -5-카복실레이트;  (46) ethyl 6-amino-3- (benzo [ί] [1,3] dioxol-5-carboxamido) -1-pyrazolo [3,4-] pyridine-5-carboxylate;
(47) Κ6-아미노 -5- (히드록시메틸) 피라졸로 [3 , 4-6]피리딘 -3ᅳ일 ]니코틴 아미드 하이드로클로라이드;  (47) Κ6-amino-5- (hydroxymethyl) pyrazolo [3,4-6] pyridin-3xyl] nicotin amide hydrochloride;
(48) 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-ώ]피리딘 -5-카복실릭 엑시 드 하이드로클로라이드;  (48) 6-amino-3- (nicotinamido) pyrazolo [3,4-ώ] pyridine-5-carboxylic acid hydrochloride;
(49) 에틸 6-아미노 -3-(1^벤조 [ί/]이미다졸 -5-카복사아미도 )-1^피라졸로 [3， 4-?]피리딘 -5-카복실레이트 하이드로클로라이드；  (49) ethyl 6-amino-3- (1 ^ benzo [ί /] imidazole-5-carboxamido) -1 ^ pyrazolo [3,4-?] Pyridine-5-carboxylate hydrochloride;
(50) 에틸 6-아미노 -3-(4-메록시벤즈아미도) -1^피라졸로 [3, 4- ]피리딘 -5-카 복실레이트;  (50) ethyl 6-amino-3- (4-methoxybenzamido) -1 ^ pyrazolo [3,4-] pyridine-5-carboxylate;
(51) 에틸 6-아미노-3-(1 -인돌-5-카복사아미도)-1그피라졸로[3,4-/?]피리딘 -5-카복실레이트 하이드로클로라이드;  (51) ethyl 6-amino-3- (1-indole-5-carboxamido) -1gpyrazolo [3,4-/?] Pyridine-5-carboxylate hydrochloride;
(52) 에틸 6-아미노 -3-(6-클로로니코틴아미도 피라졸로 [3,4-b]피리딘 -5- 카복실레이트 하이드로클로라이드;  (52) ethyl 6-amino-3- (6-chloronicotinamido pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(53) 에틸 6-아미노 -3-(3—아미노 -4-메록시벤즈아미도) -1 -피라졸로 [3,4-6]피 리딘 -5-카복실레이트 하이드로클로라이드;  (53) ethyl 6-amino-3- (3-amino-4-methoxybenzamido) -1-pyrazolo [3,4-6] pyridine-5-carboxylate hydrochloride;
(54) 에틸 6-아미노 -3_(6-히드록시니코틴아미도)— 1 -피라졸로 [3，4- 피리딘 -5-카복실레이트 하이드로클로라이드;  (54) ethyl 6-amino-3_ (6-hydroxynicotinamido) — 1-pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(55) 에틸 6-아미노 -3-(4-메틸— 3,4-디히드로 -2 ^벤조 [ [1,4]옥사진 -7-카복 사아미도) 피라졸로 [3 , 4ᅳ ]피리딘 -5-카복실레이트 하이드로클로라이드;  (55) ethyl 6-amino-3- (4-methyl— 3,4-dihydro-2 ^ benzo [[1,4] oxazine-7-carboxamido) pyrazolo [3,4 ′] pyridine -5-carboxylate hydrochloride;
(56) 에틸 6-아미노 -3-(6-아미노니코틴아미도 )-1 ᅳ피라졸로 [3,4->]피리딘 -5- 카복실레이트 하이드로클로라이드; (57) 에틸 6-아미노 -3-(4-니트로벤즈아미도) -1 -피라졸로 [3,4-/?]피리딘 -5-카 복실레이트; (56) ethyl 6-amino-3- (6-aminonicotinamido) -1 cappyrazolo [3,4->] pyridine-5-carboxylate hydrochloride; (57) ethyl 6-amino-3- (4-nitrobenzamido) -1 -pyrazolo [3,4-/?] Pyridine-5-carboxylate;
(58) 에틸 6-아미노 -3-(4-아미노벤즈아미도) -1 -피라졸로 [3，4ᅳ /?]피리딘 5-카 복실레이트 하이드로클로라이드;  (58) ethyl 6-amino-3- (4-aminobenzamido) -1-pyrazolo [3,4 ′ /?] Pyridine 5-carboxylate hydrochloride;
(59) 에틸 6-아미노 -3-(1-메틸 -1가인돌 -3-카복사아미도) 피라졸로 [3，4-/?] 피리딘 -5-카복실레이트;  (59) ethyl 6-amino-3- (1-methyl-1gaindole-3-carboxamido) pyrazolo [3,4-/?] Pyridine-5-carboxylate;
(60) 에틸 6-아미노 -3-(4-히드록시벤즈아미도 )— 1 ^피라졸로 [3,4-b]피리딘 -5- 카복실레이트;  (60) ethyl 6-amino-3- (4-hydroxybenzamido) —1 ^ pyrazolo [3,4-b] pyridine-5-carboxylate;
(61) 에틸 6- (메틸아미노 )—3- (니코틴아미도) -1 -피라졸로 [3, 4-b]피리딘 -5-카 복실레이트 하이드로클로라이드;  (61) ethyl 6- (methylamino) —3- (nicotinamido) -1-pyrazolo [3, 4-b] pyridine-5-carboxylate hydrochloride;
(62) 에틸 6-아미노 -3-(1，3-디옥소이소인돌린 -2-일) 피라졸로 [3,4-Ζ?]피리 딘 -5-카복실레이트;  (62) ethyl 6-amino-3- (1,3-dioxoisoindolin-2-yl) pyrazolo [3,4-VII?] Pyridine-5-carboxylate;
(63) 1-{4- [(디메틸아미노)메틸]페닐 }-3-[5-(4-메톡시페닐) -1^피라졸로 [4, 3-b]피라진 -3-일]우레아 하이드로클로라이드;  (63) 1- {4-[(dimethylamino) methyl] phenyl} -3- [5- (4-methoxyphenyl) -1 ^ pyrazolo [4,3-b] pyrazin-3-yl] urea hydro Chloride;
(64) 1-(4-메록시페닐 )— 3-[5-(4-메록시페닐 )— 피라졸로 [3 , 4—6]피라진 -3- 일]우레아;  (64) 1- (4-methoxyphenyl) — 3- [5- (4-methoxyphenyl) —pyrazolo [3, 4-6] pyrazin-3-yl] urea;
65) 1-(4-플루오로페닐 )-3-[5-(4-메록시페닐 )ᅳ1^피라졸로 [3， 4 ]피라진 -3- 일]우레아;  65) 1- (4-fluorophenyl) -3- [5- (4-methoxyphenyl) ᅳ 1 ^ pyrazolo [3, 4] pyrazin-3-yl] urea;
(66) 1- [ 5- ( 4-메톡시페닐 ) - 피라졸로 [ 3 , 4 -6]피라진 -3-일] -3- (피리딘 -4—일) 우레아;  (66) 1- [5- (4-methoxyphenyl) -pyrazolo [3, 4-6] pyrazin-3-yl] -3- (pyridin-4-yl) urea;
(67) 1-(4-시아노페닐 )-3- [5-(4-메록시페닐 )-1 ^피라졸로 [4 , 3 - ]피라진 -3- 일]우레아;  (67) 1- (4-cyanophenyl) -3- [5- (4-methoxyphenyl) -1 ^ pyrazolo [4, 3-] pyrazin-3-yl] urea;
(68) 1-[5-(4-메특시페닐 )-1 ^피라졸로 [3 , 4-b]피라진 -3-일 ] -3- (피리딘 -3-일 ) 우레아 하이드로클로라이드;  (68) 1- [5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] -3- (pyridin-3-yl) urea hydrochloride;
(69) 1-(4-메록시페닐 )-3-(5-페닐 -1 -피라졸로 [3 , 4-b]피라진 -3-일)우레아； (69) 1- (4-methoxyphenyl) -3- (5-phenyl-1 -pyrazolo [3,4-b] pyrazin-3-yl) urea;
(70) 1-(4-시아노페닐 )-3-(5-페닐— 피라졸로 [3，4- 피라진 -3-일 )우레아；(70) 1- (4-cyanophenyl) -3- (5-phenyl-pyrazolo [3,4-pyrazin-3-yl) urea;
(71) 1-(3-시아노페닐) _3-[5-(4-메록시페닐) -1^피라졸로 [4，3- 피라진 -3- 일]우레아; (71) 1- (3-cyanophenyl) _3- [5- (4-methoxyphenyl) -1 ^ pyrazolo [4,3-pyrazin-3-yl] urea;
(72) 1-(4-시아노페닐 )-3-[5-(3-히드록시페닐 )-1^피라졸로 [3 , 4- 피라진 -3- 일]우레아;  (72) 1- (4-cyanophenyl) -3- [5- (3-hydroxyphenyl) -1 ^ pyrazolo [3,4-pyrazin-3-yl] urea;
(73) 1-[5-(4-메록시페닐) 피라졸로 [3,4-?]피라진 -3-일] -3- (나프탈렌 -1ᅳ 일)우레아;  (73) 1- [5- (4-methoxyphenyl) pyrazolo [3,4-?] Pyrazin-3-yl] -3- (naphthalene-1′yl) urea;
(74) 1-(4-플루오로페닐 )-3_[5-페닐 피라졸로 [3，4- 피라진 -3-일]우레아; (74) 1- (4-fluorophenyl) -3_ [5-phenyl pyrazolo [3,4-pyrazin-3-yl] urea;
(75) 1-(3-메록시페닐 )-3-[5-(4-메록시페닐 피라졸로 [3 A~b]피라진 -3- 일]우레아; (75) 1- (3-methoxyphenyl) -3- [5- (4-methoxyphenyl pyrazolo [3 A to b] pyrazin-3-yl] urea;
(76) 1-(6-시아노피리딘 -3-일 )-3-[5-(4-메톡시페닐 )-L 피라졸로 [3， 4-Z?]피라 진 -3-일]우레아 하이드로클로라이드;  (76) 1- (6-cyanopyridin-3-yl) -3- [5- (4-methoxyphenyl) -L pyrazolo [3,4-Z?] Pyrazin-3-yl] urea hydro Chloride;
(77) 1- [5-(4-메톡시페닐 )-1 -피라졸로 [3， 4- 피라진 -3-일 ] 3-(3-니트로페 닐)우레아;  (77) 1- [5- (4-methoxyphenyl) -1-pyrazolo [3,4-pyrazin-3-yl] 3- (3-nitrophenyl) urea;
(78) 1-[5-(4-메록시페닐) -1^피라졸로 [3,4-b]피라진 -3-일]— 3- (피리딘 -2-일 메틸)우레아 하이드로클로라이드;  (78) 1- [5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] — 3- (pyridin-2-yl methyl) urea hydrochloride;
(79) 메틸 3_(3-{3-[3-(4-시아노페닐)우레이도] -1^피라졸로 [3,4-?]피라진 -5_일}페녹시)프로파노에이트; (80) l-(6—시아노피리딘 -3-일 )-3— [5— (3-히드록시페닐) -I 피라졸로 [4，3- 피 라진 -3-일]우레아; (79) methyl 3_ (3- {3- [3- (4-cyanophenyl) ureido] -1 ^ pyrazolo [3,4-?] Pyrazin-5_yl} phenoxy) propanoate; (80) l- (6—cyanopyridin-3-yl) -3— [5— (3-hydroxyphenyl) -I pyrazolo [4,3-pyrazin-3-yl] urea;
(81) 1-(4-히드록시페닐) -3-[5-(4-메록시페닐 )-1 피라졸로 [3， 4-/?]피라진 -3- 일]우레아;  (81) 1- (4-hydroxyphenyl) -3- [5- (4-hydroxyphenyl) -1 pyrazolo [3, 4-/?] Pyrazin-3-yl] urea;
(82) 1-[5-(4-메특시페닐) -1^피라졸로 [4,3-b]피라진 -3—일] -3- (피페리딘 -4- 일)우레아 하이드로클로라이드;  (82) 1- [5- (4-methoxyphenyl) -1 ^ pyrazolo [4,3-b] pyrazin-3-yl] -3- (piperidin-4-yl) urea hydrochloride;
(83) 1-(6-시아노피리딘 -3-일 )-3-[5-(4-히드록시페닐) -1 ^피라졸로 [3，4- 피 라진— 3-일]우레아 하이드로클로라이드;  (83) 1- (6-cyanopyridin-3-yl) -3- [5- (4-hydroxyphenyl) -1 ^ pyrazolo [3,4-pyrazine- 3-yl] urea hydrochloride;
(84) 1-[5-(4-메록시페닐) 피라졸로 [3,4— b]피라진 -3-일] -3-(2-메틸이소인 돌린 -4-일)우레아 하이드로클로라이드;  (84) 1- [5- (4-methoxyphenyl) pyrazolo [3,4—b] pyrazin-3-yl] -3- (2-methylisoin dolin-4-yl) urea hydrochloride;
(85) 1-[2-(4-메록시벤질)이소인돌린 -4-일]— 3-[5-(4-메록시페닐) 피라졸 로 [3， 4- 피라진 -3-일 ]우레아 하이드로클로라이드；  (85) 1- [2- (4-methoxybenzyl) isoindolin-4-yl] — 3- [5- (4-methoxyphenyl) pyrazolo [3,4-pyrazin-3-yl] Urea hydrochloride;
(86) 1-[5-(4-메톡시페닐 )-1^피라졸로 [3 ,4-Ζ?]피라진 -3-일] -3-( 1-메틸피페리 딘 -4-일)우레아 하이드로클로라이드;  (86) 1- [5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-VII?] Pyrazin-3-yl] -3- (1-methylpiperidin-4-yl) urea Hydrochloride;
(87) 1-[5-(4-아미노페닐 )-1 -피라졸로 [3，4— b]피라진 -3-일] -3-(4ᅳ플루오로페 닐)우레아;  (87) 1- [5- (4-aminophenyl) -1 -pyrazolo [3,4—b] pyrazin-3-yl] -3- (4 ᅳ fluorophenyl) urea;
(88) 소듐 4-{3-[5-(4-메톡시페닐) -L7-피라졸로 [3,4-b]피라진 -3-일]우레이 도}벤조에이트;  (88) sodium 4- {3- [5- (4-methoxyphenyl) -L7-pyrazolo [3,4-b] pyrazin-3-yl] ureidodobenzoate;
(89) 1- [ 5- ( 4-아미노페닐) - 1 ^피라졸로 [ 3 , 4ᅳ 피라진 -3-일] -3— ( 4-메톡시페 닐)우레아;  (89) 1- [5- (4-aminophenyl) -1 ^ pyrazolo [3,4′pyrazin-3-yl] -3— (4-methoxyphenyl) urea;
(90) 1-(4-히드록시페닐 )-3-[5-(4—히드록시페닐 )-1^피라졸로 [3 , 4- ^피라진 -3-일]우레아;  (90) 1- (4-hydroxyphenyl) -3- [5- (4—hydroxyphenyl) -1 ^ pyrazolo [3, 4- ^ pyrazin-3-yl] urea;
(91) 1-(4-히드록시페닐 )-3-[5-(2-히드톡시페닐 )-1^꾀라졸로 [3，4- 피라진 -3-일]우레아;  (91) 1- (4-hydroxyphenyl) -3- [5- (2-hydroxyphenyl) -1 ^ turazolo [3,4-pyrazin-3-yl] urea;
(92) 1-(4-히드톡시페닐 )-3-[5- (피리딘 -3-일) 피라졸로 [3,4-b]피라진 -3- 일]우레아 하이드로클로라이드;  (92) 1- (4-hydroxythoxyphenyl) -3- [5- (pyridin-3-yl) pyrazolo [3,4-b] pyrazin-3-yl] urea hydrochloride;
(93) 에틸 6-아미노 -3-[3-(4-메록시페닐)우레이도] -1^피라졸로 [3,4-b]피리 딘 -5-카복실레이트;  (93) ethyl 6-amino-3- [3- (4-methoxyphenyl) ureido] -1 ^ pyrazolo [3,4-b] pyridine-5-carboxylate;
(94) 에틸 6-아미노 -3-[3-(4-히드록시페닐)우레이도)] -1^피라졸로 [3,4— Z?]피 리딘— 5-카복실레이트;  (94) ethyl 6-amino-3- [3- (4-hydroxyphenyl) ureido)]-1 ^ pyrazolo [3,4—Z?] Pyridine—5-carboxylate;
(95) 4-[3-(5-{3-[2-(디메틸아미노)에톡시]페닐}-1^피라졸로[3,4-/?]피라진 -3-일)우레이도]벤즈아미드 하이드로클로라이드；  (95) 4- [3- (5- {3- [2- (dimethylamino) ethoxy] phenyl} -1 ^ pyrazolo [3,4-/?] Pyrazin-3-yl) ureido] benzamide Hydrochloride;
(96) 2-{3-[4- (피리딘 -4-일)부틸아미노] 피라졸로 [3，4-6]피라진ᅳ 5ᅳ일 }페 놀 하이드로클로라이드;  (96) 2- {3- [4- (pyridin-4-yl) butylamino] pyrazolo [3,4-6] pyrazinyl 5holyl} phenol hydrochloride;
(97) ^벤질 -5—(4-메록시페닐 )-1그피라졸로 [3， 4-b]피라진ᅳ 3-아민；  (97) ^ benzyl-5- (4-methoxyphenyl) -1gpyrazolo [3,4-b] pyrazin-3-amine;
(98) 5-(4-메록시페닐) -Λ 피리딘 -3-일메틸) -1^피라졸로 [3， 4- 피라진ᅳ 3ᅳ아 민 하이드로클로라이드;  (98) 5- (4-methoxyphenyl) -Λ pyridin-3-ylmethyl) -1 ^ pyrazolo [3,4-pyrazine ᅳ 3 ᅳ amine hydrochloride;
(99) 5-(4-메톡시페닐 )— - (피리딘 -4-일메틸 )-1 -피라졸로 [3 , 4-Z?]피라진 -3-아 민 하이드로클로라이드;  (99) 5- (4-methoxyphenyl) —— (pyridin-4-ylmethyl) -1-pyrazolo [3,4-Z?] Pyrazine-3-aminemine chloride;
(100) 에틸 6-아미노 -3- (피리딘 -3-일메틸아미노 )-1 -피라졸로 [3,4-b]피리딘 -5-카복실레이트 하이드로클로라이드;  (100) ethyl 6-amino-3- (pyridin-3-ylmethylamino) -1 -pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(101) 2-{3-[3- (피리딘 -4-일)프로필아미노 ]-1 -피라졸로 [3，4ᅳ ]피라진 -5-일} 페놀 하이드로클로라이드; (102) 2-[3- (피리딘 -3-일메틸아미노 )-L 피라졸로 [3,4-b]피라진 -5-일]페놀 하이드로클로라이드; (101) 2- {3- [3- (pyridin-4-yl) propylamino] -1 -pyrazolo [3,4 '] pyrazin-5-yl} phenol hydrochloride; (102) 2- [3- (pyridin-3-ylmethylamino) -L pyrazolo [3,4-b] pyrazin-5-yl] phenol hydrochloride;
(103) 2- [3- (벤질아미노) 피라졸로 [3， 4-b]피라진 -5-일]페놀;  (103) 2- [3- (benzylamino) pyrazolo [3, 4-b] pyrazin-5-yl] phenol;
( 104) 2-[3- (시클로펜틸아미노) -1^피라졸로 [3 ,4-?]피라진 -5-일 ]페놀;  (104) 2- [3- (cyclopentylamino) -1 ^ pyrazolo [3,4-?] Pyrazin-5-yl] phenol;
(105) Λ46-아미노 -5- [(디메틸아미노)메틸 ] 피라졸로 [3， 4- 피리딘 -3-일 } 니코틴아미드 디하이드로클로라이드;  (105) Λ46-amino-5 [(dimethylamino) methyl] pyrazolo [3,4-pyridin-3-yl} nicotinamide dihydrochloride;
(106) 피리딘 -3-일메틸 6-아미노 -3-(4—메톡시벤즈아미도) -1^피라졸로 [3,4-Α]피리딘 -5-카복실레이트 하이드로클로라이드；  (106) pyridin-3-ylmethyl 6-amino-3- (4—methoxybenzamido) -1 ^ pyrazolo [3,4-Α] pyridine-5-carboxylate hydrochloride;
(107) 페닐 6-아미노—3- (니코틴아미도) -1 ―피라졸로 [3， 4ᅳ/?]피리딘—5-카복실 레이트 하이드로클로라이드;  (107) phenyl 6-amino—3- (nicotinamido) -1 -pyrazolo [3, 4 '/?] Pyridine—5-carboxylate hydrochloride;
(108) 3- (디메틸아미노)프로필 6-아미노 -3-(4-메특시벤즈아미도) -1^피라졸 로 [3， 4-)]피리딘 -5-카복실레이트 하이드로클로라이드；  (108) 3- (dimethylamino) propyl 6-amino-3- (4-mesoxybenzamido) -1 ^ pyrazolo [3,4-)] pyridine-5-carboxylate hydrochloride;
(109) 메틸 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-b]피리딘 -5-카복실 레이트 하이드로클로라이드;  (109) methyl 6-amino-3- (nicotinamido) pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(110) 피리딘 -3-일메틸 6-아미노 -3- (니코틴아미도) -L 피라졸로 [3,4-b]피리 딘 -5-카복실레이트 디하이드로클로라이드;  (110) pyridin-3-ylmethyl 6-amino-3- (nicotinamido) -L pyrazolo [3,4-b] pyridine-5-carboxylate dihydrochloride;
(111) 피리딘 -3-일메틸 6-아미노 -3-(4-니트로벤즈아미도) -1 -피라졸로 [3 A-b]피리딘 -5-카복실레이트 하이드로클로라이드；  (111) pyridin-3-ylmethyl 6-amino-3- (4-nitrobenzamido) -1 -pyrazolo [3 A-b] pyridine-5-carboxylate hydrochloride;
(112) 6-아미노-씨디메틸 -3- (니코틴아미도) - 1 -피라졸로 [ 3 , 4 - ]피리딘 -5- 카복사아미드 하이드로클로라이드;  (112) 6-amino-cidimethyl-3- (nicotinamido) -1-pyrazolo [3,4-] pyridine-5-carboxamide hydrochloride;
(113) 에틸 6-아미노 -3-{4-[2- (디메틸아미노)에틸]벤즈아미도 }-1 -피라졸로 [3 , 4- 피리딘 -5-카복실레이트 하이드로클로라이드；  (113) ethyl 6-amino-3- {4- [2- (dimethylamino) ethyl] benzamido} -1 -pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(114) 에틸 6-아미노 -3-[3- (디메틸아미노)프로판아미도]— 1 -피라졸로 [3,4-Δ] 피리딘 -5-카복실레이트 하이드로클로라이드;  (114) ethyl 6-amino-3- [3- (dimethylamino) propaneamido] — 1-pyrazolo [3,4-Δ] pyridine-5-carboxylate hydrochloride;
(115) 에틸 6-아미노 -3-(3-모폴리노프로판아미도) -1 -피라졸로 [3,4-?]피리딘 -5-카복실레이트 하이드로클로라이드;  (115) ethyl 6-amino-3- (3-morpholinopropaneamido) -1 -pyrazolo [3,4-?] Pyridine-5-carboxylate hydrochloride;
(116) 에틸 6-아미ᅵ노 -3-{4- [(디메틸아미노)메틸]벤즈아미도 }-1 -피라졸로 [3， 4-Ζ)]피리딘 -5-카복실레이트 하이드로클로라이드； (116) ethyl 6- ami L --3- {4-[(dimethylamino) methyl] benzamido} -1 -pyrazolo [3,4-VII)] pyridine-5-carboxylate hydrochloride;
(117) 에틸 6-아미노 -3-{4- (모폴리노메틸)벤즈아미도] 피라졸로 [3, 4-b]피 리딘 -5-카복실레이트 하이드로클로라이드;  (117) ethyl 6-amino-3- {4- (morpholinomethyl) benzamido] pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(118) 에틸 6-아미노 -3-[4-(2-모폴리노에틸)벤즈아미도] -1 -피라졸로 [3,4-Ζ?] 피리딘 -5-카복실레이트 하이드로클로라이드;  (118) ethyl 6-amino-3- [4- (2-morpholinoethyl) benzamido] -1-pyrazolo [3,4-d?] Pyridine-5-carboxylate hydrochloride;
(119) 에틸 6-아미노 -3-{3-[3- (디메틸아미노)프로판아미도]벤즈아미도 }-1 - 피라졸로 [3 , 4-Z?]피리딘 -5-카복실레이트 하이드로클로라이드；  (119) ethyl 6-amino-3- {3- [3- (dimethylamino) propaneamido] benzamido} -1 -pyrazolo [3,4-Z?] Pyridine-5-carboxylate hydrochloride;
(120) 에틸 6-아미노 -3-[3ᅳ(3_모폴리노프로판아미도)벤즈아미도] -1 —피라졸 로 [3， 4-b]피리딘 -5-카복실레이트 하이드로클로라이드；  (120) ethyl 6-amino-3- [3 ′ (3_morpholinopropaneamido) benzamido] -1 —pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(121) 피리딘 -3-일메틸 6—아미노 -3_[4- (피리딘 -3-일메록시 )벤즈아미도] -L 피라졸로 [3, 4- 피리딘 -5-카복실레이트 디하이드로클로라이드;  (121) pyridin-3-ylmethyl 6—amino-3_ [4- (pyridin-3-ylmethoxy) benzamido] -L pyrazolo [3,4-pyridine-5-carboxylate dihydrochloride;
(122) 에틸 6—아미노 -3-{4-[2- (디메틸아미노)에톡시]벤즈아미도 }ᅳ1^피라졸 로 [3, 4-6]피리딘 -5-카복실레이트 하이드로클로라이드;  (122) ethyl 6-amino-3- {4- [2- (dimethylamino) ethoxy] benzamido} ᅳ 1 ^ pyrazolo [3, 4-6] pyridine-5-carboxylate hydrochloride;
(123) 에틸 6-아미노 -3-[4— (피리딘 -3-일메록시)벤즈아미도] -1 -피라졸로 [3 , 4- 피리딘 -5-카복실레이트 하이드로클로라이드；  (123) ethyl 6-amino-3- [4— (pyridin-3-ylmethoxy) benzamido] -1-pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(124) 에틸 6-아미노 -3-{6-[2- (디메틸아미노)에록시]니코틴아미도 }-L-피라 졸로 [3， 4-b]피리딘 -5-카복실레이트 디하이드로클로라이드； (124) ethyl 6-amino-3- {6- [2- (dimethylamino) ethoxy] nicotinamido} -L-pyra Solo [3, 4-b] pyridine-5-carboxylate dihydrochloride;
(125) 에틸 6-아미노 -3-[6- (피리딘 -3-일메특시)니코틴아미도] 피라졸로 [3， 4- 피리딘 -5-카복실레이트 디하이드로클로라이드；  (125) ethyl 6-amino-3- [6- (pyridin-3-ylmethoxy) nicotinamido] pyrazolo [3,4-pyridine-5-carboxylate dihydrochloride;
(126) 에틸 6-아미노 -3-[4-(2-모폴리노에톡시)벤즈아미도]ᅳ 1 -피라졸로 [3 , 4-b]피리딘 -5-카복실레이트 하이드로클로라이드；  (126) ethyl 6-amino-3- [4- (2-morpholinoethoxy) benzamido] '1-pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(127) 에틸 6-아미노 -3-[4- (니코티노일옥시)벤즈아미도] -L7-피라졸로 [3,4-Ζ?] 피리딘 -5-카복실레이트 하이드로클로라이드;  (127) ethyl 6-amino-3- [4- (nicotinoyloxy) benzamido] -L7-pyrazolo [3,4-VII?] Pyridine-5-carboxylate hydrochloride;
(128) 에틸 6-아미노 _3-{4-[2- (피리딘 -4-일)에톡시]벤즈아미도 }-1 -피라졸로 [3， 4-?]피리딘 -5-카복실레이트 하이드로클로라이드；  (128) ethyl 6-amino_3- {4- [2- (pyridin-4-yl) ethoxy] benzamido} -1 -pyrazolo [3,4-?] Pyridine-5-carboxylate hydrochloride;
(129) yV-[6-아미노 -5-(4-메톡시페닐) -1그피라졸로 [3,4- ]피라진 -3-일] -2-(4- 메톡시페닐) - 2-옥소아세트아미드;  (129) yV- [6-amino-5- (4-methoxyphenyl) -1gpyrazolo [3,4-] pyrazin-3-yl] -2- (4-methoxyphenyl) -2-oxo Acetamide;
(130) 2- (4-아미노페닐 ) -V-[5-(4-메톡시페닐) -1 -피라졸로 [3， 4— ]피라진 -3- 일] -2-옥소아세트아미드 하이드로클로라이드；  (130) 2- (4-aminophenyl) -V- [5- (4-methoxyphenyl) -1-pyrazolo [3,4—] pyrazin-3-yl] -2-oxoacetamide hydrochloride;
(131) 에틸 6-아미노 -3-[2-(4-메특시페닐) -2-옥소아세트아미도ᅵ— 1 -피라졸로 [3， 4-Z?]피리딘ᅳ 5-카복실레이트；  (131) ethyl 6-amino-3- [2- (4-methoxyphenyl) -2-oxoacetamido—— 1-pyrazolo [3, 4-Z?] Pyridine ᅳ 5-carboxylate;
(132) 에틸 6-아미노 -3-[3_ (핵실옥시술포닐)벤즈아미도] -1 -피라졸로 [3,4-¾ 피리딘 -5-카복실레이트;  (132) ethyl 6-amino-3- [3_ (nuxyloxysulfonyl) benzamido] -1-pyrazolo [3,4-¾ pyridine-5-carboxylate;
(133) 3- [ 6-아미노 -5- (에록시카보닐) - 1 -피라졸로 [ 3， 4 -A]피리딘 -3-일카바모 일]벤젠술포닉 액시드;  (133) 3- [6-amino-5- (ethoxycarbonyl) -1-pyrazolo [3,4-A] pyridin-3-ylcarbamoyl] benzenesulfonic acid;
(134) 에틸 6-아미노 -3-[3- (에록시술포닐)밴즈아미도] -1가피라졸로 [3,4-b]피 리딘 -5-카복실레이트;  (134) ethyl 6-amino-3- [3- (ethoxysulfonyl) bansamido] -1gapyrazolo [3,4-b] pyridine-5-carboxylate;
(135) 에틸 6-아미노 -3-[3- (프로폭시술포닐)벤즈아미도] -1 -피라졸로 [3,4-Ζ?] 피리딘 -5-카복실레이트;  (135) ethyl 6-amino-3- [3- (propoxysulfonyl) benzamido] -1-pyrazolo [3,4-d?] Pyridine-5-carboxylate;
(136) 소듐 3-{3-[5-(4-메록시페닐) -1 -피라졸로 [3，4-싀피라진 -3-일]우레이 도}프로파노에이트;  (136) sodium 3- {3- [5- (4-methoxyphenyl) -1-pyrazolo [3,4-pypyrazin-3-yl] urei do} propanoate;
(137) 에틸 6-아미노 -1-(2-아미노아세틸 )-3— (니코틴아미도) -1 ^피라졸로 [3， 4 - 피리딘 -5-카복실레이트 디하이드로클로라이드;  (137) ethyl 6-amino-1- (2-aminoacetyl) -3— (nicotinamido) -1 ^ pyrazolo [3,4-pyridine-5-carboxylate dihydrochloride;
(138) 에틸 6-아미노 _1-(2-아미노 -3-메틸부타노일 )-3- (니코틴아미도)— 1 ^피 라졸로 [3ᅳ 4-Δ]피리딘 -5-카복실레이트 디하이드로클로라이드；  (138) ethyl 6-amino _1- (2-amino-3-methylbutanoyl) -3- (nicotinamido) — 1 ^ pyrazolo [3 ′ 4-Δ] pyridine-5-carboxylate dihydrochloride ;
(139) 에틸 6-아미노 -1_[2- (메틸아미노)아세틸 ]-3- (니코틴아미도) -1 -피라졸 로 [3,4-b]피리딘— 5-카복실레이트 디하이드로클로라이드;  (139) ethyl 6-amino-1_ [2- (methylamino) acetyl] -3- (nicotinamido) -1-pyrazolo [3,4-b] pyridine— 5-carboxylate dihydrochloride;
(140) 에틸 6-아미노 -1-(2-모폴리노아세틸) -3- (니코틴아미도) -1 -피라졸로 [3， 4-b]피리딘 -5-카복실레이트 디하이드로클로라이드；  (140) ethyl 6-amino-1- (2-morpholinoacetyl) -3- (nicotinamido) -1-pyrazolo [3,4-b] pyridine-5-carboxylate dihydrochloride;
(141) 에틸 6-아미노 -1-[2-( ·^부특시카보닐아미노)아세틸 ]-3- (니코틴아미 도) -L-피라졸로 [3， 4 - ]피리딘 -5-카복실레이트；  (141) ethyl 6-amino-1- [2-(. ^ Subspecificcarbonylamino) acetyl] -3- (nicotinamido) -L-pyrazolo [3,4-] pyridine-5-carboxylate;
(142) 에틸 6-아미노 -1-[2-(2-아미노아세트아미도)아세틸 ]-3- (니코틴아미 도) -1 -피라졸로 [3 , 4-/?]피리딘 -5-카복실레이트 디하이드로클로라이드；  (142) ethyl 6-amino-1- [2- (2-aminoacetamido) acetyl] -3- (nicotinamido) -1-pyrazolo [3,4-/?] Pyridine-5-carboxylate Dihydrochloride;
(143) 에틸 1-(2-아세트아미도아세틸 )-6-아미노 -3- (니코틴아미도) -1 -피라졸 로 [3， 4-0]피리딘 -5-카복실레이트 하이드로클로라이드；  (143) ethyl 1- (2-acetamidoacetyl) -6-amino-3- (nicotinamido) -1-pyrazolo [3,4-0] pyridine-5-carboxylate hydrochloride;
(144) 에틸 6-아미노 -3- (니코틴아미도) -1-{2-[(2,2,2-트리클로로에톡시)카보 닐아미노]아세틸 }-1 -피라졸로 [3 , 4-b]피리딘 -5-카복실레이트；  (144) ethyl 6-amino-3- (nicotinamido) -1- {2-[(2,2,2-trichloroethoxy) carbonylamino] acetyl} -1 -pyrazolo [3, 4- b] pyridine-5-carboxylate;
(145) 에틸 6-아미노 -1-(2,6-디아미노핵사노일 )ᅳ3- (니코틴아미도) 피라졸 로 [3 ,4-?]피리딘 -5-카복실레이트 트리하이드로클로라이드； (146) 에틸 6-아미노 -l-(3-아미노프로파노일) -3— (니코틴아미도) -1 ―피라졸로 [3， 피리딘 -5-카복실레이트 디하이드로클로라이드； (145) ethyl 6-amino-1- (2,6-diaminonucleoanoyl) ᅳ 3- (nicotinamido) pyrazolo [3,4-?] Pyridine-5-carboxylate trihydrochloride; (146) ethyl 6-amino-l- (3-aminopropanoyl) -3— (nicotinamido) -1 -pyrazolo [3, pyridine-5-carboxylate dihydrochloride;
(147) 5-에틸 1-페닐 6-아미노 -3- (니코틴아미도) -1 -피라졸로 [3, 4- ]피리딘 -1,5-디카복실레이트 하이드로클로라이드;  (147) 5-ethyl 1-phenyl 6-amino-3- (nicotinamido) -1-pyrazolo [3,4-] pyridine-1,5-dicarboxylate hydrochloride;
148) 디에틸 6-아미노 -3- (니코틴아미도) -L¥-피라졸로 [3, 4- 피리딘 -1,5-디카 복실레이트 하이드로클로라이드;  148) diethyl 6-amino-3- (nicotinamido) -L-pyrazolo [3,4-pyridine-1,5-dicarboxylate hydrochloride;
(149) 에틸 5-(2-히드록시페닐 )-3- (니코틴아미도) 피라졸로 [3,4-b]피라진 -1-카복실레이트;  (149) ethyl 5- (2-hydroxyphenyl) -3- (nicotinamido) pyrazolo [3,4-b] pyrazine-1-carboxylate;
(150) 에틸 6-아미노 -1-[3- (디메틸아미노)프로필 ]-3- (니코틴아미도) -1 -피라 졸로 [3， 4 -b]피리딘 -5-카복실레이트 디하이드로클로라이드;  (150) ethyl 6-amino-1- [3- (dimethylamino) propyl] -3- (nicotinamido) -1-pyrazolo [3,4-b] pyridine-5-carboxylate dihydrochloride;
( 151) 6-(4-히드록시페닐 )-L 피라졸 S [3， 4 피리딘 -3-아민；  (151) 6- (4-hydroxyphenyl) -L pyrazole S [3, 4 pyridin-3-amine;
(152) 6— (4-메록시페닐) -3- (피를리딘 -1-일) -1^피라졸로 [3,4- 피리딘; 및 (152) 6— (4-methoxyphenyl) -3- (pyridin-1-yl) -1 ^ pyrazolo [3,4-pyridine; And
(153) 6-(4-히드록시페닐 )-3- (피를리딘 -1-일) -1^피라졸로 [3，4- 피리딘으로 이루어지는 군으로부터 선택되는 어느 하나이다. 본 발명의 화학식 1의 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며， 염으로는 약학적으로 허용 가능한 유리산 (free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산， 인산， 황산， 브롬화수소산， 요드화수 소산， 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트， 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류， 지방족 및 방향족 설폰산류와 같은 무독성 유기산， 아세트산， 안식향산, 구 연산 젖산， 말레인산 글루콘산, 메탄설폰산， 4-틀루엔설폰산， 주석산， 푸마르산 과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트， 피 로설페이트， 바이설페이트， 설파이트， 바이설파이트， 니트레이트， 포스페이트, 모 노하이드로겐 포스페이트, 디하이드로겐 포스페이트， 메타포스페이트， 피로포스페 이트 클로라이드, 브로마이드， 아이오다이드, 플루오라이드， 아세테이트， 프로피오 네이트， 데카노에이트, 카프릴레이트， 아크릴레이트, 포메이트， 이소부티레이트， 카프레이트， 헵타노에이트， 프로피올레이트， 옥살레이트， 말로네이트， 석시네이트, 수베레이트， 세바케이트, 푸마레이트， 말리에이트， 부틴 -1,4-디오에이트， 핵산 -1，6-디오에이트， 벤조에이트， 클로로벤조에이트， 메틸벤조에이트, 디니트로 벤조 에이트， 하이드록시벤조에이트, 메록시벤조에이트， 프탈레이트， 테레프탈레이트， 벤젠설포네이트， 를루엔설포네이트, 클로로벤젠설포네이트， 크실렌설포네이트， 페 닐아세테이트， 페닐프로피오네이트, 페닐부티레이트， 시트레이트， 락테이트, β-하 이드록시부티레이트, 글리콜레이트, 말레이트， 타트레이트， 메탄설포네이트， 프로 판설포네이트, 나프탈렌 -1-설포네이트, 나프탈렌 -2-설포네이트 또는 만델레이트를 포함한다. (153) 6- (4-hydroxyphenyl) -3- (pyridin-1-yl) -1 ^ pyrazolo is one selected from the group consisting of [3,4-pyridine. The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydrochloric acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid lactic acid, maleic acid gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate Nate, Suberic, Sebacate, Fumarate, Maleate, Butine-1,4-Diate, Nucleic Acid-1,6-Diate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxy Benzoate, Meoxybenzoate, Phthalate, Terephthalate Benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tart Ethylene, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면， 화학식 1의 유도체를 유기용매， 예를 들면 메탄을， 에탄올， 아세톤， 메틸렌클로라이드, 아세토니트릴 등 에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과， 건조하여 제조되거 나， 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜셔 제조할 수 있다.  Acid addition salt according to the present invention is a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent, for example methane, ethanol, acetone, methylene chloride, acetonitrile and the like, and adding an organic or inorganic acid It can be prepared by filtration, drying, or by distillation under reduced pressure of the solvent and excess acid and dried or crystallized in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알 칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산 화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고， 비용해 화합물 염을 여과 하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속 염으로는 나트륨， 칼륨 또는 칼 슘염을 제조하는 것이 제약상 적합하다. 또한， 이에 대웅하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예， 질산은)과 반응시켜 얻는다. 나아가， 본 발명은 상기 화학식 1로 표시되는 피라졸로 피리딘 유도체 및 이 의 약학적으로 허용되는 염뿐만 아니라， 이로부터 제조될 수 있는 가능한 용매화 물， 수화물， 입체이성질체 등을 모두 포함한다. 또한, 본 발명은 상기 화학식 1로 표시되는 피라졸로 피리딘 유도체의 제조 방법을 제공한다. Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts, for example, compounds in excess of alkali metal It is dissolved in a cargo or alkaline earth metal hydroxide solution, and is obtained by filtering the insoluble compound salt and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate). Furthermore, the present invention includes not only pyrazolo pyridine derivatives represented by the general formula (1) and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, stereoisomers and the like that can be prepared therefrom. The present invention also provides a method for preparing a pyrazolo pyridine derivative represented by the formula (1).
본 발명에 따른 화학식 1의 유도체의 제조방법은 하기 반웅식 1에 나타낸 바 와 같이， 화학식 2로 표시되는 케톤 화합물을 산화시켜 화학식 3으로 표시되는 화 합물을 얻는 단계 (단계 1);  Method for preparing a derivative of Formula 1 according to the present invention, as shown in the following reaction formula 1, the step of oxidizing the ketone compound represented by the formula (2) to obtain a compound represented by the formula (3) (step 1);
상기 단계 1에서 제조된 화학식 3으로 표시되는 화합물을 탈수반웅을 수행하 여 화학식 4로 표시되는 화합물을 얻는 단계 (단계 2);  Dehydrating the compound represented by Chemical Formula 3 prepared in Step 1 to obtain a compound represented by Chemical Formula 4 (step 2);
상기 단계 2에서 제조된 화학식 4로 표시되는 화합물올 2-아미노말로노니트 릴과 축합반웅을 수행하여 화학식 5로 표시되는 화합물을 얻는 단계 (단계 3); 상기 단계 3에서 제조된 화학식 5로 표시되는 화합물을 삼염화인과 환원반웅 시켜 화학식 6으로 표시되는 화합물을 얻는 단계 (단계 4);  Performing a condensation reaction with the compoundol 2-aminomalononitrile represented by Chemical Formula 4 prepared in Step 2 to obtain a compound represented by Chemical Formula 5 (step 3); Reducing the compound represented by Chemical Formula 5 prepared in Step 3 with phosphorus trichloride to obtain a compound represented by Chemical Formula 6 (step 4);
상기 단계 4에서 제조된 화학식 6으로 표시되는 화합물을 샌드마이어 (sandmeyer)반응을 수행하여 화학식 7로 표시되는 화합물을 얻는 단계 (단계 5); 상기 단계 5에서 제조된 화학식 7로 표시되는 화합물을 보호기로 보호된 히 드라진 수화물과 고리화반웅을 수행하여 화학식 8로 표시되는 화합물을 얻는 단계 (단계 6)；  Performing a sandmeyer reaction on the compound represented by Chemical Formula 6 prepared in Step 4 to obtain a compound represented by Chemical Formula 7 (step 5); Performing a cyclization reaction with a hydrazine hydrate protected with a protecting group, the compound represented by Chemical Formula 7 prepared in Step 5 to obtain a compound represented by Chemical Formula 8 (step 6);
화학식 8로 표시되는 화합물을 화학식 9로 표시되는 각각의 화합물과 반웅을 수행하여 화학식 10으로 표시되는 화합물을 얻는 단계 (단계 7); 및  Reacting the compound represented by the formula (8) with each compound represented by the formula (9) to obtain a compound represented by the formula (10) (step 7); And
상기 화학식 10으로 표시되는 화합물의 보호기를 제거하는 반응을 수행하여 화학식 la로 표시되는 화합물을 얻는 단계 (단계 8)를 포함하는 제조방법:  A process for preparing a compound represented by Chemical Formula la by performing a reaction for removing a protecting group of the compound represented by Chemical Formula 10 (Step 8):
[반응식 1] Scheme 1
단계 2 O 단계 3Step 2 O Step 3
Figure imgf000024_0001
Figure imgf000024_0001
5 단계 4  5 steps 4
Figure imgf000024_0002
단계 7
Figure imgf000024_0002
Step 7
Figure imgf000024_0003
Figure imgf000024_0003
10 1a  10 1a
(상기 반웅식 1에서 A, R5, R10은 상기 화학식 1에서 정의한 바와 같고， P 보호기로써 , 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), p-메록시벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). (In the reaction formula 1, A, R 5 , R 10 are as defined in Formula 1, and as a P protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxy Benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
. 상기 단계 1은 상업적으로 쉽게 확보할 수 있거나 종래에 알려져 있는 방법 에 의하여 제조된 화학식 2로 표시되는 케톤 화합물을 셀레늄옥사이드를 사용하여 산화시켜 화학식 3으로 표시되는 화합물을 제조하는 단계이다. . Step 1 is a step of preparing a compound represented by Chemical Formula 3 by oxidizing a ketone compound represented by Chemical Formula 2 using selenium oxide, which may be easily obtained commercially or prepared by a conventionally known method.
이때, 사용 가능한 유기용매로는 반웅에 악영향을 미치지 않는 용매를 사용 할수 있고， 바람직하게는 디옥산과 물을 흔합하여 사용할 수 있다.  In this case, as the organic solvent that can be used, a solvent that does not adversely affect reaction can be used, and preferably dioxane and water can be used in combination.
또한, 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, the reaction temperature is not particularly limited, but may be performed within a boiling point range of the room temperature to the solvent.
구체적으로, 상기 화학식 2로 표시되는 화합물을 1,4-디옥산 및 물에 용해한 후， 60 °C에서 셀레늄옥사이드를 첨가하여 교반하고, 반웅 종결 후, 컬럼 크로마토 그래피를 수행하여 화학식 3으로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 2는 상기 1 단계에서 제조된 화학식 3으로 표시되는 화합물 을 히드록시아민과 아세트산나트륨를 이용하여 탈수 반웅을 수행하여 화학식 4로 표시되는 화합물을 제조하는 단계이다. Specifically, after dissolving the compound represented by Chemical Formula 2 in 1,4-dioxane and water, the mixture is stirred by adding selenium oxide at 60 ° C. After the reaction is completed, column chromatography is performed to perform the column chromatography. Compounds can be obtained. In addition, step 2 is a step of preparing a compound represented by Formula 4 by performing a dehydration reaction using hydroxyamine and sodium acetate to the compound represented by Formula 3 prepared in step 1.
이때， 사용 가능한 용매는 유기용매를 사용하지 않고, 물에서 반웅을 수행할 수 있다.  In this case, the usable solvent may be reacted in water without using an organic solvent.
또한, 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다. In addition, the reaction temperature is not particularly limited, but the boiling point range of the room temperature to the solvent It can be performed within the stomach.
구체적으로， 상기 화학식 3으로 표시되는 화합물을 1,4-디옥산 및 물에 녹힌 후， 히드록시아민 하이드로클로라이드와 무수 소듐 아세테이트를 첨가하고， 70 °C 에서 교반하고, 반웅 종결 후， 컬럼 크로마토그래피를 수행하여 화학식 4로 표시되 는 화합물을 얻을 수 있다. 나아가， 상기 단계 3은 상기 제 2 단계에서 제조된 화학식 4로 표시되는 화 합물을 2-아미노말로노니트릴과 축합 반웅시켜 화학식 5로 표시되는 화합물을 얻는 단계이다.  Specifically, after dissolving the compound represented by Chemical Formula 3 in 1,4-dioxane and water, hydroxyamine hydrochloride and anhydrous sodium acetate are added, stirred at 70 ° C, and after completion of reaction, column chromatography To obtain a compound represented by the formula (4). Furthermore, step 3 is a step of condensing the compound represented by Formula 4 prepared in the second step with 2-aminomalononitrile to obtain a compound represented by Formula 5.
이때, 사용 가능한 유기용매로는 반응에 악영향을 미치지 않는 메탄을， 에탄 올, 2-프로판을， 이소부탄올 또는 부탄을 등을 이용하여 반웅을 수행할 수 있고ᅳ 바람직하게는 2-프로판올을 사용할 수 있다.  At this time, the usable organic solvent may be reacted using methane, ethanol, 2-propane, isobutanol or butane, etc., which does not adversely affect the reaction, and preferably 2-propanol may be used. have.
또한， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, the reaction temperature is not particularly limited, but may be performed within a boiling point range of the room temperature to the solvent.
구체적으로， 화학식 4로 표시되는 화합물올 2-프로판올에 녹인 후， 2—아미노 말로노니트릴을 첨가하고， 교반 한 후， 생성된 고체를 여과하여 화학식 5로 표시되 는 화합물을 얻을 수 있다. 또한， 상기 단계 4는 상기 제 3 단계에서 제조된 화학식 5로 표시되는 화합 물을 삼염화인과 환원반응을 수행하여 화학식 6으로 표시되는 화합물을 얻는 단계 이다.  Specifically, the compound represented by Chemical Formula 4 may be dissolved in 2-propanol, 2—amino malononitrile is added, stirred, and the resulting solid is filtered to obtain a compound represented by Chemical Formula 5. In addition, step 4 is a step of obtaining a compound represented by the formula (6) by reducing the compound represented by the formula (5) prepared in the third step with phosphorus trichloride.
이때， 사용 가능한 유기용매로는 반웅에 악영향을 미치지 않는 디클로로메 탄， 클로로포름, 테트라히드로퓨란, 디에틸에테르, 를루엔 또는 디메틸포름아미드 등을 이용할 수 있고， 바람직하게는 테트라히드로퓨란을 이용할 수 있다.  In this case, as the organic solvent that can be used, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not adversely affect reaction, can be used, and preferably tetrahydrofuran can be used. .
또한， 반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, the reaction temperature is not particularly limited, but may be performed in a boiling point range of room temperature to the solvent.
구체적으로， 상기 화학식 5로 표시되는 화합물을 테트라히드로퓨란에 녹인 후， 0 °C로 온도를 낮추고， 삼염화인을 천천히 첨가한 후, 교반한다. 반웅 종결 후, 생성된 고체를 물로 세척하여 화학식 6으로 표시되는 화합물을 얻을 수 있다. 나아가, 상기 단계 5는 상기 제 4 단계에서 제조된 화학삭 6으로 표시되는 화합물과 촉매량의 염화구리 (II)를 첨가하고 이소아밀나이트리트를 사용하여 샌드 마이어 (sandmeyer)반응을 수행하여 화학식 7로 표시되는 화합물을 얻는 단계이다. 이때， 사용가능한 유기용매로는 반웅에 악영향을 미치지 않는 용매인 디클로 로메탄， 클로로포름, 아세토니트릴, 테트라히드로퓨란, 디에틸에테르, 를루엔 또는 디메틸포름아미드 등을 이용하여 반웅을 수행할 수 있고, 바람직하게는 아세토니트 릴을사용할 수 있다. Specifically, after dissolving the compound represented by the formula (5) in tetrahydrofuran, lowering the temperature to 0 ° C, slowly adding phosphorus trichloride, and then stirred. After completion of reaction, the resulting solid may be washed with water to obtain a compound represented by Chemical Formula 6. Further, the step 5 is added to the compound represented by the chemical machination 6 prepared in the fourth step and the catalytic amount of copper chloride (II) and subjected to a sandmeyer reaction using isoamyl nitrite to formula (7) It is a step of obtaining the displayed compound. In this case, the usable organic solvent may be subjected to reaction using dichloromethane, chloroform, acetonitrile, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, which do not adversely affect reaction. Preferably, acetonitrile can be used.
또한， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, the reaction temperature is not particularly limited, but may be performed within a boiling point range of the room temperature to the solvent.
구체적으로, 화학식 6으로 표시되는 화합물을 아세토니트릴에 녹인 후， 염화 구리 및 이소아밀 니트릴을 첨가하여 50 °C에서 환류 교반하고， 반웅 종결 후， 컬 럼 크로마토그래피를 수행하여 화학식 7로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 6은 상기 5 단계에서 제조된 화학식 7로 표시되는 화합물을 보호기로 보호된 히드라진 수화물과 고리화반응을 수행하여 화학식 8로 표시되는 화합물을 얻는 단계이다. Specifically, after dissolving the compound represented by the formula (6) in acetonitrile, the reaction was stirred under reflux at 50 ° C by addition of copper chloride and isoamyl nitrile, and after completion of the reaction to perform a column chromatography to the compound represented by the formula (7) Can be obtained. In addition, step 6 is a step of obtaining a compound represented by the formula (8) by performing a cyclization reaction of the compound represented by the formula (7) prepared in step 5 with a hydrazine hydrate protected with a protecting group.
이때, 사용가능한 유기용매로는 반응에 악영향을 미치지 않는 용매인 메탄 을， 에탄올， 아세토니트릴, 피리딘， 테트라히드로퓨란 또는 디메틸포름아미드 등을 이용하여 반응을 수행할 수 있고, 바람직하게는 에탄올을 사용할 수 있다.  At this time, the usable organic solvent may be reacted with methane, a solvent which does not adversely affect the reaction, using ethanol, acetonitrile, pyridine, tetrahydrofuran or dimethylformamide, preferably ethanol. Can be.
또한, 반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, the reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
구체적으로， 상기 단계 5에서 제조된 화학식 7로 표시되는 화합물을 에탄을 에 녹인 후， 4-메톡시벤질히드라진 화합물을 첨가하고 90 °C에서 환류 교반하여 반웅을 수행하고, 반응 종결 후， 화학식 8로 표시되는 화합물올 얻을 수 있다. 나아가， 상기 단계 7은 상기 단계 6에서 제조된 화학식 8로 표시되는 화합물 과 화학식 9로 표시되는 화합물을 반응시켜 화학식 10으로 표시되는 화합물을 얻는 단계이다. Specifically, after dissolving ethane in the compound represented by Chemical Formula 7 prepared in step 5, 4-methoxybenzylhydrazine compound is added and reacted by stirring under reflux at 90 ° C., after completion of the reaction, Formula 8 The compound represented by can be obtained. Furthermore, Step 7 is a step of obtaining a compound represented by Chemical Formula 10 by reacting the compound represented by Chemical Formula 8 prepared in Step 6 with the compound represented by Chemical Formula 9.
상기 단계 7은 상기 단계 6에서 제조된 화학식 8로 표시되는 화합물을 치오 닐클로라이드 또는 옥살릴클로라이드 등을 이용하여 제조된 화학식 9로 표시되는 카보닐클로라이드 화합물과 아미드화 반웅 (amidation react ion)을 수행하여 화학식 10으로 표시되는 화합물을 제조할 수 있다.  Step 7 is amidation reaction ion with the carbonyl chloride compound represented by the formula (9) prepared by using a cheonyl chloride or oxalyl chloride prepared in step 6 To prepare a compound represented by Formula 10.
상기 단계 7의 반응은 염기를 사용하지 않고 수행할 수 있으나， 일반적으로 는 아미드화 반응에 사용될 수 있는 염기인 피리딘， 트리에틸아민, 디에틸이소프로 필아민 또는 N-메틸모르폴린 등을 사용할 수 있고， 바람직하게는 DMF를 사용할 수 ¬다  The reaction of step 7 may be performed without using a base, but generally, pyridine, triethylamine, diethylisopropylamine, N-methylmorpholine, or the like, which may be used for the amidation reaction, may be used. Can be used, preferably using DMF.
또한， 사용가능한 용매로는 반응에 영향을 미치지 않는 디클로로메탄， 클로 로포름， 테트라히드로퓨란, 디에틸에테르, 틀루엔 또는 디메틸포름아미드 등을 이 용할수 있고， 바람직하게는 디클로로메탄을 사용할 수 있다.  In addition, as the solvent which can be used, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not affect the reaction, can be used, and preferably dichloromethane can be used. .
나아가， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.  Further, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
구체적으로， 상기 화학식 9로 표시되는 화합물을 디클로로메탄에 녹인 후， 0 °C에서 옥살릴클로라이드 및 DMF를 천천히 첨가하여 교반하고， 화학식 8로 표시되 는 화합물을 피리딘에 녹여 반웅흔합물에 첨가하고 교반하여 반웅을 수행하고, 반 응 종결 후， 컬럼 크로마토그래피를 수행하여 화학식 10으로 표시되는 화합물을 얻 을 수 있다. 또한, 상기 단계 8은 상기 단계 7에서 제조된 화학식 10으로 표시되는 화합 물을 탈보호 반응을 수행하여 화학식 la로 표시되는 화합물을 제조하는 단계이다. Specifically, after dissolving the compound represented by the formula (9) in dichloromethane, and slowly adding and stirring oxalyl chloride and DMF at 0 ° C., the compound represented by the formula (8) is dissolved in pyridine and added to the semi-ungmul mixture The reaction is carried out by stirring, and after completion of the reaction, column chromatography may be performed to obtain a compound represented by Chemical Formula 10. In addition, step 8 is a step of preparing a compound represented by the formula la by performing a deprotection reaction of the compound represented by the formula (10) prepared in step 7.
상기 화학식 10으로 표시되는 화합물을 용매에 녹인 후， 산을 첨가한 후 반 웅을 수행하여 화학식 la로 표시되는 화합물올 얻을 수 있다.  After dissolving the compound represented by Chemical Formula 10 in a solvent, an acid may be added followed by reaction to obtain a compound represented by Chemical Formula la.
이때， 사용 가능한산으로는 염산， 황산， 질산， 아세트산 또는 트리플루오르 아세트산 등을 사용할 수 있고, 바람직하게는 트리플루오르아세트산을 사용할 수 있다.  At this time, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, or the like can be used, and preferably trifluoroacetic acid can be used.
또한， 사용가능한 용매로는 반웅에 악영향을 미치지 않는 디클로로메탄, 클 로로포름， 테트라히드로퓨란， 디에틸에테르， 틀루엔 또는 디메틸포름아미드 등을 사용할 수 있고， 바람직하게는사용을 하지 않을 수 있다. In addition, usable solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, which do not adversely affect reaction. Can be used, preferably may not be used.
나아가， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.  Further, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
구체적으로， 상기 화학식 10으로 표시되는 화합물을 트리플루오르아세트산에 녹인 후， 교반하여 반웅을 수행한 후, 반웅 종결 후, 반웅물을 감압 여과하여 화학 식 la로 표시되는 화합물을 얻을 수 있다. 또한, 본 발명에 따른 화학식 1의 유도체의 다른 제조방법은 하기 반웅식 2 에 나타낸 바와 같이， 화학식 11로 표시되는 시아노아세테이트 화합물에 에틸클로 로포르메이트를 첨가하여 화학식 12로 표시되는 화합물을 얻는 단계 (단계 1);  Specifically, the compound represented by Chemical Formula 10 may be dissolved in trifluoroacetic acid, stirred to perform reaction, and after completion of reaction, the reaction product may be filtered under reduced pressure to obtain a compound represented by Chemical Formula la. In addition, another method for preparing a derivative of Formula 1 according to the present invention is obtained by adding ethyl chloroformate to the cyanoacetate compound represented by Formula 11 to obtain a compound represented by Formula 12, as shown in Reaction Formula 2 below. Step (step 1);
상기 단계 1에서 제조된 화학식 12로 표시되는 화합물을 메틸화 반웅을 수행 하여 화학식 13으로 표시되는 화합물을 얻는 단계 (단계 2);  Performing a methylation reaction on the compound represented by Chemical Formula 12 prepared in Step 1 to obtain a compound represented by Chemical Formula 13 (step 2);
상기 단계 2에서 제조된 화학식 13으로 표시되는 화합물을 2—시아노아세트아 미드와축합 반응시켜 화학식 14로 표시되는 화합물을 얻는 단계 (단계 3);  Condensing the compound represented by Chemical Formula 13 prepared in Step 2 with 2—cyanoacetamide to obtain a compound represented by Chemical Formula 14 (step 3);
상기 단계 3에서 제조된 화학식 14로 표시되는 화합물에 할로겐화반웅을 수 행하여 화학식 15로 표시되는 화합물올 얻는 단계 (단계 4);  Performing a halogenation reaction on the compound represented by Chemical Formula 14 prepared in Step 3 to obtain a compound represented by Chemical Formula 15 (step 4);
상기 단계 4에서 제조된 화학식 15로 표시되는 화합물을 보호기로 보호된 히 드라진 수화물과 고리화반웅을 수행하여 화학식 16으로 표시되는 화합물을 얻는 단 계 (단계 5)；  Performing a cyclization reaction with the hydrazine hydrate protected with a protecting group by the compound represented by Chemical Formula 15 prepared in Step 4 to obtain a compound represented by Chemical Formula 16 (step 5);
상기 단계 5에서 제조된 화학식 16으로 표시되는 화합물과 화학식 9로 표시 되는 화합물을 반웅시켜 화학식 17로 표시되는 화합물을 얻는 단계 (단계 6); 및 상기 단계 6에서 제조된 화학식 17로 표시되는 화합물의 보호기를 제거하는 반응을 수행하여 화학식 lb로 표시되는 화합물을 얻는 단계 (단계 7)을 포함하는 제 조 방법：  Reacting the compound represented by Chemical Formula 16 and the compound represented by Chemical Formula 9 prepared in Step 5 to obtain a compound represented by Chemical Formula 17 (step 6); And a step (step 7) of obtaining a compound represented by the formula lb by performing a reaction of removing the protecting group of the compound represented by the formula (17) prepared in step 6 above:
[반웅식 2] [Bungungsik 2]
Figure imgf000028_0001
Figure imgf000028_0001
(상기 반응식 2에서 A, R1 및 R5는 상기 화학식 1에서 정의한 바와 같고， P 보호기로써， 밴질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc) P-메톡시벤질기 (PMB) 또는 9-플루오렌일메특시카보닐기 (Fmoc)이다). 본 발명에 따른 반웅식 2에 있어서, (A, R 1 and R 5 in Scheme 2 are as defined in Formula 1, and as a P protecting group, a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc) P-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)). In the semiungkuk 2 according to the present invention,
상기 단계 1은 화학식 11로 표시되는 시아노아세테이트 화합물에 염기를 첨 가한 후, 에틸클로로포르메이트를 첨가하여 화학식 12로 표시되는 화합물을 얻는 단계이다.  Step 1 is a step of obtaining a compound represented by Formula 12 by adding a base to the cyanoacetate compound represented by Formula 11, and then adding ethylchloroformate.
이때， 사용가능한 염기로는 소듬하이드라이드 소듐 알코홀레이트 (sodium alcoholate), 탄산칼륨， 디이소프로필아민， 트리에틸아민， n-부틸리튬 또는 포타슘 t-부톡시드 등을 사용할 수 있고， 바람직하게는 소듐에록사이드를 사용할 수 있다. 또한， 사용가능한 용매로는 반응에 악영향을 미치지 않는 용매인 메탄을， 에 탄을, 테트라히드로퓨란, 또는 디에틸에테르 등을 이용할 수 있고, 바람직하게는 에탄올을 사용할 수 있다.  In this case, as the base that can be used, sodium hydride sodium alcoholate, potassium carbonate, diisopropylamine, triethylamine, n-butyllithium or potassium t-butoxide may be used, preferably sodium Eroxide can be used. As the solvent that can be used, methane which is a solvent which does not adversely affect the reaction, ethane, tetrahydrofuran, diethyl ether or the like can be used, and preferably ethanol can be used.
나아가， 반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.  Further, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
구체적으로， 에탄올 용매에서 화학식 11로 표시되는 에틸 시아노아세테이트 를 소듐에특사이드를 사용하여 엔올레이트로 제조한 후， 에틸 클로로포르메이트를 첨가하여 반웅을 수행하고, 반응 종료 후 반웅물을 여과하여 화학식 12로 표시되 는 화합물을 얻을 수 있다. 또한， 상기 단계 2는 상기 단계 1에서 제조된 화학식 12로 표시되는 화합물 을 메틸화 반웅을 수행하여 화학식 13으로 표시되는 화합물을 얻는 단계이다. 사용 가능한 용매는 반웅에 악영향을 미치지 않는 디클로로메탄， 클로로포 름， 테트라히드로퓨란， 디에틸에테르 또는 디메틸포름아미드 등이 있고 , 바람직하 게는 ^^디메틸포름아미드를 사용할 수 있다. Specifically, the ethyl cyanoacetate represented by the formula (11) in ethanol solvent was prepared as an enolate using sodium eoxide, and then reaction was performed by adding ethyl chloroformate, and the reaction product was filtered after completion of the reaction. The compound represented by Chemical Formula 12 can be obtained. In addition, step 2 is a step of obtaining a compound represented by the formula (13) by performing a methylation reaction to the compound represented by the formula (12) prepared in step 1. Solvents that can be used include dichloromethane, chloroform, tetrahydrofuran, diethyl ether or dimethylformamide, which do not adversely affect reaction, and ^^ dimethylformamide may be preferably used.
또한， 반응 온도는 특별히 제한되지는 않으나, 상은 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, the reaction temperature is not particularly limited, but the phase may be carried out within the boiling point range of the solvent.
구체적으로， 화학식 12로 표시되는 화합물을 씨디메틸포름아미드에 녹인 후, 디메틸설페이트를 첨가한 후， 상온에서 반웅을 수행한다. 반웅 종결 후, 화학 식 13으로 표시되는 화합물을 얻을 수 있다. 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 13으로 표시되는 화 합물을 염기존재 하에서 2-시아노아세트아미드와 축합 반응시켜 화학식 14로 표시 되는 화합물을 얻는 단계이다.  Specifically, after dissolving the compound represented by the formula (12) in seed dimethylformamide, after adding dimethyl sulfate, reaction is performed at room temperature. After completion of reaction, the compound represented by the formula (13) can be obtained. Furthermore, step 3 is a step of obtaining a compound represented by Chemical Formula 14 by condensation reaction of 2-cyanoacetamide with a compound represented by Chemical Formula 13 prepared in Step 2 in the presence of a base.
상기 사용가능한 염기로는 소듬하이드라이드， 소듐 알코홀레이트 (sodium alcoholate), 탄산칼륨， 디이소프로필아민， 트리에틸아민, n-부틸리튬 또는 포타슘 t-부톡시드 등을 사용할 수 있고, 바람직하게는 소듐에록사이드를 사용할 수 있다. 또한， 용매는 용매는 반웅에 악영향을 미치지 않는 메탄올， 에탄올, 테트라 히드로퓨란， 또는 디에틸에테르 등을 사용할 수 있고， 바람직하게는 에탄을을 사용 할수 있다.  Examples of the base that can be used include sodium hydride, sodium alcoholate, potassium carbonate, diisopropylamine, triethylamine, n-butyllithium or potassium t-butoxide, and preferably sodium Eroxide can be used. The solvent may be methanol, ethanol, tetrahydrofuran, diethyl ether, or the like, which does not adversely affect the reaction. Preferably, ethane may be used.
나아가, 반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.  Furthermore, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
구체적으로， 상기 제 2 단계에서 제조된 화학식 13으로 표시되는 화합물을 에탄올에 녹인 후， 소듐에톡사이드를 첨가하여 엔을레이트로 제조한 후， 2-시아노 아세트아미드와 축합반응시켜 화학식 14로 표시되는 화합물을 제조할 수 있다. 또한， 상기 단계 4는 상기 단계 3에서 제조된 화학식 14로 표시되는 화합물 에 할로겐화반웅을 수행하여 화학식 15로 표시되는 화합물을 얻는 단계이다.  Specifically, after dissolving the compound represented by the formula (13) prepared in the second step in ethanol, by adding sodium ethoxide to prepare the enelate, and condensation reaction with 2-cyano acetamide to the formula (14) The compound shown can be manufactured. In addition, step 4 is a step of obtaining a compound represented by the formula (15) by performing a halogenated reaction to the compound represented by the formula (14) prepared in step 3.
이때， 할로겐화 반응에 사용가능한 시약으로는 삼염화인， 오염화인， 염화포 스포릴， 올살릴클로라이드 또한 티오닐클로라이드 등을 사용할 수 있고， 바람직하 게는 삼염화인을 사용할 수 있다.  At this time, as the reagent that can be used for the halogenation reaction, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, olsalyl chloride, thionyl chloride, and the like may be used. Preferably, phosphorus trichloride may be used.
또한， 사용가능한 용매로는 용매는 반응에 악영향을 미치지 않는 메탄을, 에탄을， 테트라히드로퓨란， 디에틸에테르 또는 디메틸포름아미드 등을 이용할 수 있고， 바람직하게는 사용하지 않는다.  In addition, as a solvent which can be used, methane which does not adversely affect a reaction, ethane, tetrahydrofuran, diethyl ether, dimethylformamide, etc. can be used, Preferably it is not used.
나아가， 반웅 온도는특별히 제한되지는 않으나, 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.  Furthermore, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
구체적으로， 상기 제 3 단계에서 제조된 화학식 15로 표시되는 화합물에 삼 염화인을 첨가하고， 반웅흔합물을 110 °C에서 환류 교반하고, 반웅을 종결한 후, 얼음물을 첨가한 후， 생성된 고체를 여과하여 화학식 16으로 표시되는 화합물을 얻 을 수 있다. 나아가， 상기 단계 5 ~ 7은 상기 반응식 1의 단계 6 ~ 7의 화학식 la로 표시 되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 lb로 표시되는 화합 물을 얻을 수 있다. 또한， 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 3에 나타낸 바와 같이， 화학식 a로 표시되는 화합물은 트리포스젠을 이용하여 화학 식 a'로 표시되는 화합물을 얻는 단계 (단계 A); Specifically, phosphorus trichloride is added to the compound represented by Chemical Formula 15 prepared in the third step, the reaction mixture is stirred under reflux at 110 ° C, the reaction is terminated, and after the addition of ice water, The solid may be filtered to obtain a compound represented by Formula 16. Furthermore, the steps 5 to 7 may be performed by the same method as the method for obtaining the compound represented by the formula la of the above formulas 6 to 7 to obtain the compound represented by the formula lb. In addition, another method for preparing a derivative of Formula 1 according to the present invention is as shown in the following formula 3, wherein the compound represented by the formula a is obtained by using a triphosgene to obtain a compound represented by the formula a '( Step A);
화학식 8 또는 16으로 표시되는 화합물을 상기 반응식 A에서 제조된 화학식 a'로 표시되는 화합물과 반응을 수행하여 화학식 18로 표시되는 화합물을 얻는 단 계 (단계 1); 및  Reacting the compound represented by Formula 8 or 16 with the compound represented by Formula a ′ prepared in Scheme A to obtain a compound represented by Formula 18 (Step 1); And
상기 화학식 18로 표시되는 화합물의 보호기를 제거하는 반웅을 수행하여 화 학식 lc로 표시되는 화합물을 얻는 단계 (단계 2)를 포함하는 방법에  Performing a reaction to remove the protecting group of the compound represented by Chemical Formula 18 to obtain a compound represented by Chemical Formula lc (step 2)
수 있다: Can:
[반응식 3]  Scheme 3
H,N-R 10  H, N-R 10
Figure imgf000030_0001
Figure imgf000030_0001
(상기 반응식 3에서 A, R1, R2 및 R10은 상기 화학식 1에서 정의한 바와 같 고， P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), pᅳ메톡시 벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). 본 발명에 따른 반웅식 3에 있어서， (In Scheme 3, A, R 1 , R 2 and R 10 are as defined in Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc), p ᅳ methoxy benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)). In reaction 3 according to the present invention,
상기 단계 A는 상기 화학식 a로 표시되는 화합물을 염기 및 용매하에서 트리 포스젠과 축합반응을 수행하여 화학식 a'로 표시되는 이소시아네이트 화합물을 얻 는 단계이다.  Step A is a step of condensing the compound represented by Chemical Formula a with triphosgene under a base and a solvent to obtain an isocyanate compound represented by Chemical Formula a '.
이때， 사용가능한 염기는 트리에틸아민， 디이소프로필에틸아민 등을 들 수 있고， 바람직하게는 트리에틸아민을 사용할 수 있다.  At this time, usable bases include triethylamine, diisopropylethylamine and the like, and preferably triethylamine can be used.
또한， 사용가능한 용매로는 반응에 악영향을 미치지 않는 디클로로메탄， 클 로로포름 또는 디메틸포름아미드 등을 이용할 수 있고， 바람직하게는 디클로로메탄 을사용할 수 있다.  In addition, as the solvent that can be used, dichloromethane, chloroform, dimethylformamide, or the like, which does not adversely affect the reaction, can be used, and preferably dichloromethane can be used.
나아가，반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다. 또한, 상기 단계 1은 상기 화학식 a'로 표시되는 이소시아네이트 화합물과 상기 화학식 8 또는 16으로 표시되는 화합물과 우레아 반웅 (urea reaction)을 수행 하여 화학식 18로 표시되는 화합물을 얻는 단계이다.  Furthermore, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent. In addition, step 1 is a step of obtaining a compound represented by the formula (18) by performing a urea reaction with the isocyanate compound represented by the formula (a ') and the compound represented by the formula (8) or (16).
이때， 염기를 사용하지 않고 수행할 수 있으나, 일반적으로 사용될 수 있는 염기인 피리딘， 트리에틸아민， 디에틸이소프로필아민 또는 N-메틸모르폴린 등의 존 재 하에서 수행할 수 있고， 바람직하게는 피리딘을 사용할 수 있다.  At this time, it can be carried out without using a base, but may be carried out in the presence of a base which can be generally used, such as pyridine, triethylamine, diethylisopropylamine or N-methylmorpholine, preferably pyridine Can be used.
또한， 사용가능한 용매로는 반웅에 악영향을 미치지 않는 디클로로메탄, 클 로로포름, 테트라히드로퓨란， 디에틸에테르， 틀루엔 또는 디메틸포름아미드 등을 이용할 수 있고， 바람직하게는 디클로로메탄을 사용할 수 있다 . In addition, usable solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, which do not adversely affect reaction. It is possible to use, preferably dichloromethane.
나아가， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.  Further, the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
구체적으로， 화학식 a로 표시되는 이소시아네이트 화합물을 디클로로메탄에 녹인 후， 0 °C에서 트리에틸아민 및 트리포스젠올 첨가하여 교반 한 후， 화학식 8 또는 16으로 표시되는 화합물을 피 리딘에 녹인 후， 반웅 흔합물에 첨가하고 , 60 °C 로 가열하며 반웅을 수행하였다 . 반응 종결 후 , 컬럼 크로마토그래피를 수행하여 화학식 18로 표시되는 화합물을 얻을 수 있다 . 또한， 상기 단계 2는 상기 반응식 1의 단계 8의 화학식 la로 표시 되는 화합 물을 얻는 방법과 동일한 방법을 수행하여 화학식 lc로 표시 되는 화합물을 얻을 수 있다 . 본 발명에 따른 화학식 1의 유도체의 제조방법은 하기 반웅식 4에 나타낸 바 와 같이， 상기 반응식 2에서 제조된 화학식 15로 표시되는 화합물에 보호기를 도입 하여 화학식 19로 표시 되는 화합물을 얻는 단계 (단계 1) ; Specifically, after dissolving the isocyanate compound represented by Chemical Formula a in dichloromethane, adding triethylamine and triphosgeneol at 0 ° C., stirring, and dissolving the compound represented by Chemical Formula 8 or 16 in pyridine, The reaction was added to the mixture and heated to 60 ° C. After completion of the reaction, column chromatography may be performed to obtain a compound represented by Chemical Formula 18. In addition, step 2 may be carried out in the same manner as the method of obtaining the compound represented by the formula la in the step 8 of Scheme 1 to obtain a compound represented by the formula (lc). Method for preparing a derivative of Formula 1 according to the present invention is to obtain a compound represented by the formula (19) by introducing a protecting group to the compound represented by the formula (15) prepared in Scheme 2 as shown in One) ;
상기 단계 1에서 제조된 화학식 19로 표시되는 화합물을 보호기로 보호된 히 드라진 수화물과 고리화반웅을 수행하여 화학식 20으로 표시되는 화합물을 얻는 단 계 (단계 2)；  Performing a cyclization reaction with a hydrazine hydrate protected with a protecting group, the compound represented by Chemical Formula 19 prepared in Step 1 to obtain a compound represented by Chemical Formula 20 (step 2);
상기 단계 2에서 제조된 화학식 20으로 표시되는 화합물을 화학식 21로 표시 되는 알데하이드 화합물과 환원성 아미노 반응을 수행하여 화학식 22로 표시되는 화합물을 얻는 단계 (단계 3) ; 및  Performing a reducing amino reaction with an aldehyde compound represented by Formula 21 to a compound represented by Formula 20 prepared in Step 2 to obtain a compound represented by Formula 22 (step 3); And
상기 단계 3에서 제조된 화학식 22로 표시되는 화합물의 보호기를 제거하는 반웅을 수행하여 화학식 Id로 표시되는 화합물을 얻는 단계 (단계 4)를 포함하는 제 조방법：  A preparation method comprising the step (step 4) of obtaining a compound represented by Chemical Formula Id by performing a reaction to remove the protecting group of the compound represented by Chemical Formula 22 prepared in Step 3 above:
[반응식 4]  Scheme 4
Figure imgf000031_0001
Figure imgf000031_0001
1d 22  1d 22
(상기 반웅식 4에서 A, R1은 상기 화학식 1에서 정 의 한 바와 같고， R10 은 피 리딘， 벤질 및 시클로펜탄으로 이루어지는 군으로부터 선택되고 , P는 보호기로써 , 벤질옥시카보닐기 (Cbz) , t-부톡시카보닐기 (t-Boc) , P-메록시 벤질기 (PMB) 또는 9-플 루오렌일메록시카보닐기 (Fmoc)이다) . 본 발명에 따른 반웅식 4에 있어서, (A, R 1 in the formula 4 is as defined in Formula 1, R 10 is selected from the group consisting of pyridine, benzyl and cyclopentane, P is a protecting group, benzyloxycarbonyl group (Cbz) , t-butoxycarbonyl group (t-Boc), P-methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc). In the semiungkuk 4 according to the present invention,
상기 단계 1은 상기 반응식 2에서 제조된 화학식 15로 표시되는 화합물에 보 호기를 도입하여 화학식 19로 표시되는 화합물을 얻는 단계이다.  Step 1 is a step of obtaining a compound represented by the formula (19) by introducing a protective group to the compound represented by the formula (15) prepared in Scheme 2.
상기 반응에서 보호기로는 벤질옥시카보닐기 (Cbz), t-부특시카보닐기 (t-Boc), P-메록시벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)등을 사용할 수 있고， 바람직하게는 t-부톡시카보닐기 (t-Boc)를 사용할 수 있다.  As the protecting group in the reaction, a benzyloxycarbonyl group (Cbz), t-subspecific carbonyl group (t-Boc), P-methoxybenzyl group (PMB), or 9-fluorenyl methoxycarbonyl group (Fmoc) can be used. And preferably t-butoxycarbonyl group (t-Boc).
이때 사용가능한 유기용매로는 반응에 악영향을 미치지 않는 용매인 메탄올, 에탄올, 아세토니트릴, 피리딘, 테트라히드로퓨란 또는 디메틸포름아미드 등을 이 용할수 있고， 바람직하게는 디클로로메탄을 사용할 수 있다.  At this time, as an organic solvent that can be used may be a solvent that does not adversely affect the reaction of methanol, ethanol, acetonitrile, pyridine, tetrahydrofuran or dimethylformamide, and the like, preferably dichloromethane.
반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범위 내에 서 수행될 수 있다.  The reaction temperature is not particularly limited, but may be performed in a range of room temperature to the boiling point of the solvent.
구체적으로， 화학식 15로 표시되는 화합물을 디클로로메탄에 녹인 후， 0 °C 로 온도를 낮춘 후, 디 t-부틸 디카보네이트 및 트리에틸아민, 4-디메틸아미노피리 딘을 첨가하여 교반하고， 반웅 종결 후， 컬럼 크로마토그래피를 수행하여 화학식 19로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 2 는 상기 단계 1에서 제조된 화학식 19로 표시되는 화합물 과 보호기로 보호된 히드라진 수화물과 반웅하여 화학식 20으로 표시되는 화합물을 얻는 단계로 상기 반응식 1의 단계 6의 화학식 8로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 얻을 수 있다. 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 20으로 표시되는 화 합물과 화학식 21로 표시되는 알데하이드 화합물과 환원성 아미노 반응을 수행하여 화학삭 22로 표시되는 화합물을 얻는 단계이다.  Specifically, after dissolving the compound represented by the formula (15) in dichloromethane, lowering the temperature to 0 ° C, stirring by adding di t- butyl dicarbonate and triethylamine, 4-dimethylaminopyridine, the reaction is finished Thereafter, column chromatography may be performed to obtain a compound represented by Chemical Formula 19. In addition, step 2 is a step of obtaining a compound represented by the formula (20) by reacting with the compound represented by the formula (19) prepared in step 1 and the hydrazine hydrate protected with a protecting group represented by the formula (8) It can be obtained by performing the same method as the method for obtaining the compound. Furthermore, Step 3 is a step of obtaining a compound represented by Chemical Schematic 22 by performing a reducing amino reaction with the compound represented by Formula 20 prepared in Step 2 and the aldehyde compound represented by Formula 21.
사용 가능한 환원제로는 소듐시아노보로하이드라이드， 소듐보로하이드라이드 또는 트리아세특시보로하이드라이드 등과 아세트산을 사용할 수 있고， 바람직하게 는 소듐시아노보로하이드라이드를 사용할 수 있다.  As a reducing agent that can be used, sodium cyanoborohydride, sodium borohydride or triacetic borohydride and the like can be used as acetic acid, preferably sodium cyanoborohydride.
또한， 사용 가능한 용매로는 반웅에 악영향을 미치지 않는 메탄을， 디클로로 메탄， 클로로포름, 테트라히드로퓨란， 디에틸에테르, 를루엔 또는 디메틸포름아미 드 등을 이용하여 반응을 수행할 수 있고, 바람직하게는 메탄올을 사용할 수 있다. 이때, 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다. 또한， 상기 단계 4는 상기 단계 3에서 제조된 화학식 22로 표시되는 화합물 의 보호기를 제거하는 반웅을 수행하여 화학식 Id로 표시되는 화합물을 얻는 단계 로 상기 반웅식 1의 단계 8의 화학식 la를 얻는 단계와 동일한 방법으로 수행하여 화학식 Id로 표시되는 화합물을 얻을 수 있다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 5에 나타낸 바와 같이, 화학식 17로 표시되는 화합물을 환원 반웅을 수행하여 화학식 23으로 표시되는 화합물을 먿는 단계 (단계 1);  In addition, as a solvent usable, the reaction may be performed using methane which does not adversely affect reaction, using dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, and the like. Methanol can be used. At this time, the reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent. In addition, step 4 is a step of obtaining a compound represented by the formula Id by performing a reaction to remove the protecting group of the compound represented by the formula (22) prepared in step 3 to obtain a formula la of step 8 of the reaction formula 1 The compound represented by Chemical Formula Id may be obtained by the same method as described above. Another method for preparing a derivative of Formula 1 according to the present invention includes the steps of performing a reduction reaction on a compound represented by Formula 17 to obtain a compound represented by Formula 23, as shown in Step 5 below (Step 1);
상기 단계 1에서 제조된 화학식 23으로 표시되는 화합물을 산화 반웅을 수행 하여 화학식 24로 표시되는 화합물을 얻는 단계 (단계 2); 상기 단계 2에서 제조된 화학식 24로 표시되는 화합물을 환원성 아미노화 반 웅을 수행하여 화학식 25로 표시되는 화합물을 얻는 단계 (단계 3); 및 Performing a reaction reaction on the compound represented by Chemical Formula 23 prepared in Step 1 to obtain a compound represented by Chemical Formula 24 (step 2); Performing a reductive amination reaction on the compound represented by Chemical Formula 24 prepared in Step 2 to obtain a compound represented by Chemical Formula 25 (step 3); And
상기 단계 3에서 제조된 화학식 25로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 le로 표시되는 화합물을 얻는 단계 (단계 4)를 포함하는 제조방법: Deprotection reaction of the compound represented by Formula 25 prepared in Step 3 to obtain a compound represented by Formula l e (Step 4):
[반웅식 5]  [Bungungsik 5]
Figure imgf000033_0001
Figure imgf000033_0001
1e 25  1e 25
(상기 반응식 5에서 R6, R7 및 R10은 상기 화학식 1에서 정의한 바와 같고， R5'는 H, 에틸， (CH2)3N(C¾)2, 를루엔 및 벤젠으로 이루어진 군으로부터 선택되고, P 는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), p-메록시벤질기 (PMB) 또는 9-플루오렌일메특사카보닐기 (Fmoc)이다). 본 발명에 따른 반웅식 5에 있어서， (In Scheme 5, R 6 , R 7 and R 10 are as defined in Formula 1, R 5 ' is selected from the group consisting of H, ethyl, (CH 2 ) 3 N (C¾) 2 , toluene and benzene And P is a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethamic carbonyl group (Fmoc) as a protecting group) . In the reaction formula 5 according to the present invention,
상기 단계 1은 상기 반웅식 2의 단계 6에서 제조된 화학식 17로 표시되는 화 합물을 환원 반응을 수행하여 화학삭 23으로 표시되는 화합물을 얻는 단계이다. 상기 환원반웅을 수행하기 위한 환원제로는 소듐 보로하이드라이드， 트리알 루미늄하이드라이드, 리튬알루미늄하이드라이드， 보레인 또는 리튬트리 부록시 알 루미늄 하이드라이드 등을 사용할 수 있고， 바람직하게는 리튬 알루미늄하이드라이 드를 사용할 수 있다.  Step 1 is a step of obtaining a compound represented by the chemical process 23 by performing a reduction reaction on the compound represented by Formula 17 prepared in Step 6 of the reaction formula 2. As a reducing agent for performing the reduction reaction, sodium borohydride, trialuminum hydride, lithium aluminum hydride, borane or lithium tri-addendum aluminum hydride may be used, preferably lithium aluminum hydride. Can be used.
또한, 사용가능한 용매로는 반웅에 악영향을 미치지 않는 메탄을ᅳ 에탄올, 이소프로판올， 에틸이써， 테트라히드로퓨란， 디에틸렌 글리콜， 아세토니트릴 , Ν,Ν- 디메틸아세트아미드 등을 사용할 수 있고， 바람직하게는 메탄올을 사용할 수 있다. 이때， 반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  In addition, as the solvent which can be used, ethanol, isopropanol, ethyl ether, tetrahydrofuran, diethylene glycol, acetonitrile, Ν, Ν-dimethylacetamide, etc., which does not adversely affect reaction, can be used. Methanol can be used. At this time, the reaction temperature is not particularly limited, but may be carried out at room temperature to the boiling point of the solvent.
구체적으로, 리튬 알루미늄하이드라이드에 테트라히드라퓨란을 첨가한 후， 0 °C에서 교반하고， 상기 반웅식 2의 단계 6에서 제조된 화학식 17로 표시되는 화합 물을 천천히 첨가한 후, 교반하고， 수산화나트륨을 첨가하여 반웅을 종결 한 후， 컬럼 크로마토그래피를 수행하여 화학식 23으로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 2는 상기 단계 1에서 제조된 화학식 23으로 표시되는 화합 물을산화 반응을 수행하여 화학식 24로 표시되는 화합물을 얻는 단계이다. Specifically, after adding tetrahydrafuran to lithium aluminum hydride, stirred at 0 ° C., and slowly adding the compound represented by the formula (17) prepared in step 6 of the reaction formula 2, stirred, and hydroxide After the reaction is completed by adding sodium, column chromatography may be performed to obtain a compound represented by Chemical Formula 23. In addition, the step 2 is a compound represented by the formula (23) prepared in step 1 It is a step of obtaining a compound represented by Chemical Formula 24 by performing an oxidation reaction of water.
상기 산화반응은 피리디늄클로로크로메이트 (pyridinium chlorochromate) , 데 스 -마틴 (Dess-Martin) 산화반응 또는 스원산화반웅 (Swern oxidation)을 수행할 수 있으며, 사용가능한 용매로는 반응에 악영향을 미치지 않는 디클로로메탄, 클로로 포름, 테트라히드로퓨란 디에틸에테르， 를루엔 또는 디메틸포름아미드 등을 사용 할 수 있고, 바람직하게는 디클로로메탄을 사용할 수 있다.  The oxidation reaction may be pyridinium chlorochromate, Dess-Martin oxidation or Swern oxidation, and as a usable solvent, dichloro does not adversely affect the reaction. Methane, chloroform, tetrahydrofuran diethyl ether, toluene or dimethylformamide can be used, and preferably dichloromethane can be used.
이때, 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  At this time, the reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
구체적으로， 화학식 23으로 표시되는 화합물을 디클로로메탄에 녹인 후, 데 스 -마틴 퍼아이오딘을 첨가하여 교반하고, 반응 종결 후， 컬럼 크로마토그래피를 수행하여 화학식 24로 표시되는 화합물을 얻을 수 있다. 나아가, 상기 단계 3은 상기 단계 2에서 제조된 화학식 24로 표시되는 화합 물을 환원성 아미노화 반웅을 수행하여 화학식 25로 표시되는 화합물을 얻는 단계 로 상기 반응식 4의 화학식 22로 표시되는 화합물을 얻는 반응과 동일한 반웅을 수 행하여 화학식 25으로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 3에서 제조된 화학식 25로 표시되는 화합물을 탈보호화 반 웅을 수행하여 화학식 le로 표시되는 화합물을 얻는 단계로 상기 반웅식 1의 화학 식 la를 얻는 방법과 동일한 방법으로 수행하여 화학식 le로 표시되는 화합물을 얻 을 수 있다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반응식 6에 나타낸 바와 같이， 화학식 15로 표시되는 화합물에 보호기를 도입하여 화학식 26으 로 표시되는 화합물을 얻는 단계 (단계 1);  Specifically, after dissolving the compound represented by the formula (23) in dichloromethane, des-Martin periodine is added and stirred, after completion of the reaction can be performed by column chromatography to obtain the compound represented by the formula (24). Furthermore, Step 3 is a step of obtaining a compound represented by Chemical Formula 22 of Scheme 4 by performing a reductive amination reaction on the compound represented by Chemical Formula 24 prepared in Step 2 to obtain a compound represented by Chemical Formula 25. The compound represented by the formula (25) can be obtained by performing the same reaction as. In addition, performing a deprotection reaction of the compound represented by the formula (25) prepared in step 3 to obtain a compound represented by the formula le by performing the same method as the method of obtaining the chemical formula la of the formula (1) The compound represented by le can be obtained. Another method for preparing a derivative of Formula 1 according to the present invention comprises the steps of obtaining a compound represented by Formula 26 by introducing a protecting group into a compound represented by Formula 15, as shown in Scheme 6 below (Step 1);
상기 단계 1에서 제조된 화학식 26으로 표시되는 화합물을 보호기로 보호된 히드라진 수화물과 고리화반웅을 수행하여 화학식 27로 표시되는 화합물을 얻는 단 계 (단계 2)；  Performing a cyclization reaction with the hydrazine hydrate protected with a protecting group by the compound represented by Chemical Formula 26 prepared in Step 1 to obtain a compound represented by Chemical Formula 27 (step 2);
상기 단계 2에서 제조된 화학식 27로 표시되는 화합물과 화학식 9로 표시되 는 화합물을 반웅시켜 화학식 28로 표시되는 화합물을 얻는 단계 (단계 3);  Reacting the compound represented by Chemical Formula 27 and the compound represented by Chemical Formula 9 prepared in Step 2 to obtain a compound represented by Chemical Formula 28 (step 3);
상기 단계 3에서 제조된 화학식 28로 표시되는 화합물을 가수분해하여 화학 식 29로 표시되는 화합물을 얻는 단계 (단계 4);  Hydrolyzing the compound represented by Chemical Formula 28 prepared in Step 3 to obtain a compound represented by Chemical Formula 29 (step 4);
상기 단계 4에서 제조된 화학식 29로 표시되는 화합물을 알코올과 커플링 반 웅 (coupling react ion)을 수행하여 화학식 30으로 표시되는 화합물을 얻는 단계 (단 계 5); 및  Coupling a compound represented by Chemical Formula 29 prepared in Step 4 with alcohol to obtain a compound represented by Chemical Formula 30 by performing coupling reaction ion (step 5); And
상기 단계 5에서 제조된 화학식 30으로 표시되는 화합물을 탈보호화 반응을 수행하여 화학식 if로 표시되는 화합물을 얻는 단계 (단계 6)를 포함하는 제조방법:  A process for preparing a compound represented by Chemical Formula if (Step 6) by performing a deprotection reaction on the compound represented by Chemical Formula 30 prepared in Step 5 (Step 6):
[반웅식 6] [Bandungsik 6]
Figure imgf000035_0001
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000035_0002
1f  1f
(상기 반응식 6에서 , 및 R10은 상기 화학식 1에서 정의한 바와 같고, R5'는 H, 에틸， (C¾)3N(C¾)2, 를루엔 및 벤젠으로 이루어진 군으로부터 선택되고, P는 보 호기로써， 벤질옥시카보닐기 (Cbz), t—부록시카보닐기 (t-Boc), p-메특시벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다) . 본 발명에 따른 반웅식 6에 있어서， (In Scheme 6, and R 10 is as defined in Formula 1, R 5 ' is selected from the group consisting of H, ethyl, (C¾) 3 N (C¾) 2 , toluene and benzene, P is As an expiration group, it is a benzyloxycarbonyl group (Cbz), t- butyloxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB), or 9-fluorenyl methoxycarbonyl group (Fmoc). In the reaction system 6 according to the present invention,
상기 단계 1은 상기 반웅식 2의 단계 4에서 제조된 화학식 15로 표시되는 화 합물에 보호기를 도입하여 화학식 26으로 표시되는 화합물을 얻는 단계로, 상기 반 응식 4의 단계 1에서 화학식 19로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 26으로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 2는 상기 단계 1에서 제조된 화학식 26으로 표시되는 화합 물을 보호기로 보호된 히드라진 수화물과 고리화반웅을 수행하여 화학식 27로 표시 되는 화합물을 얻는 단계로， 상기 반웅식 4의 단계 2에서 화학식 20으로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 27로 표시되는 화합물을 얻을 수 있다. 나아가, 상기 단계 3은 상기 단계 2에서 제조된 화학식 27로 표시되는 화합 물과 화학식 9로 표시되는 화합물을 반웅시켜 화학식 28로 표시되는 화합물을 얻는 단계로， 상기 반웅식 2의 단계 6에서 화학식 17로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 28로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 4는 상기 단계 3에서 제조된 화학식 28로 표시되는 화합물 을 가수분해하여 화학식 29로 표시되는 화합물을 얻는 단계이다. Step 1 is a step of obtaining a compound represented by the formula (26) by introducing a protecting group to the compound represented by the formula (15) prepared in step 4 of the reaction formula 2, represented by the formula (19) in step 1 of the reaction The compound represented by the formula (26) can be obtained by the same method as the method for obtaining the compound. In addition, the step 2 is a step of obtaining a compound represented by the formula (27) by performing a cyclization reaction with the hydrazine hydrate protected with a protecting group to the compound represented by the formula (26) prepared in step 1, the step of the formula 4 The compound represented by the formula (27) can be obtained by performing the same method as the method for obtaining the compound represented by the formula (20). Further, Step 3 is a step of obtaining a compound represented by Formula 28 by reacting the compound represented by Formula 27 and the compound represented by Formula 9 prepared in Step 2, wherein the compound represented by Formula 17 in Step 6 The compound represented by Chemical Formula 28 may be obtained by performing the same method as the method for obtaining the compound represented by. In addition, step 4 is a step of obtaining a compound represented by the formula (29) by hydrolysis of the compound represented by the formula (28) prepared in step 3.
사용가능한 염기로는 수산화칼륨， 소듐히드록사이드 또는 포타슴히드록사이 드 등이 있고, 바람직하게는 수산화칼륨을 사용할 수 있다.  Bases that can be used include potassium hydroxide, sodium hydroxide or potassium hydroxide, and preferably potassium hydroxide.
또한， 사용가능한 용매로는 반응에 악영향을 미치지 않는 물， 메탄올， 에탄 을， 이소프로판올， 에틸에테르， 테트라히드로퓨란ᅳ 디에틸렌 글리콜， 아세토니트릴 등을 사용할 수 있고, 바람직하게는 물 및 에탄올을 흔합하여 사용할 수 있다.  In addition, as a solvent which can be used, water, methanol, ethane, isopropanol, ethyl ether, tetrahydrofuranium diethylene glycol, acetonitrile, etc. which do not adversely affect the reaction can be used, and preferably water and ethanol are mixed, Can be used.
이때， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  At this time, the reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
구체적으로， 상기 화학식 28로 표시되는 화합물을 에탄올과 물에 용해시킨 후， 수산화칼륨을 첨가한 후， 80 °C에서 환류 교반하고， 반웅을 종결하여 화학식 29로 표시되는 화합물을 얻을 수 있다. 나아가, 상기 단계 5는 상기 단계 4에서 제조된 화학식 29로 표시되는 화합 물을 알코올과 커플링 반응 (coupling react ion)을 수행하여 화학식 30으로 표시되 는 화합물을 얻는 단계이다. Specifically, after dissolving the compound represented by the formula (28) in ethanol and water, after adding potassium hydroxide, stirring at reflux at 80 ° C, the reaction can be terminated to obtain a compound represented by the formula (29). Further, step 5 is a step of obtaining a compound represented by the formula (30) by performing a coupling reaction (coupling react ion) with the compound represented by the formula (29) prepared in step 4.
상기 커플링 반웅은 커플링 시약 (coupling reagent)인 1-(3-디메틸아미노프 로필) -3-에틸카보디이미드 (l-(3-dimethylaminopropyl)—3-ethylcarbodi imide,EDC) , 1-하이드록시벤조트리아졸 하이드레이트 (l-hydroxylbenzotriazole, HOBt) 또는 1,3-디사이클로핵실 카보디이미드 (l,3_dicyclohexyl carbodi imide, DCC) 등을 사용 할 수 있고， 바람직하게는 1-(3-디메틸아미노프로필 )-3-에틸카보디이미드 (1— (3-dimethylaminopropyl)-3 ethylcarbodiiniide,EIX:)를 사용할 수 있다.  The coupling reaction is a coupling reagent 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (l- (3-dimethylaminopropyl) —3-ethylcarbodi imide, EDC), 1-hydride Hydroxybenzotriazole hydrate (l-hydroxylbenzotriazole, HOBt) or 1,3-dicyclonuxyl carbodiimide (l, 3_dicyclohexyl carbodi imide, DCC) and the like can be used, preferably 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide (1— (3-dimethylaminopropyl) -3 ethylcarbodiiniide, EIX :) can be used.
상기 커플링 반웅은 염기를 사용하지 않고 반응을 수행할 수 있으나, 아미드 화반웅에 사용될 수 있는 일반적인 염기인 4-디메틸아미노피리딘， 피리딘， 트리에 틸아민， 디에틸이소프로필아민, N-메틸모폴린 또는 디메틸페닐아민 등을 사용할 수 있고, 바람직하게는 피리딘 -3-일-메탄올을 사용할 수 있다.  The coupling reaction can be carried out without using a base, but 4-dimethylaminopyridine, pyridine, triethylamine, diethylisopropylamine, N-methylmo, which are general bases that can be used for the amide reaction reaction. Pauline or dimethylphenylamine and the like can be used, and preferably pyridin-3-yl-methanol can be used.
또한, 사용가능한 용매로는 반응에 악영향을 미치지 않는 아세토니트릴， 디 메틸포름아미드， 디클로로메탄 등을 사용할 수 있고, 바람직하게는 디메틸포름아미 드를사용할 수 있다.  In addition, acetonitrile, dimethylformamide, dichloromethane, and the like, which do not adversely affect the reaction, may be used as the solvent, and dimethylformamide may be preferably used.
이때， 반웅 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  At this time, the reaction temperature is not particularly limited, but may be performed in a boiling point range of the room temperature to the solvent.
구체적으로， 상기 단계 3에서 제조된 화학식 29로 표시되는 화합물을 디메틸 포름아미드 (DMF)에 녹인 후， 피리딘 -3-일-메탄을, EDC, HOBt, DIPEA를 첨가한 후， 상온에서 교반하고， 반응종결 후， 컬럼 크로마토그래피를 수행하여 화학식 30으로 표시되는 화합물을 얻을 수 있다. 또한， 상기 단계 5에서 제조된 화학식 30으로 표시되는 화합물을 탈보호화 반웅을 수행하여 화학식 H로 표시되는 화합물을 얻는 단계로， 상기 반웅식 1의 단 계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 반웅을 수행하여 화 학식 If로 표시되는 화합물을 얻을 수 있다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 7에 나타낸 바와 같이， 화학식 29로 표시되는 화합물과 아민 화합물을 커폴링 반웅을 수행하여 화학식 31로 표시되는 화합물을 얻는 단계 (단계 1) ; 및 Specifically, the compound represented by Chemical Formula 29 prepared in Step 3 is dissolved in dimethyl formamide (DMF), pyridin-3-yl-methane is added after adding EDC, HOBt, DIPEA, and stirred at room temperature, After completion of the reaction, column chromatography may be performed to obtain a compound represented by Chemical Formula 30. In addition, performing a deprotection reaction of the compound represented by Formula 30 prepared in step 5 to obtain a compound represented by Formula H, a method of obtaining a compound represented by the formula la in step 8 of the reaction formula 1 The same reaction can be performed to obtain a compound represented by the formula If. Another method for preparing a derivative of Formula 1 according to the present invention is to combine the amine compound and the compound represented by the formula (29) Carrying out to obtain a compound represented by formula (31) (step 1); And
상기 단계 1에서 제조된 화학식 31로 표시되는 화합물을 탈보호화 반응을 수 행하여 화학식 lg로 표시 되는 화합물을 얻는 단계 (단계 2)를 포함하는 제조방법 :  A process for preparing a compound represented by Chemical Formula lg by performing a deprotection reaction on the compound represented by Chemical Formula 31 prepared in Step 1 (Step 2):
[반응식 7]  Scheme 7
Figure imgf000037_0001
Figure imgf000037_0001
29 31 i g 29 31 i g
(상기 반응식 7에서 R6, R7 및 R10은 상기 화학식 1에서 정의 한 바와 같고， P 는 보호기로써， 벤질옥시카보닐기 (Cbz) , t-부특시카보닐기 (t-Boc) , p-메톡시 벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다) . 본 발명에 따른 반웅식 7에 있어서， R 6 , R 7 and R 10 in Scheme 7 are as defined in Chemical Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p- Methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)). In half-fung 7, according to the present invention,
상기 단계 1은 상기 반웅식 6의 단계 4에서 제조된 화학식 29로 표시되는 화 합물과 아민 화합물을 커플링 반응을 수행하여 화학식 31로 표시 되는 화합물을 얻 는 단계로 , 상기 반웅식 6의 단계 5에서 화학식 30으로 표시되는 화합물을 얻는 단 계를 수행하여 화학식 31로 표시되는 화합물을 얻을 수 았으나 이 에 한정하지 않는 다. 또한， 상기 단계 2는 상기 단계 1에서 제조된 화학식 31로 표시되는 화합물 을 탈보호화 반웅을 수행하여 화학식 lg로 표시되는 화합물을 얻는 단계로 상기 반 웅식 1의 단계 8에서 화학식 la를 얻는 방법과 동일한 방법으로 수행하여 화학식 lg로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는다 . 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 8에 나타낸 바와 같이 , 화학식 16으로 표시되는 화합물과 화학식 32로 표시되는 화합물 을 반응시 켜 화학식 33으로 표시되는 화합물을 얻는 단계 (단계 1) ;  The step 1 is a step of performing a coupling reaction between the compound represented by formula 29 and the amine compound prepared in step 4 of the reaction formula 6 to obtain a compound represented by formula 31, step 5 of the reaction formula 6 By performing the step of obtaining a compound represented by the formula in 30 to obtain a compound represented by the formula (31), but is not limited thereto. In addition, step 2 is a step of obtaining a compound represented by the formula lg by performing a deprotection reaction of the compound represented by the formula (31) prepared in step 1 in the same manner as the method for obtaining the formula la in the step 8 of the semi-formula 1 It can be carried out by the method to obtain a compound represented by the formula (lg), but is not limited thereto. Another method of preparing a derivative of Formula 1 according to the present invention includes the steps of obtaining a compound represented by Chemical Formula 33 by reacting a compound represented by Chemical Formula 16 with a compound represented by Chemical Formula 32, Step 1);
상기 단계 1에서 제조된 화학식 33으로 표시되는 화합물과 아민 화합물을 N- 알킬화 반웅을 수행하여 화학식 34로 표시되는 화합물을 얻는 단계 (단계 2) ; 및 상기 단계 2에서 제조된 화학식 34로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lh로 표시 되는 화합물을 얻는 단계 (단계 3)를 포함하는 제조방법 :  Performing a N-alkylation reaction of the compound represented by Formula 33 and the amine compound prepared in Step 1 to obtain a compound represented by Formula 34 (step 2); And deprotecting the compound represented by Chemical Formula 34 prepared in Step 2 to obtain a compound represented by Chemical Formula lh (Step 3).
[반웅식 8]
Figure imgf000038_0001
[Banungsik 8]
Figure imgf000038_0001
(상기 반웅식 8에서 A, R6 및 R7은 상기 화학식 1에서 정의한 바와 같고， R5 는 H, 에틸， (CH2)3N(CH3)2, 를루엔 및 벤젠으로 이루어진 군으로부터 선택되고， P는 보호기로써, 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), p-메록시밴질기 (PMB) 또는 9-플루오렌일메특시카보닐기 (Fmoc)이다). 본 발명에 따른 반응식 8에 있어서， (In the reaction formula 8, A, R 6 and R 7 are the same as defined in Chemical Formula 1, and R 5 is selected from the group consisting of H, ethyl, (CH 2 ) 3 N (CH 3 ) 2 , toluene and benzene. And P is a benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc) as a protecting group. ). In Scheme 8 according to the present invention,
상기 단계 1은 상기 반웅식 2의 단계 5에서 제조된 화학식 16으로 표시되는 화합물과 화학식 32로 표시되는 화합물을 반웅시켜 화학식 33으로 표시되는 화합물 을 얻는 단계로, 상기 반웅식 2의 단계 6에서 화학식 17로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 33으로 표시되는 화합물올 얻을 수 있으 나 이에 한정하지 않는다. 또한, 상기 단계 2는 상기 단계 1에서 제조된 화학식 33으로 표시되는 화합 물과 아민 화합물과 N-알킬화 반응을 수행하여 화학식 34로 표시되는 화합물을 얻 는 단계이다.  Step 1 is a step of obtaining a compound represented by Formula 33 by reacting the compound represented by Formula 16 and the compound represented by Formula 32 prepared in Step 5 of Banung Formula 2, wherein Formula 6 is used in Step 6 of Banung Formula 2. The compound represented by Chemical Formula 33 may be obtained by the same method as the method of obtaining the compound represented by 17, but is not limited thereto. In addition, step 2 is a step of obtaining a compound represented by the formula (34) by performing an N-alkylation reaction with the compound represented by the formula (33) prepared in step 1 and the amine compound.
사용가능한 용매로는 반응에 악영향을 미치지 않는 메탄을， 에탄을， 아세토 니트릴, 피리딘, 테트라히드로퓨란 또는 디메틸포름아미드 등을 사용할 수 있고, 바람직하게는 디메틸포름아미드를사용할수 있다.  As the solvent to be used, methane, ethane, acetonitrile, pyridine, tetrahydrofuran or dimethylformamide, etc., which do not adversely affect the reaction can be used, and preferably dimethylformamide can be used.
이때, 반응 온도는 특별히 제한되지는 않으나， 상온 내지 용매의 비등점 범 위 내에서 수행될 수 있다.  At this time, the reaction temperature is not particularly limited, but may be performed in a boiling point range of room temperature to the solvent.
구체적으로， 상기 단계 1에서 제조된 화학식 33으로 표시되는 화합물올 디메 틸포름아미드 (DMF)에 녹인 후， 과량의 아민 화합물을 첨가한 후， 실드ᅳ튜 £ί를 이용 하여 70 °C에서 교반하고， 반웅 종결 후， 감압농축하여 화학식 34로 표시되는 화합 물을 얻을 수 있다. 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 34로 표시되는 화합 물을 탈보호화 반웅을 수행하여 화학식 lh로 표시되는 화합물을 얻는 단계로， 상기 반웅식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법으 로 수행하여 화학식 lh로 표시되는 화합물을 얻을 수 있으나， 이에 한정하지 않는 다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반응식 9에 나타낸 바와 같이， 화학식 27로 표시되는 화합물과 화학식 35로 표시되는 화합물을 반웅시켜 화학식 36으로 표시되는 화합물을 얻는 단계 (단계 1); Specifically, after dissolving in the compound ol dimethylformamide (DMF) represented by the formula (33) prepared in Step 1, after adding the excess amine compound, and stirred at 70 ° C using a shield tube £ ί After completion of reaction, the mixture was concentrated under reduced pressure to obtain a compound represented by Chemical Formula 34. Further, step 3 is a step of performing a deprotection reaction of the compound represented by the formula (34) prepared in step 2 to obtain a compound represented by the formula lh, which is represented by the formula la in step 8 of the reaction formula 1 In the same way as for obtaining the compound The compound represented by Chemical Formula lh may be obtained by performing the same process, but is not limited thereto. Another method of preparing a derivative of Formula 1 according to the present invention includes the steps of obtaining a compound represented by Formula 36 by reacting a compound represented by Formula 27 with a compound represented by Formula 35, as shown in Scheme 9 below (Step 1 );
상기 단계 1에서 제조된 화학식 36으로 표시되는 화합물과 화학식 37로 표시 되는 화합물을 반웅시켜 화학식 38로표시되는 화합물을 얻는 단계 (단계 2);  Reacting the compound represented by Chemical Formula 36 and the compound represented by Chemical Formula 37 prepared in Step 1 to obtain a compound represented by Chemical Formula 38 (step 2);
상기 단계 2에서 제조된 화학식 38로 표시되는 화합물과 아민 화합물을 반웅 시켜 화학식 39로 표시되는 화합물을 얻는 단계 (단계 3); 및  Reacting the compound represented by Formula 38 and the amine compound prepared in Step 2 to obtain a compound represented by Formula 39 (step 3); And
상기 단계 3에서 제조된 화학식 39로 표시되는 화합물을 탈보호화 반응을 수 행하여 화학식 li로 표시되는 화합물을 얻는 단계 (단계 4)를 포함하는 제조방법:  A process for preparing a compound represented by Chemical Formula li by performing a deprotection reaction of the compound represented by Chemical Formula 39 prepared in Step 3 (Step 4):
[반응식 9]  Scheme 9
Figure imgf000039_0001
Figure imgf000039_0001
1i  1i
(상기 반응식 9에서 A, R6 및 R7은 상기 화학식 1에서 정의한 바와 같고, R5 는 H, 에틸， (CH2)3N(C¾)2, 를루엔 및 벤젠으로 이투어진 군으로부터 선택되고, P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부특시카보닐기 (t-Boc), p—메톡시벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). 본 발명에 따른 반웅식 9에 있어서 상기 단계 1은 상기 반응식 6의 단계 2에서 제조된 화학식 27로 표시되는 화 합물과 화학식 35로 표시되는 화합물을 반응시켜 화학식 36으로 표시되는 화합물을 얻는 단계로, 상기 반웅식 6의 단계 3에서 화학식 28로 표시되는 화합물을 얻는 방 법과 동일한 방법으로 수행하여 화학식 36으로 표시되는 화합물을 얻을 수 있으나， 이에 한정하지 않는다. 또한， 상기 단계 2는 상기 단계 1에서 제조된 화학식 36으로 표시되는 화합 물과 화학식 37로 표시되는 화합물을 반웅시켜 화학식 38로 표시되는 화합물을 얻 는 단계로， 상기 반웅식 1의 단계 7에서 화학식 10으로 표시되는 화합물을 얻는 방 법과 동일한 방법으로 수행하여 화학식 38로 표시되는 화합물을 얻을 수 있으나, 이에 한정하지 않는다. 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 38로 표시되는 화합 물과 아민 화합물을 반웅시켜 화학식 39로 표시되는 화합물을 얻는 단계로 상기 반 응식 8의 단계 2에서 화학식 33으로 표시되는 화합물을 얻는 방법과 동일한 방법으 로 수행하여 화학식 39로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는 다. (In Scheme 9, A, R 6 and R 7 are as defined in Formula 1 above, R 5 is selected from the group consisting of H, ethyl, (CH 2 ) 3 N (C¾) 2 , toluene and benzene. , P is a protecting group, benzyloxycarbonyl group (Cbz), t-subspecific carbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc). In half-figure 9 according to the present invention Step 1 is a step of reacting the compound represented by Formula 27 prepared in Step 2 of Scheme 6 with the compound represented by Formula 35 to obtain a compound represented by Formula 36. The compound represented by Chemical Formula 36 may be obtained by the same method as the method for obtaining the compound represented by 28, but is not limited thereto. In addition, step 2 is a step of obtaining a compound represented by the formula 38 by reacting the compound represented by the formula (36) and the compound represented by the formula 37 prepared in step 1, the formula in step 7 of the reaction formula 1 The compound represented by Chemical Formula 38 may be obtained by the same method as the method of obtaining the compound represented by 10, but is not limited thereto. Further, Step 3 is a step of obtaining a compound represented by Formula 39 by reacting the compound represented by Formula 38 and the amine compound prepared in Step 2, wherein the compound represented by Formula 33 in Step 2 of Reaction Scheme 8 is obtained. The compound represented by Chemical Formula 39 may be obtained by the same method as the method of obtaining the compound, but is not limited thereto.
또한， 상기 단계 4는 상기 단계 3에서 제조된 화학식 39로 표시되는 화합물 을 탈보호화 반웅을 수행하여 화학식 li로 표시되는 화합물을 얻는 단계로 상기 반 응식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 li로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 10에 나타낸 바와 같이， 화학식 40으로 표시되는 화합물에 산을 첨가하여 화학식 41로 표시되는 화합물을 얻는 단계 (단계 1);  In addition, step 4 is a step of performing a deprotection reaction of the compound represented by the formula (39) prepared in step 3 to obtain a compound represented by the formula li to the compound represented by the formula la in step 8 of the reaction The compound represented by Chemical Formula li may be obtained by the same method as the obtaining method, but is not limited thereto. Another method for preparing a derivative of Formula 1 according to the present invention comprises the steps of obtaining an compound represented by Formula 41 by adding an acid to the compound represented by Formula 40, as shown in the following formula (Step 1);
상기 단계 1에서 제조된 화학식 41로 표시되는 화합물과 화학식 42로 표시되 는 화합물을 0-알킬화 반응을 수행하여 화학식 43으로 표시되는 화합물을 얻는 단 계 (단계 2);  Performing a 0-alkylation reaction of the compound represented by Chemical Formula 41 and the compound represented by Chemical Formula 42 prepared in Step 1 to obtain a compound represented by Chemical Formula 43 (step 2);
상기 단계 2에서 제조된 화학식 43으로 표시되는 화합물을 가수분해하여 화 학식 44로 표시되는 화합물을 얻는 단계 (단계 3);  Hydrolyzing the compound represented by Chemical Formula 43 prepared in Step 2 to obtain a compound represented by Chemical Formula 44 (step 3);
상기 단계 3에서 제조된 화학식 44로 표시되는 화합물과 화학식 20으로 표시 되는 화합물을 반웅시켜 화학식 45로 표시되는 화합물을 얻는 단계 (단계 4); 및  Reacting the compound represented by Chemical Formula 44 and the compound represented by Chemical Formula 20 prepared in Step 3 to obtain a compound represented by Chemical Formula 45 (step 4); And
상기 단계 4에서 제조된 화학식 45로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lj로 표시되는 화합물을 얻는 단계 (단계 5)를 포함하는 제조방법:  Deprotection reaction of the compound represented by Formula 45 prepared in step 4 to obtain a compound represented by the formula (lj) (Step 5):
[반응식 10] Scheme 10
Figure imgf000041_0001
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000041_0002
1j  1j
(상기 반웅식 10에서 R1은 상기 화학식 1에서 정의한 바와 같고， R5'는 메틸 기 이고， R10'은 몰폴린 또는 피리딘 이고， P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부특시카보닐기 (t— Boc), p-메록시벤질기 (PMB) 또는 9-폴루오렌일메록시카보닐기 (Fmoc)이다). 본 발명에 따른 반웅식 10에 있어서， (In Formula 1, R 1 is as defined in Formula 1, R 5 ' is a methyl group, R 10' is morpholine or pyridine, P is a protecting group, benzyloxycarbonyl group (Cbz), t- Subspecific carbonyl group (t— Boc), p-methoxybenzyl group (PMB) or 9-polorenyl methoxycarbonyl group (Fmoc)). In the reaction system 10 according to the present invention,
상기 단계 1은 화학식 40으로 표시되는 화합물에 산올 첨가하여 화학식 41로 표시되는 화합물을 얻는 단계이다.  Step 1 is a step of obtaining a compound represented by the formula 41 by adding an acid to the compound represented by the formula (40).
구체적으로， 상기 화학식 40으로 표시되는 화합물에 메탄을과 물을 첨가한 후， 황산을 첨가하여 교반하고， 반응 종결 후， 화학식 41로 표시되는 화합물을 얻 을 수 있다. 또한， 상기 단계 2는 상기 단계 1에서 제조된 화학식 41로 표시되는 화합물 과 화학식 42로 표시되는 화합물을 0-알킬화 반웅을 수행하여 화학식 43으로 표시 되는 화합물을 얻는 단계로， 상기 반웅식 8의 단계 2에서 화학식 34로 표시되는 화 합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 43으로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는다. 나아가, 상기 단계 3은 상기 단계 2에서 제조된 화학식 43으로 표시되는 화 합물을 가수분해하여 화학식 44로 표시되는 화합물을 얻는 단계로, 상기 반웅식 6 의 단계 4에서 화학식 29로 표시되는 화합물을 얻는 방법과 동일한 방법을 수행하 여 화학식 44로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는다. 또한， 상기 단계 4는 상기 단계 3에서 제조된 화학식 44로 표시되는 화합물 과 화학식 20으로 표시되는 화합물을 반응시켜 화학식 45로 표시되는 화합물을 얻 는 단계로， 상기 반웅식 1의 단계 7에서 화학식 10으로 표시되는 화합물을 얻는 방 법과 동일한 방법을 수행하여 화학식 45로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는다. 나아가， 상기 단계 5는 상기 단계 4에서 제조된 화학식 45로 표시되는 화합 물을 탈보호화 반웅을 수행하여 화학식 lj로 표시되는 화합물을 얻는 단계로, 상기 반응식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법을 수행하여 화학식 lj로 표시되는 화합물을 얻을 수 있으나， 이에 한정하지 않는다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 11에 나타낸 바와 같이, '화학식 46으로 표시되는 화합물을 셀레늄옥사이드와 반웅을 수 행하여 화학식 47로 표시되는 화합물을 얻는 단계 (단계 1); Specifically, after the addition of methane and water to the compound represented by the formula (40), the sulfuric acid is added and stirred, after completion of the reaction, the compound represented by the formula (41) can be obtained. In addition, step 2 is a step of obtaining a compound represented by the formula 43 by performing 0-alkylation reaction of the compound represented by the formula 41 and the compound represented by the formula 42 prepared in step 1, the step of the formula 8 The compound represented by the chemical formula 43 may be obtained by performing the same method as the method for obtaining the compound represented by the chemical formula 34 in 2, but is not limited thereto. Furthermore, step 3 is a step of obtaining a compound represented by the formula (44) by hydrolyzing the compound represented by the formula (43) prepared in step 2, to obtain a compound represented by the formula (29) in step 4 of the reaction formula 6 The compound represented by Chemical Formula 44 may be obtained by the same method as the method, but is not limited thereto. In addition, the step 4 is a step of obtaining a compound represented by the formula 45 by reacting the compound represented by the formula (44) prepared in step 3 with the compound represented by the formula (20), Formula 10 in step 7 of the reaction formula 1 The compound represented by Chemical Formula 45 may be obtained by the same method as the method of obtaining the compound represented by, but is not limited thereto. Furthermore, step 5 is a step of deprotecting the compound represented by Formula 45 prepared in Step 4 to obtain a compound represented by Formula lj, the compound represented by Formula la in Step 8 of Scheme 1 The compound represented by the formula lj may be obtained by the same method as the method for obtaining the compound, but is not limited thereto. As shown in another manufacturing method of a derivative of the general formula (I) according to the present invention is to banung formula 11, "step carried out with a compound represented by Formula 46 can selenium oxide and banung for obtaining a compound represented by the formula 47 (step 1 );
상기 단계 1에서 제조된 화학식 47로 표시되는 화합물과 화학식 20으로 표시 되는 화합물을 반웅시켜 화학식 48로 표시되는 화합물을 얻는 단계 (단계 2); 및 상기 단계 2에서 제조된 화학식 48로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lk로 표시되는 화합물을 얻는 단계 (단계 3)를 포함하는 제조방법 :  Reacting the compound represented by Chemical Formula 47 and the compound represented by Chemical Formula 20 prepared in Step 1 to obtain a compound represented by Chemical Formula 48 (step 2); And deprotecting the compound represented by Chemical Formula 48 prepared in Step 2 to obtain a compound represented by Chemical Formula lk (Step 3).
[반웅식 11]  [Banungsik 11]
Figure imgf000042_0001
Figure imgf000042_0001
(상기 반옹식 11에서 A, R1 및 R10은 상기 화학식 1에서 정의한 바와 같고， P 는 보호기로써 , 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), p—메톡시벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다). 본 발명에 따른 반응식 11에 있어서， (A, R 1 and R 10 in the reaction formula 11 is as defined in Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p—meth Oxybenzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)). In Scheme 11 according to the present invention,
상기 단계 1은 화학식 46으로 표시되는 화합물올 셀레늄옥사이드와 반웅을 수행하여 화학식 47로 표시되는 화합물을 얻는 단계이다.  Step 1 is a step of obtaining a compound represented by the formula 47 by performing a reaction with the compound ol selenium oxide represented by the formula (46).
사용가능한 용매로는 피리딘, 디메틸포름아미드, 아세토니트릴 등을 이용할 수 있고， 바람직하게는 피리딘을 사용할 수 있다.  Pyridine, dimethylformamide, acetonitrile, and the like may be used as the solvent, and pyridine may be preferably used.
구체적으로, 화학식 46으로 표시되는 화합물을 피리딘에 녹인 후， 셀레늄옥 사이드를 첨가한 후， 80 °C에서 교반하고, 반웅 종결 후， 컬럼 크로마토그래피를 수행하여 화학식 47로 표시되는 화합물을 얻을 수 있다. 또한, 상기 단계 2는 상기 단계 1에서 제조된 화학식 47로 표시되는 화합물 과 화학식 20으로 표시되는 화합물을 반웅시켜 화학식 48로 표시되는 화합물을 얻 는 단계로, 상기 반응식 1의 단계 7에서 화학식 10으로 표시되는 화합물을 얻는 방 법과 동일한 방법으로 반옹을 수행하여 화학식 48로 표시되는 화합물을 얻을 수 있 으나 이에 한정하지 않는다. 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 48로 표시되는 화합 물을 탈보호화 반웅을 수행하여 화학식 lk로 표시되는 화합물을 얻는 단계로, 상기 반응식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법으 로 반웅을 수행하여 화학식 lk로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반응식 12에 나타낸 바와 같이， 화학식 49로 표시되는 화합물과 화학식 20으로 표시되는 화합물 을 반웅시켜 화학식 50으로 표시되는 화합물을 얻는 단계 (단계 1); Specifically, after dissolving the compound represented by the formula 46 in pyridine, selenium jade After adding the side, the mixture is stirred at 80 ° C., and after completion of reaction, column chromatography may be performed to obtain a compound represented by Chemical Formula 47. In addition, Step 2 is a step of obtaining a compound represented by Formula 48 by reacting the compound represented by Formula 47 and the compound represented by Formula 20 prepared in Step 1, wherein from step 7 of Scheme 1 to Formula 10 Reaction may be carried out in the same manner as the method for obtaining the compound, to obtain the compound represented by Chemical Formula 48, but is not limited thereto. Furthermore, step 3 is a step of deprotecting the compound represented by Formula 48 prepared in Step 2 to obtain a compound represented by Formula lk, and the compound represented by Formula la in Step 8 of Scheme 1 The reaction may be performed in the same manner as to obtain the compound represented by Chemical Formula lk, but is not limited thereto. Another method for preparing a derivative of Formula 1 according to the present invention is to obtain a compound represented by Formula 50 by reacting the compound represented by Formula 49 with the compound represented by Formula 20, as shown in Scheme 12 below (Step 1 );
상기 단계 1에서 제조된 화학식 50으로 표시되는 화합물과 알코을을 커플링 반응을 수행하여 화학식 51로 표시되는 화합물을 얻는 단계 (단계 2); 및  Performing a coupling reaction between the compound represented by Formula 50 prepared in step 1 and an alcohol to obtain a compound represented by Formula 51 (step 2); And
상기 단계 2에서 제조된 화학식 51로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 11로 표시되는 화합물을 얻는 단계 (단계 3)을 포함하는 제조방법:  A process for preparing a compound represented by Chemical Formula 11 by performing deprotection reaction of the compound represented by Chemical Formula 51 prepared in Step 2 (Step 3):
[반응식 12]  Scheme 12
Figure imgf000043_0001
Figure imgf000043_0001
11 51  11 51
(상기 반응식 12에서 A 및 R1은 상기 화학식 1에서 정의한 바와 같고， R10은 H및 d-6 직쇄알킬로 이루어진 군으로부터 선택되고, P는 보호기로써， 벤질옥시카보 닐기 (Cbz), t-부록시카보닐기 (t-Boc), P-메특시벤질기 (PMB) 또는 9-플루오렌일메톡 시카보닐기 (Fmoc)이다). 본 발명에 따른 반옹식 12에 있어서， (A and R 1 in Scheme 12 are as defined in Formula 1, R 10 is selected from the group consisting of H and d- 6 linear alkyl, P is a protecting group, benzyloxycarbonyl group (Cbz), t- Appendix is a carbonyl group (t-Boc), a P-methoxybenzyl group (PMB) or a 9-fluorenyl methoxy carbonyl group (Fmoc)). In the reaction system 12 according to the present invention,
상기 단계 1은 화학식 49로 표시되는 화합물과 화학식 20으로 표시 되는 화합 물을 반응시켜 화학식 50으로 표시되는 화합물을 얻는 단계로， 상기 반웅식 1의 단 계 7에서 화학식 10으로 표시 되는 화합물을 얻는 방법과 동일한 방법으로 반웅을 수행하여 화학식 50으로 표시되는 화합물을 얻을 수 있으나 이 에 한정 하지 않는다 . 또한 상기 단계 2는 상기 단계 1에서 제조된 화학식 50으로 표시 되는 화합물 과 알코올을 커플링 반웅을 수행하여 화학식 51로 표시되는 화합물을 얻는 단계로 상기 반응식 6의 단계 5에서 화학식 30으로 표시되는 화합물을 얻는 방법 과 동일한 방법으로 반응을 수행하여 화학식 51로 표시되는 화합물을 얻을 수 있으나 이 에 한 정하지 않는다 . 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 51로 표시되는 화합 물을 탈보호화 반웅을 수행하여 화학식 11로 표시되는 화합물을 얻는 단계로 상기 반웅식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법으 로 수행하여 화학식 11로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는 다 .  Step 1 is a step of obtaining a compound represented by the formula (50) by reacting the compound represented by the formula (49) and the compound represented by the formula (20), a method of obtaining a compound represented by the formula (10) in step 7 of the reaction formula 1 The reaction may be performed in the same manner as described above to obtain a compound represented by Chemical Formula 50, but is not limited thereto. In addition, Step 2 is a step of coupling the compound and the alcohol represented by Formula 50 prepared in Step 1 to obtain a compound represented by Formula 51 to the compound represented by Formula 30 in Step 5 of Scheme 6 The reaction can be carried out in the same manner as in the obtaining method to obtain a compound represented by Chemical Formula 51, but is not limited thereto. Further, Step 3 is a step of performing a deprotection reaction of the compound represented by Formula 51 prepared in Step 2 to obtain a compound represented by Formula 11, the compound represented by Formula la in Step 8 of the reaction formula 1 The compound represented by the formula (11) can be obtained by the same method as the method of obtaining the compound, but is not limited thereto.
본 발명 에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 13에 나타낸 바와 같이， 화학식 16으로 표시되는 화합물과 아민 화합물을 우레아 반웅을 수행하여 화학식 52로 표시 되는 화합물을 얻는 단계 (단계 1) ;  Another method for preparing a derivative of Formula 1 according to the present invention is to obtain a compound represented by Formula 52 by performing a urea reaction between a compound represented by Formula 16 and an amine compound as shown in Reaction Formula 13 below (Step 1 );
상기 단계 1에서 제조된 화학식 52로 표시 되는 화합물을 가수분해하여 화학 식 53으로 표시되는 화합물을 얻는 단계 (단계 2) ; 및  Hydrolyzing the compound represented by Chemical Formula 52 prepared in Step 1 to obtain a compound represented by Chemical Formula 53 (step 2); And
상기 단계 2에서 제조된 화학식 53으로 표시되는 화합물을 탈보호화 반웅을 수행하여 화학식 lm으로 표시되는 화합물을 얻는 단계 (단계 3)를 포함하는 제조방 법 :  Deprotection reaction of the compound represented by Formula 53 prepared in Step 2 to obtain a compound represented by Formula lm (Step 3):
[반웅식 13] [Banungsik 13]
-(CH2)nC02R10'
Figure imgf000045_0001
-(CH 2 ) n C0 2 R 10 '
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0002
1m 53  1 m 53
(상기 반응식 13에서 A, R1 및 n은 상기 화학식 1에서 정의한 바와 같고， R10'은 다이메틸아민 또는 몰폴린이고, P는 보호기로써， 벤질옥시카보닐기 (Cbz), t- 부록시카보닐기 ( t -Boc ), p-메특시벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). 본 발명에 따른 반웅식 13에 있어서, (In Scheme 13, A, R 1 and n are as defined in Formula 1, R 10 ' is dimethylamine or morpholine, P is a protecting group, benzyloxycarbonyl group (Cbz), t-addition Nyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)). In the reaction system 13 according to the present invention,
상기 단계 1은 상기 반응식 2의 단계 1에서 제조된 화학식 16으로 표시되는 화합물과 아민 화합물을 우레아 반웅을 수행하여 화학식 52로 표시되는 화합물을 얻는 단계로， 상기 반웅식 3의 단계 1에서 화학식 18로 표시되는 화합물을 얻는 방 법과 동일한 방법으로 반응을 수행하여 화학식 52로 표시되는 화합물을 얻을 수 있 으나 이에 한정하지 않는다. 또한 상기 단계 2는 상기 단계 1에서 제조된 화학식 52로 표시되는 화합물을 가수분해하여 화학식 53으로 표시되는 화합물을 얻는 단계로 상기 반응식 6의 단계 4에서 화학식 29로 표시되는 화합물을 얻는 방법과 동일한 방법으로 반웅을 수행하 여 화학식 53으로 표시되는 화합물을 얻을 수 있으나， 이에 한정하지 않는다. 나아가， 상기 단계 3은 상기 단계 2에서 제조된 화학식 53으로 표시되는 화 합물을 탈보호화 반응을 수행하여 화학식 lm으로 표시되는 화합물을 얻는 단계로 상기 반웅식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법으로 수행하여 화학식 lm으로 표시되는 화합물을 얻을 수 있으나 이에 한정하 지 않는다. 본 발명에 따른 화학식 1의 유도체의 다른 제조방법은 하기 반응식 14에 나 타낸 바와 같이， 화학식 lb로 표시되는 화합물과 화학식 54로 표시되는 화합물을 커플링 반웅을 수행하여 화학식 55로 표시되는 화합물을 얻는 단계 (단계 1); 및 상기 단계 1에서 제조된 화학식 55로 표시되는 화합물을 탈보호화 반응을 수 행하여 화학식 In으로 표시되는 화합물을 얻는 단계 (단계 2)를 더 포함하는 제조방 법 : Step 1 is a step of performing a urea reaction of the compound represented by the formula (16) and the amine compound prepared in step 1 of Scheme 2 to obtain a compound represented by the formula 52, to the formula 18 in step 1 of the reaction formula 3 The reaction represented by Chemical Formula 52 may be obtained by the same method as the method for obtaining the compound, but is not limited thereto. In addition, step 2 is a step of obtaining a compound represented by formula 53 by hydrolyzing the compound represented by formula 52 prepared in step 1, the same method as the method of obtaining a compound represented by formula 29 in step 4 of Scheme 6 The reaction may be performed to obtain a compound represented by Chemical Formula 53, but is not limited thereto. Furthermore, step 3 is a step of performing a deprotection reaction of the compound represented by Formula 53 prepared in Step 2 to obtain a compound represented by Formula lm. Compound represented by Formula la in Step 8 of Banung Formula 1 The compound represented by the formula lm may be obtained by the same method as the method of obtaining the compound, but is not limited thereto. Another method for preparing a derivative of Formula 1 according to the present invention, as shown in the following Scheme 14, by performing a coupling reaction between the compound represented by the formula lb and the compound represented by the formula 54 to obtain a compound represented by the formula (55) Step (step 1); And Further comprising the step (step 2) of performing a deprotection reaction of the compound represented by formula 55 prepared in step 1 to obtain a compound represented by formula In:
[반응식 14]  Scheme 14
Figure imgf000046_0001
Figure imgf000046_0001
(상기 반웅식 14에서 R1, R9 및 R10은 상기 화학식 1에서 정의한 바와 같고， P는 보호기로써， 벤질옥시카보닐기 (Cbz) , t-부록시카보닐기 (t-Boc) , pᅳ메톡시 벤질 기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다) . 본 발명 에 따른 반웅식 14에 있어서， (In the reaction formula 14, R 1 , R 9 and R 10 are the same as defined in Chemical Formula 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc), p ᅳ me Methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)). In the reaction formula 14 according to the present invention,
상기 단계 1은 상기 반웅식 2의 단계 7에서 제조된 화학식 lb로 표시 되는 화 합물과 화학식 54로 표시되는 화합물을 커플링 반웅을 수행하여 화학식 55로 표시 되는 화합물을 얻는 단계로， 상기 반웅식 6의 단계 5에서 화학식 30으로 표시 되는 화합물을 얻는 방법과 동일한 방법을 수행하여 화학식 55로 표시되는 화합물을 얻 을 수 있으나 이에 한정하지 않는다 . 또한, 상기 단계 2는 상기 단계 1에서 제조된 화학식 55로 표시되는 화합물 을 탈보호화 반응을 수행하여 화학식 In으로 표시되는 화합물을 얻는 단계로 , 상기 반응식 1의 단계 8에서 화학식 la로 표시되는 화합물을 얻는 방법과 동일한 방법으 로 수행하여 화학식 In으로 표시되는 화합물을 얻을 수 있으나 이에 한정하지 않는 다. 본 발명에 따른 화학식 1의 유도체의 또 다른 제조방법은 하기 반웅식 15에 나타낸 바와 같이 , 화학식 lb로 표시되는 화합물과 화학식 56으로 표시 되는 화합물 을 반응시 켜 화학식 lo로 표시되는 화합물을 얻는 단계 (단계 1)를 더 포함하는 제 조방법：  Step 1 is a step of performing a coupling reaction between the compound represented by Formula lb and the compound represented by Formula 54 prepared in Step 7 of Reaction Formula 2 to obtain a compound represented by Formula 55. The compound represented by Chemical Formula 55 may be obtained by performing the same method as the method of obtaining the compound represented by Chemical Formula 30 in step 5, but is not limited thereto. In addition, Step 2 is a step of obtaining a compound represented by the formula In by performing a deprotection reaction of the compound represented by Formula 55 prepared in Step 1, the compound represented by the formula la in step 8 of Scheme 1 The compound represented by the formula In may be obtained by the same method as the obtaining method, but is not limited thereto. Another method of preparing a derivative of Formula 1 according to the present invention includes the steps of obtaining a compound represented by Formula lo by reacting a compound represented by Formula lb with a compound represented by Formula 56, as shown in Reaction Formula 15 below. Manufacturing method further comprising step 1):
. [반웅식 15]
Figure imgf000047_0001
. [Banungsik 15]
Figure imgf000047_0001
1b 56 1o  1b 56 1o
(상기 반응식 15에서 R1 및 R10은 상기 화학식 1에서 정의한 바와 같고， R9'는 벤젠 또는 에틸이다). 본 발명에 따른 반응식 15에 있어서， (In Scheme 15, R 1 and R 10 are as defined in Formula 1, R 9 ' is benzene or ethyl). In Scheme 15 according to the present invention,
상기 단계 1은 상기 반웅식 2의 단계 7에서 제조된 화학식 lb로 표시되는 화 합물을 화학식 56으로 표시되는 화합물과 반웅시켜 화학식 lo로 표시되는 화합물을 얻는 단계로， 상기 반응식 6의 단계 5에서 화학식 30으로 표시되는 화합물을 얻는 방법과 동일한 방법을 수행하여 화학식 lo로 표시되는 화합물을 얻을 수 있으나 이 에 한정하지 않는다. 나아가, 본 발명은 화학식 1로 표시되는 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 GSK-313(글리코겐 합성 효소 카이네이즈 -3 β) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.  Step 1 is a step of obtaining a compound represented by formula lo by reacting the compound represented by Formula lb prepared in Step 7 of Reaction Formula 2 with the compound represented by Formula 56. The compound represented by the formula lo may be obtained by the same method as the method of obtaining the compound represented by 30, but is not limited thereto. Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease related to GSK-313 (glycogen synthase kinase-3 β) containing a pyrazolo pyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
상기 GSK-3|3(글리코겐 합성 효소 카이네이즈— 3 ) 관련 질환으로는 치매, 알츠하이머 병， 파킨슨 병 , 전두측두 (Frontotemporal) 치매 파킨슨 유형， 괌 (Guam) 파킨슨 치매 복합증， HIV 치매 또는 신경섬유 얽힘 병리학과 관련된 질환을 포함할 수 있다. 본 발명에 따른 화학식 1로 표시되는 피라졸로 피리딘 유도체는 GSK-3P (글 리코겐 합성 효소 카이네이즈 -3β) 효소 저해 실험결과, 0.1 μΜ이하의 우수한 IC50 값올 나타냄으로써， GSK-3|3(글리코겐 합성 효소 카이네이즈 -3β) 효소에 대하여 우수한 억제 효과를 나타내는 것을 알 수 있고 (표 12 참조), 또한， 세포 -기재 글루 코스 생성 억제 분석을 이용한 GSK-3^ (글리코겐 합성 효소 카이네이즈 -3β) 저해 활성 결과， 5.0μΜ이하의 우수한 IC50 값을 나타냄으로써， GSK-3|3(글리코겐 합성 효소 카이네이즈 -3β) 효소에 대하여 우수한 억제 효과를 나타내는 것을 알 수 있 다 (표 13 참조). 따라서， 본 발명에 따른 화학식 1로 표시되는 피라졸로 피리딘 유도체는 GSK-3P (글리코겐 합성 효소 카이네이즈 -3β) 효소에 대한 억제작용을 함으로써 GSK-3P에 의해 유발되는 치매 , 알츠하이머 병， 파킨슨 병， 전두측두 (Frontotemporal) 치매 파킨슨 유형, 괌 (Guam) 파킨슨 치매 복합증, HIV 치매 또는 신경섬유 얽힘 병리학과 관련된 질환을 예방 또는 치료하는 데 유용하게 사용될 수 있다. 본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1로 표시되는 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성 물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여 될 수 있으나， 이에 한정되는 것은 아니다. The GSK-3 | 3 (glycogen synthase kinase— 3) related diseases include dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary tangle Diseases associated with pathology. The pyrazolopyridine derivative represented by the formula (1) according to the present invention shows an excellent IC 50 value of less than 0.1 μΜ as a result of GSK-3P (glycogen synthase kinase -3β) enzyme inhibition experiment, GSK-3 | 3 (glycogen It can be seen that it shows an excellent inhibitory effect on the synthase kinase-3β enzyme (see Table 12), and also the GSK-3 ^ (glycogen synthase kinase-3β) inhibitory activity using a cell-based glucose production inhibition assay As a result, by showing an excellent IC 50 value of 5.0 μM or less, it can be seen that an excellent inhibitory effect on the GSK-3 | 3 (glycogen synthase kinase-3β) enzyme (see Table 13). Therefore, the pyrazolopyridine derivative represented by Formula 1 according to the present invention has an inhibitory effect on the GSK-3P (glycogen synthase kinase-3β) enzyme, which is induced by GSK-3P, Alzheimer's disease, Parkinson's disease, and frontal It can be usefully used to prevent or treat diseases associated with the Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complications, HIV dementia or neurofibrillary pathology. When using the composition of the present invention as a medicine, a pharmaceutical composition containing a derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Water may be formulated and administered in various oral or parenteral dosage forms as described below, but is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제， 환제， 경 /연질 캅셀제, 액제, 현탁 제， 유화제， 시럽제， 과립제, 엘릭시르제， 트로키제 등이 있는데， 이들 제형은 유 효성분 이외에 희석제 (예: 락토즈， 텍스트로즈， 수크로즈， 만니를， 솔비를, 셀를로 즈 및 / 또는 글리신)， 활택제 (예: 실리카, 탈크， 스테아르산 및 그의 마그네슘 또 는 칼슘염 및 /또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알 루미늄 실리케이트 , 전분 페이스트 , 젤라틴， 메틸셀를로즈， 나트륨 카복시메틸셀를 로즈 및 /또는 폴리비닐피를리딘과 같은 결합제를 함유할 수 있으며， 경우에 따라 전분， 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 흔합물 및 /또는 흡수제, 착색제, 향미제， 및 감미제를 함유할 수 있다.  Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. Toze, textrose, sucrose, manny, sorbbi, celrose and / or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols) have. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcell rose and / or polyvinylpyridine, and optionally starch, agar, alginic acid or its sodium Disintegrants or boiling mixtures such as salts and / or absorbents, colorants, flavors, and sweeteners.
상기 화학식 1로 표시되는 유도체를 유효 성분으로 하는 약학적 조성물은 비 경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사， 근육 내 주사 또는 흉 부 내 주사를 주입하는 방법에 의한다.  Pharmaceutical compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered orally, and parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
이때， 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 피라졸로 피리딘 유도체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완층제와 함께 물 에 흔합하여 용액 또는 현탁액으로 제조하고， 이를 염플 또는 바이알 단위 투여형 으로 제조할 수 있다. 상기 조성물은 멸균되고 /되거나 방부제， 안정화제， 수화제 또는 유화 촉진제， 삼투압 조절을 위한 염 및 /또는 완충제 등의 보조제， 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 흔합， 과립화 또는 코팅 방법에 따라 제제화할 수 있다.  At this time, in order to formulate into a dosage form for parenteral administration, the pyrazolo pyridine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a vulcanizing agent to prepare a solution or suspension, and the salt or vial unit It may be prepared in a dosage form. The composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
상기 화학식 1의 유도체를 유효성분으로 함유하는 약학적 조성물의 인체에 대한 투여량은 환자의 나이， 몸무게, 성별, 투여형태, 상태 및 질환 정도에 따라 달라질 수 있으며， 바람직하게는 0.01 내지 200 rag/kg/일의 양으로 의사 또는 약사 의 판단에 따라 일정시간 간격을 1일 수회， 바람직하게는 1일 1회 내지 3회로 분할 하여 경구 또는 비경구적 경로를 통해 투여할 수 있다.  The dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, condition and degree of disease of the patient, and preferably 0.01 to 200 rag / In the amount of kg / day can be administered by oral or parenteral route by a predetermined time interval divided by several times a day, preferably once to three times a day, according to the judgment of the doctor or pharmacist.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하， 본 발명을 실시예에 의해 상세히 설명한다.  Hereinafter, the present invention will be described in detail by way of examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실 시예에 한정되는 것은 아니다.  However, the following examples are merely to illustrate the present invention, the contents of the present invention is not limited to the following examples.
<제조예 1> 1-(4—메톡시벤질) -5-[2-(4-메록시벤질옥시)페닐]— 피라졸로 Production Example 1 1- (4—methoxybenzyl) -5 [2- (4-methoxybenzyloxy) phenyl] —pyrazolo
[3，4-/>]피라진 -3-아민의 제조 Preparation of [3,4-/>] pyrazine-3-amine
Figure imgf000049_0001
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000049_0002
Figure imgf000049_0003
Figure imgf000049_0003
단계 1: l-[2-(4—메톡시벤질옥시)페닐]에타논의 제조 Step 1: Preparation of l- [2- (4—methoxybenzyloxy) phenyl] ethanone
화학식 b-1으로 표시되는 1-(2-하이드록시페닐)에타논 (10.0 g, 73.45 隱 ol) 을 yV V-디메틸포름아미드에 녹인 후， 탄산칼륨 (20.3 g, 146.89 隱 ol)과 4ᅳ메록시벤 질 클로라이드 (11.9 88.14 隱 ol)을 첨가하였고ᅳ 반웅 흔합물을 60 °C에서 2시 간 동안 환류 교반 하였다. 반응 종결 후,, 반웅물을 상온으로 넁각한 다음 에틸아 세테이트로 추출하고， 유기 용매층을 무수 황산마그네슘으로 건조시킨 다음 용매를 감압 농축하였다. 감압 농축한 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =9:1)로 정제하여 화학식 c-1로 표시되는 화합물 (20.0 g, 반응수율: 98%, 흰색고 체)을 얻었다. After dissolving 1- (2-hydroxyphenyl) ethanone (10.0 g, 73.45 μl) represented by Chemical Formula b-1 in yV V-dimethylformamide, potassium carbonate (20.3 g, 146.89 μl) and 4 μm Loxybenzyl chloride (11.9 88.14 μl) was added and the reaction mixture was stirred at reflux for 2 hours at 60 ° C. After completion of the reaction, the reaction product was cooled to room temperature, extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue concentrated under reduced pressure was purified by column chromatography (nucleic acid: ethyl acetate = 9: 1) to obtain a compound represented by the formula (c-1) (20.0 g, reaction yield: 98%, white solid).
¾ 腿 (400MHz, CDC ): δ 7.75(dd, M.2, 1.6Hz, 1H), 7.45(dt, J^7.0, 1.6Hz, 1H), 7.36(d, J^.8Hz, 2H), 7.04-6.98(m, 2H)， 6.93(d, J-11.2Hz, 2H), 5.08(s, 2H), 3.82(s, 3H), 2.57(s, 3H) 단계 2: 2 ,2-디하이드록시 -l-[2-(4-메록시벤질옥시)페닐]에타논의 제조 상기 단계 1에서 제조된 화학식 c-1로 표시되는 화합물 (20.0 g, 78.03瞧 ol) 을 1>4-디옥산 (36 과 물 (1.5 )의 흔합용액에 용해한 후， 반웅 온도를 60 °C까 지 올려서 교반 하였다. 셀레늄 디옥사이드 (8.7 g, 78.03 mmol)을 첨가한 후, 24 시간 동안 환류 교반 하였다. 반웅 종결 후， 반응물을 상온으로 넁각한 후， 여과를 통해 잔류물을 제거하고 용매를 감압 농축한다. 감압 농축한 잔류물을 컬럼 크로마 토그래피 (핵산：에틸아세테이트 =7:3)로 정제하여 화학식 d-1로 표시되는 화합물 (20.0 g, 반응수율 :90¾>， 갈색 액체)을 얻었다. ¾ 腿 (400 MHz, CDC): δ 7.75 (dd, M.2, 1.6 Hz, 1H), 7.45 (dt, J ^ 7.0, 1.6 Hz, 1H), 7.36 (d, J ^ .8 Hz, 2H), 7.04 -6.98 (m, 2H), 6.93 (d, J-11.2 Hz, 2H), 5.08 (s, 2H), 3.82 (s, 3H), 2.57 (s, 3H) Step 2: 2,2-dihydroxy Preparation of -l- [2- (4-methoxybenzyloxy) phenyl] ethanone The compound represented by the formula (c-1) prepared in Step 1 (20.0 g, 78.03 'ol) was prepared in 1> 4 -dioxane ( 3 6 was dissolved in a mixed solution of water (1.5), and the reaction mixture was stirred up to 60 ° C. Selenium dioxide (8.7 g, 78.03 mmol) was added, followed by stirring under reflux for 24 hours. After the reaction was cooled to room temperature, the residue was removed by filtration, and the solvent was concentrated under reduced pressure. Purified by chromatography (nucleic acid: ethyl acetate = 7: 3) to obtain a compound represented by the formula d-1 (20.0 g, reaction yield: 90¾>, brown liquid).
¾ 匿(400腿 z, CDC ): δ 9.59(s, 1H)， 7.82(dd, J^.6, 1.2Hz, 1H) , 7.60-7.55C1H, m), 7.37(t, J^8.8Hz, 1H), 7.34(d, J-6.4Hz, 2H), 7.11(d, J=6.4Hz, 1H), 6.94(d, J=8.8Hz, 2H), 5.11(s, 2H), 3.82(s, 3H) 단계 3:( )-2-[2-(4-메톡시벤질옥시)페닐] -2-옥소아세트알데히드 옥심의 제 조 ¾ 腿 (400 腿 z, CDC): δ 9.59 (s, 1H), 7.82 (dd, J ^ .6, 1.2 Hz, 1H), 7.60-7.55C1H, m), 7.37 (t, J ^ 8.8 Hz, 1H), 7.34 (d, J-6.4 Hz, 2H), 7.11 (d, J = 6.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 3.82 (s, 3H) Step 3: Preparation of () -2- [2- (4-methoxybenzyloxy) phenyl] -2-oxoacetaldehyde oxime
상기 단계 2에서 제조된 화학식 d— 1로 표시되는 화합물 (20.43 g, 70.86 ■ol)을 물 (60 과 1,4-디옥산 (20 )에 녹인 후, 하이드록시아민 하이드로클로 라이드 (4.92 g, 70.86 mmol)과 무수 소듐 아세테이트 (5.81 g, 70.86 瞧 ol)를 첨가 하였고， 반웅 흔합물을 70 °C에서 1시간 동안 교반 하였다. 반웅 종결 후， 에틸아 세테이트로 추출하고, 유기 용매층을 무수 황산 마그네슘으로 건조시킨 다음 용매 를 감압 농축하였다. 감압 농축한 잔류물은 컬럼 크로마토그래피 (핵산：에틸아세테 이트 =4:1)로 정제하여 화학식 e-1로 표시되는 화합물 (16.1 g, 반웅수율: 80%, 흰색 고체)을 얻었다. After dissolving the compound represented by Chemical Formula d-1 (20.43 g, 70.86 xol) prepared in Step 2 in water (60 and 1,4-dioxane (20)), hydroxyamine hydrochloride (4.92 g, 70.86 mmol) and anhydrous sodium acetate (5.81 g, 70.86 瞧 ol) were added and the reaction mixture was stirred for 1 hour at 70 ° C. After completion of reaction, the reaction mixture was extracted with ethyl acetate and the organic solvent layer was dried with anhydrous. After drying over magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue under reduced pressure was purified by column chromatography (nucleic acid: ethyl acetate = 4: 1) to give the compound represented by the formula (E-1) (16.1 g, semiacuum yield). : 80%, white solid).
¾ NMR(400MHz, DMSO-o ): δ 12.56(s, 1H) , 7.92(s, 1H)， 7.47(dt, ¾ NMR (400 MHz, DMSO-o): δ 12.56 (s, 1 H), 7.92 (s, 1 H), 7.47 (dt,
1.6Hz, 1H), 7.36(dd, J-8.0, 2.0Hz, 1H), 7.32(d, J^.8Hz, 1H), 7.20(d, /-β.4Ηζ, 2H), 7.01(d, J=6.4Hz, 1H), 6.92(d, J=6.0Hz, 2H) , 5.06(s, 2H), 3.74(s, 3H) 단계 4: 2-아미노 -3-시아노 -5-[2-(4-메록시벤질옥시)페닐]피라진 1-옥시드의 제조 1.6 Hz, 1H), 7.36 (dd, J-8.0, 2.0 Hz, 1H), 7.32 (d, J ^ .8 Hz, 1H), 7.20 (d, /-β.4Ηζ, 2H), 7.01 (d, J = 6.4 Hz, 1H), 6.92 (d, J = 6.0 Hz, 2H), 5.06 (s, 2H), 3.74 (s, 3H) Step 4: 2-Amino-3-cyano-5- [2- ( Preparation of 4-methoxybenzyloxy) phenyl] pyrazine 1-oxide
상기 단계 3에서 제조된 화학식 e— 1로 표시되는 화합물 (10.0 g, 35.05 mmol) 을 2-프로판올 (250 m«에 용해한 후， 2-아미노말로노니트릴 (8.9 g, 35.05 瞧 ol)을 첨가하고， 반웅 흔합물을 12시간 동안 교반 하였다. 생성된 고체를 여과한 후, 물 로 세척하여 화학식 f-1로 표시되는 화합물 (10.2 g, 반웅수율: 82%， 노란색고체)을 얻었다.  After dissolving the compound represented by Chemical Formula e-1 prepared in Step 3 (10.0 g, 35.05 mmol) in 2-propanol (250 m «, 2-aminomalononitrile (8.9 g, 35.05 μl) was added thereto. The reaction mixture was stirred for 12 hours, and the resulting solid was filtered and washed with water to obtain a compound represented by Chemical Formula f-1 (10.2 g, reaction yield: 82%, yellow solid).
¾ 證(400丽 z, SO-de) δ 8.87(s, 1H), 8.02(s, 1H), 7.74(dd, J=8.0, 2.0Hz, 1H), 7.44-7.39(m, 3H), 7.26(d, J=8.4Hz, 1H), 7.08(t, MMz, 1H)， 7.03(d' J-8.4Hz, 2H) , 5.13(s, 2H), 3.75(s, 3H) 단계 5: 3-아미노 -6-[2-(4-메톡시벤질옥시)페닐]피라진 -2-카보니트릴의 제조 상기 단계 4에서 제조된 화학식 f-1로 표시되는 화합물 (10.06 g, 28.88 mmol)을 테트라히드로퓨란 (350 )에 용해한 후， 0 °C로 온도를 낮추고， 삼염화인 (20.14 mi, 231.03 瞧 ol)을 천천히 첨가한 후， 1시간 동안 교반 하였다. 반웅 종료 후에 감압 농축하여 생성된 고체를 물로 세척하여 화학식 g-1로 표시되는 화합물 (5.6 g, 반웅수율: 58%， 노란색고체)을 얻었다. ¾ 400 (400 d z, SO-de) δ 8.87 (s, 1H), 8.02 (s, 1H), 7.74 (dd, J = 8.0, 2.0 Hz, 1H), 7.44-7.39 (m, 3H), 7.26 (d, J = 8.4 Hz, 1H), 7.08 (t, MMz, 1H), 7.03 (d 'J-8.4 Hz, 2H), 5.13 (s, 2H), 3.75 (s, 3H) Step 5: 3- Preparation of amino-6- [2- (4-methoxybenzyloxy) phenyl] pyrazine-2-carbonitrile Compound (10.06 g, 28.88 mmol) represented by the formula f-1 prepared in step 4 was converted to tetrahydrofuran. After dissolving at (350), the temperature was lowered to 0 ° C., and phosphorus trichloride (20.14 mi, 231.03 瞧 ol) was slowly added, followed by stirring for 1 hour. After completion of the reaction, the resulting solid was concentrated under reduced pressure and washed with water to obtain a compound represented by Chemical Formula g-1 (5.6 g, reaction yield: 58%, yellow solid).
¾ NMR(400MHz, DMS0— ί¾): δ 8.74(s, 1H)， 7.62(dd, J=7.2, 1.6Hz, 1H) , 7.40-7.37(m, 3H) , 7.25(d, J=8.4Hz, 1H), 7.06(t, J^7.6Hz, 1H), 6.93(d, J-8.4Hz, 2H), 5.09(s, 2H)， 3.75(s, 3H) 단계 6: 3-클로로 -6— [2-(4-메특시벤질옥시)페닐]피라진 -2-카보니트릴의 제조 상기 단계 5에서 제조된 화학식 g-1으로 표시되는 화합물 (5.6 g, 16.69 mmol)을 아세토니트릴 (200 )에 용해한 후， 염화구리 (4.5 g, 33.39 隱 ol)와 이소 아밀 니트릴 (4.47 m^, 33.39 醒 ol)을 첨가하고， 반웅 흔합물을 50 °C에서 2시간 동 안 환류 교반 하였다. 반웅 종결 후, 반웅물을 상온으로 냉각하여 에틸아세테이트 로 추출하고 유기 용매층을 무수 황산마그네슴으로 건조시킨 다음 용매를 감압 농 축하였다. 감압 농축한 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =7:3)로 정제하여 화학식 h-1으로 표시되는 화합물 (2.5 g, 반웅수율 :43%, 노란색고체)을 얻 었다. ¾ NMR (400MHz, DMS0—ί¾): δ 8.74 (s, 1H), 7.62 (dd, J = 7.2, 1.6Hz, 1H), 7.40-7.37 (m, 3H), 7.25 (d, J = 8.4Hz, 1H), 7.06 (t, J ^ 7.6 Hz, 1H), 6.93 (d, J-8.4 Hz, 2H), 5.09 (s, 2H), 3.75 (s, 3H) Step 6: of 3-chloro-6— [2- (4-mesoxybenzyloxy) phenyl] pyrazine-2-carbonitrile Preparation After dissolving the compound represented by the formula g-1 prepared in Step 5 (5.6 g, 16.69 mmol) in acetonitrile (200), copper chloride (4.5 g, 33.39 隱 ol) and isoamyl nitrile (4.47 m ^ , 33.39 醒 ol) was added, and the reaction mixture was stirred under reflux at 50 ° C for 2 hours. After completion of reaction, the reaction product was cooled to room temperature, extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue concentrated under reduced pressure was purified by column chromatography (nucleic acid: ethyl acetate = 7: 3) to obtain a compound represented by the formula (h-1) (2.5 g, semi-water yield: 43%, yellow solid).
¾ NMR(400MHz, DMS0— ο : δ 9.22(s, 1H), 7.78(dd, J^7.6, 2.0Hz, 1H), 7.55(dt, =8.4, 2.0Hz, 1H), 7.41— 7.35(m, 3H), 7.16(t, J-7.2Hz, 1H), 6.94(d, J=8.8Hz, 2H), 5.17(s, 2H), 3.76(s, 3H) 단계 7: l-(4-메톡시벤질) -5-[2-(4-메톡시벤질옥시)페닐] -I 피라졸로 [3,4— />]피라진 -3-아민의 제조 ¾ NMR (400 MHz, DMS0— ο: δ 9.22 (s, 1H), 7.78 (dd, J ^ 7.6, 2.0Hz, 1H), 7.55 (dt, = 8.4, 2.0Hz, 1H), 7.41—7.35 (m, 3H), 7.16 (t, J-7.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H), 3.76 (s, 3H) Step 7: l- (4-methoxy Benzyl) -5- [2- (4-methoxybenzyloxy) phenyl] -I pyrazolo Preparation of [3,4 — />] pyrazine-3-amine
상기 단계 6에서 제조된 화학식 h-1으로 표시되는 화합물 (2.5 g, 7.22誦 ol) 을 에탄올 (40 에 녹인 후 4-메톡시벤질 히드라진 수화물 (1.6 g, 10.83 隱 ol)을 첨가하고, 반웅 흔합물을 90 °C에서 12시간 동안 환류 교반 하였다. 반웅 종결 후， 반웅물을 실온으로 넁각하여 에틸아세테이트로 추출하고 유기 용매층을 무수 황산 마그네슴으로 건조시킨 다음 용매를 감압 농축하였다. 감압 농축한 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =3:2)로 정제하여 화학식 a-1으로 표시되는 화 합물 (1.7 g, 반응수율: 44%, 노란색고체)을 얻었다. The compound represented by the formula h-1 prepared in step 6 (2.5 g, 7.22 誦 ol) was dissolved in ethanol (40, and 4-methoxybenzyl hydrazine hydrate (1.6 g, 10.83 隱 ol) was added thereto. The mixture was stirred under reflux for 12 hours at 90 ° C. After completion of the reaction, the reaction product was stirred at room temperature, extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 3: 2) to obtain a compound represented by Chemical Formula a-1 (1.7 g, reaction yield: 44%, yellow solid).
¾ NMR(400MHz,
Figure imgf000051_0001
: δ 8.87(s, 1H), 7.72(dd, .6, 1.6Hz, 1H) ,¾ NMR (400 MHz,
Figure imgf000051_0001
: δ 8.87 (s, 1 H), 7.72 (dd, .6, 1.6 Hz, 1 H),
7.42(dt, J-9.6Hz, 1.2Hz, 1H), 7.36(d, J=8.4Hz, 2H) , 7.29(d, J-8.0Hz, 1H),7.42 (dt, J-9.6 Hz, 1.2 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J-8.0 Hz, 1H),
7.19(d, J=6.4 z, 2H), 7.11(t, J=8.0Hz, 1H), 6.92(dd, J=5.2, 3.2Hz, 2H)ᅳ7.19 (d, J = 6.4 z, 2H), 7.11 (t, J = 8.0 Hz, 1H), 6.92 (dd, J = 5.2, 3.2 Hz, 2H)
6.84(d, J=8A, 2.0Hz, 2H), 5.91(s, 2H), 5.30(s, 2H) , 5.13(s, 2H), 3.76(s, 3H)6.84 (d, J = 8A, 2.0Hz, 2H), 5.91 (s, 2H), 5.30 (s, 2H), 5.13 (s, 2H), 3.76 (s, 3H)
<실시예 i> 3—히드록시 -N-[5ᅳ (2—히드록시페닐) -1H -피라졸로 [3,4-b]피라진 -3- 일]벤즈아미드의 제조 <Example i> 3 - hydroxy - N - Preparation of [5-eu b] pyrazin-3-yl (2-hydroxyphenyl) - 1H--pyrazolo [3, 4] benzamide
Figure imgf000052_0001
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0002
Figure imgf000052_0003
Figure imgf000052_0003
1  One
단계 1: 7Hl-(4-메톡시벤질)—5-[2-(4-메톡시벤질옥시)페닐] -1 ᅳ피라졸로  Step 1: 7Hl- (4-methoxybenzyl) —5- [2- (4-methoxybenzyloxy) phenyl] -1 cappyrazolo
[3，4-/>]피라진 -3—일}-3-(4-메톡시벤질옥시)벤즈아미드의 제조 Preparation of [3,4-/>] pyrazine-3-yl} -3- (4-methoxybenzyloxy) benzamide
3-(4-메특시벤질옥시)벤조산(77.3 mg, 0.29 mmol)을 디클로로메탄 (2.0 에 녹인 후， 0 °C에서 옥살릴크로라이드 (52 2^, 0.59 隱 ol)와 TV,그디메틸포름아미드 (2방울)을 천천히 첨가한 후， 1시간 동안 교반 후 용매를 감압 하에 제거하고, 상 기 제조예 1에서 제조된 화학식 a-1로 표시되는 화합물 (70 mg, 0.14 隱 ol)을 피리 딘 (3 )에 녹여 반응 흔합물에 첨가하여 2시간 동안 교반 하였다. 디클로로메탄으 로 추출 후， 소금물로 세척하고， 유기 용매층을 무수 황산나트륨으로 건조시킨 다 음 용매를 감압 농축하였다. 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =50:1)로 정제하여 화학식 1A로 표시되는 화합물 (47 mg, 반응수율: 39%， 하얀색 고 체)을 얻었다.  3- (4-methoxybenzyloxy) benzoic acid (77.3 mg, 0.29 mmol) was dissolved in dichloromethane (2.0), followed by oxalyl chloride (52 2 ^, 0.59 隱 ol) and TV, dimethylform at 0 ° C. After slowly adding amide (2 drops), the mixture was stirred for 1 hour, and then the solvent was removed under reduced pressure, and the compound (70 mg, 0.14 隱 ol) represented by Chemical Formula a-1 prepared in Preparation Example 1 was pyridine. It was dissolved in (3), added to the reaction mixture, and stirred for 2 hours, extracted with dichloromethane, washed with brine, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Purification by chromatography (dichloromethane: methanol = 50: 1) gave a compound represented by Chemical Formula 1A (47 mg, reaction yield: 39%, white solid).
¾ 藤 (400MHz, DMS0-c¾); δ 10.86(s, 1H), 9.04(s, 1H), 7.69-7.08 (m, 12H), 6.95-6.88(m, 8H), 5.61(s, 2H), 5.14(s, 2H), 5.09(s, 2H), 3.75(s, 3H), 3.72(s, 3H), 3.71(s, 3H) 단계 2: 3-히드록시 -N-[5-(2-히드록시페닐)— 1H-피라졸로 [3,4-b]피라진 -3-일] 벤즈아미드의 제조의 제조 ¾ 藤 (400 MHz, DMS0-c¾); δ 10.86 (s, 1H), 9.04 (s, 1H), 7.69-7.08 (m, 12H), 6.95-6.88 (m, 8H), 5.61 (s, 2H), 5.14 (s, 2H), 5.09 (s , 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H) Step 2: 3-hydroxy-N- [5- (2-hydroxyphenyl) — 1H-pyrazolo [ Preparation of 3,4-b] pyrazin-3-yl] benzamide
상기 단계 1에서 제조된 화학식 1A로 표시되는 화합물 (40.7 mg, 0.05 隱 ol) 을 트리플루오로아세트산 (3 에 녹인 후， 100 °C에서 2일 동안 교반 하였다. 상 Compound (40.7 mg, 0.05 隱 ol) represented by Chemical Formula 1A prepared in Step 1 was dissolved in trifluoroacetic acid (3) and stirred at 100 ° C for 2 days.
Figure imgf000053_0001
Figure imgf000053_0001
• a^i^^륭튠
Figure imgf000053_0002
 • a ^ i ^^ Great Tune
Figure imgf000053_0002
(Η2 'ZHO 'Ρ)86·9 '(HT '^M'9- 0' '(HS '^)\ 'L-L^ L '(HI ' L '(HI 'ΖΗΟ"^ 'Ρ)ε3·Λ '(HI 'ΖΗΟ'^ 'Ρ)60·8 '(HT 's) S'6 '(HT 's)S8"6 '(HI 's)X0-n '(HT 's)90"2T '(HT 's)00*n 9 ： (^-OSWO 'zfflTOO )漏 HT (Η2 ' Z HO' Ρ) 86 · 9 '(HT' ^ M ' 9- 0 ' '(HS' ^) \ ' LL ^ L' (HI 'L' (HI ' Ζ ΗΟ " ^' Ρ) ε3 · Λ '(HI' Ζ ΗΟ '^' Ρ) 60 · 8 '(HT' s) s '6' (HT 's) S8 "6' (HI 's) X0-n' (HT 's) 90 " 2T '(HT' s) 00 * n 9: (^ -OSWO 'zfflTOO) 漏 H T
•-b¾¾ 륭
Figure imgf000053_0003
-fo- & 륭 • -b¾¾ good
Figure imgf000053_0003
-fo- & great
15 15
^ΖΖ600/ΐΐΟΖΗΜ/Χ3<Ι ZC6..0/ZT0Z OAV
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
^ ΖΖ600 / ΐΐΟΖΗΜ / Χ3 <Ι ZC6..0 / ZT0Z OAV
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
<제조예 2> 에틸 5-아미노 -2-( -부톡시카보닐아미노 )-7-(4-메록시벤 질 )-7 —피롤로 [3， 4-ύ]피리딘 -3-카복실레이트의 제조 Preparation Example 2 of ethyl 5-amino-2-(-butoxycarbonylamino) -7- (4-methoxybenzyl) -7-pyrrolo [3,4-ύ] pyridine-3-carboxylate Produce
Figure imgf000059_0001
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0002
단계 1: 소듐 )-2-시아노 -3-에톡시 -3-옥소프로프 -1-엔— 1-을레이트의 제조 화학식 b— 2로 표시되는 화합물 에틸 2-시아노아세테이트 (100.0 g, 884.01 mmol)를 에탄올에 녹인 후 소듐에톡사이드 (2M 용액, 486 ) 수용액을 천천히 첨가 한후， 에틸 포메이트 (214 2652.05 圆 ol)을 천천히 첨가하여 실온에서 12시간 동안 교반 하였다. 반웅 종결 후， 생성된 고체를 여과하여 화학식 c-2로 표시되는 화합물 (100.9 g, 반웅수율: 70%, 흰색 고체)을 얻었다. Step 1: Preparation of Sodium) -2-Cyano-3-ethoxy-3-oxoprop-1-ene—1-erlate Compound represented by Formula b-2 Ethyl 2-cyanoacetate (100.0 g, 884.01 mmol) was dissolved in ethanol, and then an aqueous solution of sodium ethoxide (2M solution, 486) was slowly added, followed by the addition of ethyl formate (214 2652.05 μl) and stirred at room temperature for 12 hours. After completion of the reaction, the resulting solid was filtered to obtain a compound represented by Chemical Formula c-2 (100.9 g, reaction yield: 70%, white solid).
¾ NMR(400MHz, DMS0-i¾)： δ 9.17(s, 1H), 3.95(q, J-6.8Hz, 2H), 1.13(t, J=7.2Hz, 3H) 단계 2: (^-에틸 2-시아노 -3—메톡시아크릴레이트의 제조 ¾ NMR (400 MHz, DMS0-i¾): δ 9.17 (s, 1H), 3.95 (q, J-6.8 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H) Step 2: (^ -ethyl 2- Preparation of Cyano-3—methoxyacrylate
상기 단계 1에서 제조된 화학식 c-2로 표시되는 화합물 (100.9 g, 613.12 mmol)을 -디메틸포름아미드 (150 )에 녹인 후， 디메틸설페이트 (292 mi, 3065.60醒 ol)올 천천히 첨가한 후， 상온에서 12시간 동안 교반 하였다. 반웅 종결 후， 에틸 아세테이트를 가하고 유기 용매층을 소금물로 세척하고, 유기 용매층을 무수 황산마그네슘으로 건조시킨 다음 용매를 감압 농축하여 화학식 d-2로 표시되 는 화합물 (68.7 g, 반웅수율: 72%， 갈색 고체)을 얻었다.  After dissolving the compound represented by Chemical Formula c-2 prepared in Step 1 (100.9 g, 613.12 mmol) in -dimethylformamide (150), slowly adding dimethylsulfate (292 mi, 3065.60 醒 ol) ol, and then room temperature Stirred for 12 h. After completion of reaction, ethyl acetate was added, the organic solvent layer was washed with brine, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the compound represented by Chemical Formula d-2 (68.7 g, reaction yield: 72). %, Brown solid).
¾ 匿 (400匪 z, DMS0-i¾)： δ 8.32(s, 1H), 4.19(q, J=6.8Hz, 2H) , 4.14(s, 3H), 1.21(t, J=5.6Hz, 3H) ' 단계 3: 에틸 2-아미노—5-시아노 -6-하이드록시니코티네이트의 제조 ¾ 匿 (400 匪 z, DMS0-i¾): δ 8.32 (s, 1H), 4.19 (q, J = 6.8Hz, 2H), 4.14 (s, 3H), 1.21 (t, J = 5.6Hz, 3H) '' Step 3: Preparation of ethyl 2-amino-5-cyano-6-hydroxynicotinate
상기 단계 2에서 제조된 화학식 d— 2로 표시되는 화합물 (68.7 g, 443.24 隱 ol)을 에탄올에 녹인 후， 0 °C로 온도를 낮추고， 소듐에록사이드 (2M 용액， 568 ) 수용액을 천천히 첨가한 후, 2-시아노아세트아미드를 첨가하였다. 반웅 흔합물 을 60 °C에서 1시간 동안 교반하고， 반응 종료 후 반응 흔합물을 상온으로 넁각하 여 용매를 감압 하에 농축하였다. 물 (300 m£)과 염산 (300 mO을 첨가한 후， 1시간 동안 교반하여 생성된 고체를 여과하여 화학식 e-2로 표시되는 화합물 (74.5 g, 반 응수율 :81%， 흰색고체)을 얻었다. After dissolving the compound represented by Chemical Formula d-2 prepared in Step 2 (68.7 g, 443.24 μl) in ethanol, the temperature was decreased to 0 ° C., and an aqueous solution of sodium hydroxide (2M solution, 568) was slowly added. Then, 2-cyanoacetamide was added. The reaction mixture was stirred at 60 ° C. for 1 hour, after completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. After adding water (300 m £) and hydrochloric acid (300 mO), the mixture was stirred for 1 hour, and the resulting solid was filtered to give the compound represented by Chemical Formula e- 2 (74.5 g, half Coagulation rate: 81%, white solid) was obtained.
¾ NMR(400MHz, MS0-d6) δ 11.54(s, 1H), 8.33(s, 1H), 8.21(s, 1H) , 7.29(s, 1H), 4.19(q, J^7.6Hz, 2H), 1.26(t, J-6.8Hz, 3H) 단계 4: 에틸 2-아미노 -6-클로로 -5-시아노니코티네이트의 제조 ¾ NMR (400MHz, MS0-d 6 ) δ 11.54 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.29 (s, 1H), 4.19 (q, J ^ 7.6Hz, 2H) , 1.26 (t, J-6.8 Hz, 3H) Step 4: Preparation of ethyl 2-amino-6-chloro-5-cyanonicotinate
상기 단계 3에서 제조된 화학식 e-2로 표시되는 화합물 (40.0 g, 193.06 腿 ol)에 삼염화인 (250 i )을 첨가하고, 반웅 흔합물을 110 °C에서 3시간 동안 환류 교반 하였다. 반응 종결 후， 흔합물을 상온으로 냉각하고， 감압 농축하였다. 감압 농축한 잔류물에 얼음물 (500 )을 넣고, 생성된 고체를 여과하여 화학식 f-2로 표 시되는 화합물 (36.2 g, 반웅수율: 83%, 질은녹색 고체)을 얻었다. 丽 (400MHz, DMSO-cfe)： δ 8.65(s, 1H), 8.48(s, 1H), 8.10(s, 1H)， 4.29(q, J-7.6Hz, 2H), 1.30(t, 7-6.0Hz, 3H) 단계 5: 에틸 5-아미노 -2- -부록시카보닐아미노 )—7-(4_메톡시벤질) _7 ^피를 로 [3， 4->]피리딘 -3-카복실레이트의 제조 Phosphorus trichloride (250 i) was added to the compound represented by Chemical Formula e-2 prepared in Step 3 (40.0 g, 193.06 腿 ol), and the reaction mixture was stirred under reflux at 110 ° C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. Ice water (500) was added to the residue, which was concentrated under reduced pressure, and the resulting solid was filtered to obtain a compound (36.2 g, semi-water yield: 83%, vaginal silver green solid) represented by Chemical Formula f-2. (400MHz, DMSO-cfe): δ 8.65 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 4.29 (q, J-7.6Hz, 2H), 1.30 (t, 7-6.0 Hz, 3H) Step 5: ethyl 5-amino-2--butoxycarbonylamino) —7- (4_methoxybenzyl) _7 ^ pyrrole of [3,4->] pyridine-3-carboxylate Produce
상기 단계 4에서 제조된 화학식 f-2로 표시되는 화합물 (30.0 g, 132.96 mmol)을 디메틸포름아미드에 녹인 후， 4-메톡시벤질히드라진 수화물 (30.4 g, 199.44 mmol)을 첨가하고， 반응 흔합물을 90 °C에서 12시간 동안 환류 교반 하였 다. 반응 종결 후， 흔합물을 상온으로 넁각하여 얼음물에 넣고， 생성된 고체를 여 과하였다. 여과한 고체를 디에틸에테르로 세척하여 화학식 a-2로 표시되는 화합물 (28.0 g, 반웅수율 :61%, 노란색 고체)을 얻었다. After dissolving the compound represented by Chemical Formula f-2 prepared in Step 4 (30.0 g, 132.96 mmol) in dimethylformamide, 4-methoxybenzylhydrazine hydrate (30.4 g, 199.44 mmol) was added to the reaction mixture. It was stirred at reflux at 90 ° C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, placed in iced water, and the resulting solid was filtered. The filtered solid was washed with diethyl ether to obtain a compound represented by the formula (a-2) (28.0 g, semi-water yield: 61%, yellow solid).
¾ 證(400丽 z, DMSO-ok)： δ 8.61(s, 1H)， 7.12(d, Μ ζ, 2H)， 6.83(d, J^.6Hz, 2H), 5.78(s, 2H), 5.05(s, 2H), 4.27(q, J^7.2Hz, 2H), 3.70(s, 3H) , 1.32(t, J-6.6Hz, 3H) ¾ 400 (400 丽 z, DMSO-ok): δ 8.61 (s, 1H), 7.12 (d, ζ, 2H), 6.83 (d, J ^ .6Hz, 2H), 5.78 (s, 2H), 5.05 (s, 2H), 4.27 (q, J ^ 7.2 Hz, 2H), 3.70 (s, 3H), 1.32 (t, J-6.6 Hz, 3H)
<실시예 37> 에틸 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-Z>]피리딘 -5- 카복실레이트 하이드로클로라이드의 제조 Example 37 Preparation of Ethyl 6-amino-3- (nicotinamido) pyrazolo [3,4-Z>] pyridine-5-carboxylate hydrochloride
Figure imgf000061_0001
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0002
단계 1: 에틸 6—아미노—1-(4-메톡시벤질) -3- (니코틴아미도) -1 -피라졸로 [3, 4-Z>]피리딘 -5-카복실레이트의 제조 Step 1: Preparation of ethyl 6—amino—1- (4-methoxybenzyl) -3- (nicotinamido) -1-pyrazolo [3,4-Z>] pyridine-5-carboxylate
상기 제조예 2에서 제조된 화학식 a-2로 표시되는 화합물 (54 mg, 0.16 mmol) 을 피리딘 (2 )에 녹인 후， 나코티노일클로라이드 (42 mg, 0.24 mmol)를 천천히 첨 가한 후, 70 °C로 3시간 동안 교반 하였다. 반응 종결 후， 반응흔합물을 감압 농축 하고 에틸아세테이트로 세척하여 화학식 37A'로 표시되는 화합물 (53.1 mg, 반웅수 율: 75%, 흰색고체)을 얻었다. After dissolving the compound represented by Chemical Formula a-2 prepared in Preparation Example 2 (54 mg, 0.16 mmol) in pyridine (2), nacotinoyl chloride (42 mg, 0.24 mmol) was slowly added thereto, and then 70 ° C. Stir with C for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain a compound represented by the formula (37A ') (53.1 mg, semi-water ratio: 75%, white solid).
¾ NMR(400MHz, DMSO— Q ; δ 11.40(s, 1H), 9.15(s, 1H), 8.98(br, 1H),¾ NMR (400 MHz, DMSO— Q; δ 11.40 (s, 1H), 9.15 (s, 1H), 8.98 (br, 1H),
8.76(br, 1H), 8.36-8.24(m, 1H), 7.60(br, 2H) , 7.55-7.49(m, 1H), 7.19(d,8.76 (br, 1H), 8.36-8.24 (m, 1H), 7.60 (br, 2H), 7.55-7.49 (m, 1H), 7.19 (d,
J=8.8Hz, 2H), 6.89(d, J^8.0Hz, 2H), 5.32(s, 2H), 4.32(q, J^.2Hz, 2H), 3.70(s, 3H), 1.31(t, J-6.8Hz, 3H) 단계 2: 에틸 6-아미노 -3- (니코틴아미도) -Ly-피라졸로 [3, 4-Z>]피리딘 -5-카복 실레이트의 제조 J = 8.8 Hz, 2H), 6.89 (d, J ^ 8.0 Hz, 2H), 5.32 (s, 2H), 4.32 (q, J ^ .2 Hz, 2H), 3.70 (s, 3H), 1.31 (t, J-6.8 Hz, 3H) Step 2: Preparation of ethyl 6-amino-3- (nicotinamido) -Ly-pyrazolo [3, 4-Z>] pyridine-5-carboxylate
상기 단계 1에서 제조된 화학식 37A'로 표시되는 화합물 (50 mg, 0.11 mmol) 을 트리플루오로아세트산 (3 m£)에 녹인 후 100 °C에서 2일 동안 교반 하였다. 상온 으로 넁각 후 차가운 포화 중탄산나트륨 수용액으로 반응을 종결시키고, 반응물을 감압 여과하여 화학식 37A로 표시되는 화합물 (29 mg, 반응수율: 75%, 갈색 고체)을 얻었다. Compound (50 mg, 0.11 mmol) represented by Chemical Formula 37A 'prepared in Step 1 was dissolved in trifluoroacetic acid (3 m £), and then stirred at 100 ° C for 2 days. After cooling to room temperature, the reaction was terminated with cold saturated aqueous sodium bicarbonate solution, and the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 37A (29 mg, reaction yield: 75%, brown solid).
¾ NMR( 400MHz, DMS0-c ; δ 12.72(s, 1Η)， 11.03(s, 1H)， 9.17(s, 1H), 8.92(s, 1H), 8.78(br, 1H) , 8.38-8.36(m, 1H), 7.59-7.55(m, 1H), 7.42(br, 2H), 4.31(q, J-6.8Hz, 2H) , 1.30(t, J=6.8Hz, 3H) 단계 3: 에틸 6-아미노 -3- (니코틴아미도) -Ly—피라졸로 [3, 4-Z>]피리딘—5-카복 실레이트 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0-c; δ 12.72 (s, 1Η), 11.03 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 8.78 (br, 1H), 8.38-8.36 (m , 1H), 7.59-7.55 (m, 1H), 7.42 (br, 2H), 4.31 (q, J-6.8 Hz, 2H), 1.30 (t, J = 6.8 Hz, 3H) Step 3: ethyl 6-amino -3- (nicotinamido) -Ly—pyrazolo [3, 4-Z>] pyridine—5-carboxy Preparation of Silate Hydrochloride
상기 단계 2에서 제조된 화학식 37A로 표시되는 화합물 (29 mg, 0.09隱 ol)을 3.7M 염산 (2 mi, 1，4-디옥산용액)에 녹이고 상온에서 12시간 동안 교반 하였다. 반 웅종결 후， 반응물을 감압 여과하여 화학식 37로 표시되는 화합물 (19.4 mg, 반웅수 율: 61%， 갈색 고체)을 얻었다.  The compound represented by Chemical Formula 37A (29 mg, 0.09 μl) prepared in Step 2 was dissolved in 3.7 M hydrochloric acid (2 mi, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After the completion of the semi-ungung, the reaction was filtered under reduced pressure to obtain a compound represented by the formula (19.4 mg, half-water rate: 61%, brown solid).
¾ 證 OOMHz, DMSO-ck); δ 11.70(s, 1H)， 9.39(br, 1H), 9.02(br, 2H), 8.83(d, J-8.4Hz, 1H), 7.99(t, J=8.4Hz, 1H), 5.64(br, 2H) , 4.31(q, J=6.8Hz, 2H), 1.31(t, J^7.6Hz, 3H) 상기 실시예 37과 동일한 방법으로 하기 표 2의 화합물을 제조하였다. ¾ OOOOMHz, DMSO-ck); δ 11.70 (s, 1H), 9.39 (br, 1H), 9.02 (br, 2H), 8.83 (d, J-8.4Hz, 1H), 7.99 (t, J = 8.4Hz, 1H), 5.64 (br, 2H), 4.31 (q, J = 6.8 Hz, 2H), 1.31 (t, J ^ 7.6 Hz, 3H) The compounds of Table 2 were prepared in the same manner as in Example 37.
【표 2】 Table 2
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
<실시 예 61> 에틸 6- (메틸아미노 )-3- (니코틴아미도) 피라졸로 [3,4-b]피리 딘 -5-카복실레이트 하이드로클로라이드의 제조 Example 61 Preparation of Ethyl 6- (methylamino) -3- (nicotinamido) pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride
Figure imgf000066_0001
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0002
61  61
단계 1: 에틸 l-(4-메록시벤질) -6- (메틸아미노 )-3- (니코틴아미도) 1 -피라졸 로 [3,4 -A]피리딘 -5-카복실레이트의 합성  Step 1: Synthesis of [3,4-A] pyridine-5-carboxylate with ethyl l- (4-methoxybenzyl) -6- (methylamino) -3- (nicotinamido) 1-pyrazol
상기 실시예 37에서 제조된 화학식 37로 표시되는 화합물 (100.0 mg, 0.44 mmol)을 를루엔 (10 )에 녹인 후， 디메틸설페이트 (4.6^， 0.49 醒 ol)와 50% 농도 로 물에 녹인 수산화나트륨 (50 mg, 1.25 隱 ol), 테트라부틸암모늄브로마이드 (14 mg, 0.04 隱 ol)를 천천히 첨가한 후， 48시간 동안 교반 하였다. 반웅 종결 후， 물 과 에틸아세테이트를 가하고 유기 용매층을 무수 황산마그네슘으로 건조시킨 후， 용매를 감압 농축한 다음 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄을 =10:1)로 정제하여 화학식 61A로 표시되는 화합물 (43 mg, 반웅수율: 42%, 흰색 고 체)을 얻었다.  After dissolving the compound represented by the formula (37) prepared in Example 37 (100.0 mg, 0.44 mmol) in toluene (10), sodium hydroxide dissolved in water at 50% concentration with dimethyl sulfate (4.6 ^, 0.49 醒 ol) (50 mg, 1.25 μl ol) and tetrabutylammonium bromide (14 mg, 0.04 μl ol) were slowly added and stirred for 48 hours. After completion of reaction, water and ethyl acetate were added, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methane = 10: 1) to give a chemical formula 61A. The compound represented by (43 mg, semi-water yield: 42%, white solid) was obtained.
¾ NMR( 400MHz, DMS0-o); δ 11.39(s, 1Η), 9.14(s, 1H), 8.95(s, 1H), 8.75(d, J-4.8Hz, 1H), 8.34(d, J-7.6Hz, 1H), 8.29(d, J-4.8H, 1H), 7.54(dd, J-5.0Hz, J=3.9Hz, 1H), 7.27(d, J=8.0Hz, 2H), 6.87(d, J=8.4Hz, 2H), 5.34(s, 2H), 4.30(q, 7^7.2Hz, 2H)， 3.69(s, 3H), 3.04(d, J-.4.4Hz, 3H), 1.29(t, J IMz, 3H) 단계 2: 에틸 6- (메틸아미노 )—3— (니코틴아미도) 피라졸로 [3,4— Z>]피리딘 -5-카복실레이트 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0-o); δ 11.39 (s, 1Η), 9.14 (s, 1H), 8.95 (s, 1H), 8.75 (d, J-4.8 Hz, 1H), 8.34 (d, J-7.6 Hz, 1H), 8.29 (d, J-4.8H, 1H), 7.54 (dd, J-5.0 Hz, J = 3.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.34 (s, 2H), 4.30 (q, 7 ^ 7.2 Hz, 2H), 3.69 (s, 3H), 3.04 (d, J-.4.4 Hz, 3H), 1.29 (t, J IMz, 3H) Step 2: Preparation of Ethyl 6- (methylamino) —3— (nicotinamido) pyrazolo [3,4— Z>] pyridine-5-carboxylate hydrochloride
상기 1단계에서 제조된 화학식 61A로 표시되는 화합물 (43 mg, 0.09 睡 ol)을 상기 실시예 37의 단계 2 및 단계 3과 동일한 방법을 수행하여 화학식 61로 표시되 는 화합물 (24 mg, 68%, 갈색 고체)로 얻었다.  The compound represented by Chemical Formula 61A (43 mg, 0.09 μl ol) prepared in step 1 was carried out in the same manner as in Step 2 and Step 3 of Example 37 (24 mg, 68% , Brown solid).
¾ NMR( 400MHz, DMS0-o ; δ 12.87(br, 1H), 11.61(s, 1H), 9.36(s, 1H), 8.98(d, J-5.2Hz, 1H), 8.96(s, 1H), 8.83(d, J-8.0Hz, 1H), 8.27(br, 1H), 7.98(t, J=6.4Hz, 1H), 4.29(q, /-6.0Hz, 2H), 2.97(s, 3H), 1.29(t, J^IMz, 3H) <제조예 3> 2-[6-( 부록시카보닐아미노 )-5- (에록시카보닐) -l-(4-메톡시벤 질 )-1 -피라졸 (3，4- ]피리딘 -3-일 -카바모일]벤조익 액시드의 제조 ¾ NMR (400 MHz, DMS0-o; δ 12.87 (br, 1H), 11.61 (s, 1H), 9.36 (s, 1H), 8.98 (d, J-5.2 Hz, 1H), 8.96 (s, 1H), 8.83 (d, J-8.0 Hz, 1H), 8.27 (br, 1H), 7.98 (t, J = 6.4 Hz, 1H), 4.29 (q, /-6.0 Hz, 2H), 2.97 (s, 3H), 1.29 (t, J ^ IMz, 3H) Preparation Example 3 2- [6- (Appendix Cicarbonylamino) -5- (Eoxycarbonyl) -l- (4-methoxybenzyl) -1 -pyrazole (3,4-] pyridine- Preparation of 3-yl-carbamoyl] benzoic acid
Figure imgf000067_0001
Figure imgf000067_0001
a -3  a -3
단계 1: 에틸 2- -부톡시카보닐아미노 )-6-클로로 -5-시아노니코티네이트의 제조 ―  Step 1: Preparation of Ethyl 2-butoxycarbonylamino) -6-chloro-5-cyanonicotinate
상기 제조예 2의 단계 4에서 제조된 화학식 f-2로 표시되는 화합물 (1.59 g, 7.04 醒 ol)을 디클로로메탄에 녹인 후 0 °C로 낮춘 후, 디 - -부틸 디카보네이트 (2.30 g, 10.57 mmol), 트리에틸아민 (0.98 7.04 mraol), 4-디메틸아미노피리딘 (86 mg, 0.70 mmol)을 첨가하였다. 반응 흔합물을 0 °C에서 1시간 동안 교반 하였 다. 반응 종결 후, 흔합물을 염화암모늄과 디클로로메탄을 가하고 유기 용매층을 무수 황산마그네슴으로 건조시켜 용매를 감압 농축한 다음 잔류물을 컬럼 크로마토 그래피 (헥산：에틸아세테이트 =1:1)로 정제하여 화학식 b-3으로 표시되는 화합물 (2.22 g, 반웅수율: 96%， 노란색 고체)을 얻었다. The compound represented by the formula f-2 prepared in Step 4 of Preparation Example 2 (1.59 g, 7.04, ol) was dissolved in dichloromethane, lowered to 0 ° C., and then di-butyl carbonate (2.30 g, 10.57 mmol), triethylamine (0.98 7.04 mraol), 4-dimethylaminopyridine (86 mg, 0.70 mmol) were added. The reaction mixture was stirred at 0 ° C for 1 h. After completion of the reaction, the mixture was added ammonium chloride and dichloromethane, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 1: 1). The compound represented by the formula (b-3) (2.22 g, semi-water yield: 96%, yellow solid) was obtained.
¾ NMR(400MHz, DMSO- )： δ 10.78(s, 1H), 8.68(s, 1H), 5.76(s, 1H), 4.25(q, J=6.8Hz, 2H)ᅳ 1.46(s, 9H)， 1.29(t, J^JMz, 3H) 단계 2: 에틸 3—아미노 -6- -부톡시카보닐아미노 )-l-(4-메톡시벤질) -I 피라 졸로 [3, 4-6]피리딘 -5-카복실레이트의 제조 ¾ NMR (400 MHz, DMSO-): δ 10.78 (s, 1H), 8.68 (s, 1H), 5.76 (s, 1H), 4.25 (q, J = 6.8 Hz, 2H) ᅳ 1.46 (s, 9H), 1.29 (t, J ^ JMz, 3H) Step 2: Ethyl 3—amino-6-butoxycarbonylamino) -l- (4-methoxybenzyl) -I pyra Preparation of zolo [3, 4-6] pyridine-5-carboxylate
상기 단계 1에서 제조된 화학식 b-3으로 표시되는 화합물 (2.22 g, 6.81 隱 ol)을 씨디메틸포름아미드에 녹인 후， 4 메톡시벤질히드라진 수화물 (1.56 g, 10.22 mmol)을 첨가하였다. 반응 흔합물을 90 °C에서 12시간 동안 환류 교반 하였 다. 반웅 종결 후， 흔합물을 상온으로 냉각하여 얼음물에 넣어 생성된 고체를 여과 하였다. 여과한 고체를 디에틸에테르로 세척하여 화학식 c-3으로 표시되는 화합물 (944 mg, 반응수율: 31%, 노란색 고체)을 얻었다. After dissolving the compound represented by the formula (b-3) prepared in step 1 (2.22 g, 6.81 녹 ol) in cydimethylformamide, 4 methoxybenzylhydrazine hydrate (1.56 g, 10.22 mmol) was added. The reaction mixture was stirred at 90 ° C. for 12 hours at reflux. After the reaction was completed, the mixture was cooled to room temperature, put into iced water, and the produced solid was filtered. The filtered solid was washed with diethyl ether to obtain a compound represented by the formula (c-3) (944 mg, reaction yield: 31%, yellow solid).
¾ NMR( 400MHz, DMS0-(¾)： δ 10.47(s, 1H), 8.77(s, 1H), 7.20(d, J-8.4Hz, 2H), 6.85(d, J=8.8Hz, 2H), 6.01(s, 2H), 5.18(sᅳ 2H), 4.30(q, J=6.8Hz, 2H) , 3.67(s, 3H), 1.48(s, 9H), 1.32(t, J .2Hz, 3H) 단계 3: 2-[6-(^부톡시카보닐아미노 )-5- (에톡시카보닐) -l-(4-메톡시벤 질) 피라졸 (3， 4-A]피리딘 -3-일 -카바모일]벤조익 액시드의 제조 ¾ NMR (400MHz, DMS0- (¾): δ 10.47 (s, 1H), 8.77 (s, 1H), 7.20 (d, J-8.4Hz, 2H), 6.85 (d, J = 8.8Hz, 2H), 6.01 (s, 2H), 5.18 (s ᅳ 2H), 4.30 (q, J = 6.8 Hz, 2H), 3.67 (s, 3H), 1.48 (s, 9H), 1.32 (t, J .2 Hz, 3H) Step 3: 2- [6-(^ butoxycarbonylamino) -5- (ethoxycarbonyl) -1- (4-methoxybenzyl) pyrazole (3, 4-A] pyridin-3-yl -Carbamoyl] benzoic acid
상기 단계 2에서 제조된 화학식 c-3으로 표시되는 화합물 (100 mg, 0.23 mmol)을 테트라히드로퓨란 (5 에 녹인 후， 무수프탈산 (52 mg, 0.35 mmol)을 천천 히 첨가한 후， 5시간 동안 교반 하였다. 반웅 종결 후， 반웅 흔합물을 감압 농축한 다음 에틸아세테이트로 세척하여 화학식 a— 3으로 표시되는 화합물 (101 mg, 반웅수 율: h, 상아색 고체)을 얻었다.  After dissolving the compound represented by Chemical Formula c-3 (100 mg, 0.23 mmol) prepared in Step 2 in tetrahydrofuran (5), slowly adding phthalic anhydride (52 mg, 0.35 mmol) for 5 hours. After completion of reaction, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain a compound represented by Chemical Formula a-3 (101 mg, reaction rate: h, ivory solid).
¾ NMR(400MHz, DMS0-i¾)； δ 13.13(br, 1H), 11.31(s, 1H) , 10.52(s, 1H), 9.15(s, 1H), 7.89(d, J^7.6Hz, 1H)， 7.69-7.57(m, 3H), 7.28(d, J^7.6Hz, 2H), 6.88(d, J=R. z, 2H), 5.42(s, 2H), 4.31(q, J-6.8Hz, 2H), 3.79(s, 3H), 1.50(s, 9H), 1.32(t, J=7.6Hz, 3H) ¾ NMR (400 MHz, DMS0-i¾); δ 13.13 (br, 1H), 11.31 (s, 1H), 10.52 (s, 1H), 9.15 (s, 1H), 7.89 (d, J ^ 7.6 Hz, 1H) ， 7.69-7.57 (m, 3H), 7.28 (d, J ^ 7.6Hz, 2H), 6.88 (d, J = R.z, 2H), 5.42 (s, 2H), 4.31 (q, J-6.8Hz , 2H), 3.79 (s, 3H), 1.50 (s, 9H), 1.32 (t, J = 7.6 Hz, 3H)
<실시예 62> 에틸 6-아미노 -3-(1，3-디옥소이소인돌린 -2-일) 피라졸로 [3, 4 - ]피리딘 -5-카복실레이트의 제조 Example 62 Preparation of Ethyl 6-amino-3- (1,3-dioxoisoindolin-2-yl) pyrazolo [3,4-] pyridine-5-carboxylate
Figure imgf000068_0001
Figure imgf000068_0001
62  62
상기 제조예 3에서 제조된 화학식 a-3으로 표시되는 화합물 (101 mg, 0.17 mmol)을 실시예 37의 단계 7의 반웅을 이용하여 화학식 62로 표시되는 화합물 (3.2 mg, 반응수율: 상아색 고체)로 얻었다.  Compound (101 mg, 0.17 mmol) represented by Chemical Formula a-3 prepared in Preparation Example 3, represented by Chemical Formula 62 using reaction of Step 7 of Example 37 (3.2 mg, reaction yield: ivory solid) Got it.
¾ NMR(400MHz, DMS0-o ; δ 13.29(s, 1H)， 8.64(s, 1H) , 8.01-7.99(m, 2H), 7.94-7.92(m, 2H)， 7.51(br, 2H), 4.26(q, J-7.2Hz, 2H), 1.26(t, J-6.8Hz, 3H) <제조예 4> 4- [(디메틸아미노)메틸]아닐린의 제조
Figure imgf000069_0001
b-4 c-4 a-4 단계 1: -디메틸 -1-(4-니트로페닐)메탄아민의 제조 ¾ NMR (400MHz, DMS0-o; δ 13.29 (s, 1H), 8.64 (s, 1H), 8.01-7.99 (m, 2H), 7.94-7.92 (m, 2H), 7.51 (br, 2H), 4.26 (q, J-7.2 Hz, 2H), 1.26 (t, J-6.8 Hz, 3H) Preparation Example 4 Preparation of 4-[(dimethylamino) methyl] aniline
Figure imgf000069_0001
b-4 c-4 a-4 Step 1: Preparation of -dimethyl-1- (4-nitrophenyl) methanamine
화학식 b-4으로 표시되는 화합물 4-니트로벤질클로라이드 (1.0 g, 5.82睡 ol) 을 건조된 테트라히드로퓨란 (5 )에 녹인 후, 2.0^디메틸아민 (5 ra^, 테트라히드 로퓨란 용액)을 첨가한 후, 상온에서 24시간 동안 교반 하였다. 반응 흔합물을 물 로 종결시키고 에틸아세테이트로 추출하여 무수 황산 마그네슘으로 건조한 다음 용 매를 감압 농축하고, 정제 과정 없이 화학식 c-4로 표시되는 화합물 (1.04 g, 반웅 수율 :99¾， 노란 액체)을 얻었다.  Compound 4-nitrobenzylchloride (1.0 g, 5.82'ol) represented by the formula (b-4) was dissolved in dried tetrahydrofuran (5), followed by 2.0 ^ dimethylamine (5ra ^, tetrahydrofuran solution). After addition, the mixture was stirred at room temperature for 24 hours. The reaction mixture was terminated with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the compound represented by Chemical Formula c-4 (1.04 g, reaction yield: 99¾, yellow liquid) was purified without purification. Got it.
¾ 證 (400MHz, CDC13): δ 8.19(d, J .8Hz, 2H), 7.51(d, /-β.8Ηζ, 2H)， 3.51(s, 2H), 2.26(s, 6H) 단계 2: 4- [(디메틸아미노)메틸]아닐린의 제조 ¾ 證 (400MHz, CDC1 3 ): δ 8.19 (d, J .8Hz, 2H), 7.51 (d, /-β.8Ηζ, 2H), 3.51 (s, 2H), 2.26 (s, 6H) Step 2: Preparation of 4- [(dimethylamino) methyl] aniline
상기 단계 1에서 제조된 화학식 c-4로 표시되는 화합물 (1.04 g, 5.77 画 ol) 을 메탄올 (30 에 녹인 후, 10%-팔라듐 (104 mg, 10 wt¾)을 첨가하고 수소가스 하 에서 30분 동안 교반 하였다. 종결된 반웅 흔합물을 셀라이트 필터를 통해 팔라듐 을 제거하고 용매를 감압 농축하여 정제 과정 없이 화학식 a-4로 표시되는 화합물 (802 mg, 반웅 수율: 9¾， 노란 액체)을 얻었다.  The compound represented by Chemical Formula c-4 (1.04 g, 5.77, ol) prepared in Step 1 was dissolved in methanol (30), and then 10% -palladium (104 mg, 10 wt¾) was added thereto, followed by 30 minutes under hydrogen gas. The finished reaction mixture was removed with palladium through a celite filter and the solvent was concentrated under reduced pressure to obtain a compound represented by Chemical Formula a-4 (802 mg, reaction yield: 9¾, yellow liquid) without purification.
¾ NMR(400MHz, DMS0-c¾)： δ 7.92(d, J=8.8Hz, 2H), 7.31(d, J-8.8Hz, 2H), 4.24(s, 2H), 2.68(s, 6H) ¾ NMR (400 MHz, DMS0-c¾): δ 7.92 (d, J = 8.8 Hz, 2H), 7.31 (d, J-8.8 Hz, 2H), 4.24 (s, 2H), 2.68 (s, 6H)
<실시예 63> l-{4- [(디메틸아미노)메틸]페닐 }-3-[5— (4-메록시페닐) -1 피라 졸로 [4,3- 피라진 -3-일]우레아 하이드로클로라이드의 제조 Example 63 l- {4-[(dimethylamino) methyl] phenyl} -3- [5— (4-methoxyphenyl) -1 pyrazolo [4,3-pyrazin-3-yl] urea hydrochloride Manufacture
Figure imgf000070_0001
Figure imgf000070_0001
Figure imgf000070_0002
Figure imgf000070_0002
Figure imgf000070_0003
단계 1: l-{4- [(디메틸아미노)메틸]페닐 }-3— [l-(4-메톡시벤질) -5-(4—메특시 페닐 )-L 피라졸로 [4 , 3-Z>]피라진 -3-일 ]우레아의 합성
Figure imgf000070_0003
Step 1: l- {4-[(dimethylamino) methyl] phenyl} -3— [l- (4-methoxybenzyl) -5 (4—methoxyphenyl) -L pyrazolo [4, 3-Z >] Synthesis of Pyrazin-3-yl] urea
상기 제조예 4에서 제조된 화학식 a-4로 표시되는 화합물 (59 mg, 0.39 mmol) 을 디클로로메탄 (3 )에 용해시키고, 0 °C에서 트리에틸아민 (0.065 ι , 0.47 瞧 ol)과 트리포스젠 (127 mg, 0.43 匪 ol)을 첨가하여 동일한 온도에서 30분 동안 교 반 하였다. 반웅 흔합물에 제조예 1의 방법으로 제조된 화학식 a-l '로 표시되는 화 합물 1-(4-메톡시벤질) -5-(4-메록시페닐) -L 피라졸로 [4,3-b]피라진 -3-아민 (50 mg, 0.13 mmol)에 과량의 피리딘 (2 을 넣고 60 °C로 가열하여 2시간 동안 교반 하였 다. 종결된 반웅 흔합물의 용매를 감압 농축하고 건조하여 얻은 잔류물을 컬럼 크 로마토그래피 (디클로로메탄:메탄올 =8:1)하여 화학식 63A-a로 표시되는 화합물 (53 mg, 반웅 수율 :76%, 노란 고체)을 얻었다. Compound (59 mg, 0.39 mmol) represented by Chemical Formula a-4 prepared in Preparation Example 4 was dissolved in dichloromethane (3), and triethylamine (0.065 ι, 0.47 瞧 ol) and triphosphate at 0 ° C. Zen (127 mg, 0.43 μl ol) was added and stirred for 30 minutes at the same temperature. Compound 1- (4-methoxybenzyl) -5 (4-methoxyphenyl) -L pyrazolo [4,3-b] represented by formula al ' prepared by the method of Preparation Example 1 in a reaction mixture. Pyrazine-3-amine (50 mg, 0.13 mmol) was added excess pyridine (2) and heated to 60 ° C., and stirred for 2 hours. The resulting reaction mixture was concentrated under reduced pressure and dried to give a residue. Chromatography (dichloromethane: methanol = 8: 1) gave the compound represented by the formula (63A-a) (53 mg, reaction yield: 76%, yellow solid).
¾ 匿 (400MHz, SO-ds)： δ 9.40-9.37 (m, 2H), 9.23(s, 1H)ᅳ 8.15(d, J=8.8Hz, 2H), 7.43(d, J=8.0Hz, 2H) , 7.31(d, J^.4Hz, 2H), 7.21(d, J^7.3Hz, 2H), 7.10(d, J-8.0Hz, 2H), 6.91(d, J-8.0Hz, 2H) , 5.56(s, 2H), 4.21(s, 2H) , 3.83(s, 3H), 3.71(s, 3H), 2.50(s, 6H) 단계 2: 1— {4- [(디메틸아미노)메틸]페닐 }-3-[5-(4-메톡시페닐) -1가피라졸로 [4，3-/>]피라진 -3-일]우레아의 제조 ¾ 匿 (400 MHz, SO-ds): δ 9.40-9.37 (m, 2H), 9.23 (s, 1H) ᅳ 8.15 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H) , 7.31 (d, J ^ .4 Hz, 2H), 7.21 (d, J ^ 7.3 Hz, 2H), 7.10 (d, J-8.0 Hz, 2H), 6.91 (d, J-8.0 Hz, 2H), 5.56 (s, 2H), 4.21 (s, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 2.50 (s, 6H) Step 2: 1— {4- [(dimethylamino) methyl] phenyl} Preparation of [4,3-/>] pyrazin-3-yl] urea with -3- [5- (4-methoxyphenyl) -1gapyrazolo
상기 단계 2에서 제조된 화학식 63A-a로 표시되는 화합물 (53 mg, 0.098 隱 ol)을 트리플루오로아세트산 (3 )에 녹인 후, 실드—튜브 (sealed tube)에서 80 °C로 가열하여 24시간 동안 교반 하였다. 반웅 흔합물을 찬 얼음물로 종결시키고 탄산수소나트륨 수용액으로 염기화한 후， 에틸아세테이트로 추출하여 무수 황산 마 그네슴으로 건조한 다음 용매를 감압 농축하였다. 얻은 잔류물을 컬럼 크로마토그 래피 (디클로로메탄:메탄올 =6:1)하여 화학식 63A로 표시되는 화합물 (31 mg, 반웅 수 율: 76%， 노란 고체)을 얻었다. The compound represented by Chemical Formula 63A-a prepared in Step 2 (53 mg, 0.098 μl) was dissolved in trifluoroacetic acid (3), and then heated to 80 ° C. in a shielded tube for 24 hours. Was stirred. The reaction mixture was terminated with cold ice water, basified with aqueous sodium bicarbonate solution, extracted with ethyl acetate, and dried over anhydrous sulfate. After drying over the swing, the solvent was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (dichloromethane: methanol = 6: 1) to obtain a compound represented by the formula (63A) (31 mg, reaction yield: 76%, yellow solid).
¾ NMR(400MHz, DMSO-ofe)： 6 9.87(br, 1H), 9.68(s, 1H), 9.49(s, 1H)ᅳ 9.16(s, 1H), 8.14(d, J-8.8Hz, 2H), 7.61(d, J-8.1Hz, 2H) , 7.41(d, J=8.4Hz, 2H), 7.19(d, J=8.1Hz, 2H), 4.21(s, 2H), 3.83(s, 3H), 2.71(s, 3H), 2.70(s, 3H) 단계 3: l-{4- [(디메틸아미노)메틸]페닐 }-3-[5-(4-메톡시페닐) -I 피라졸로 [4,3-Z>]피라진 -3-일]우레아 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMSO-ofe): 6 9.87 (br, 1H), 9.68 (s, 1H), 9.49 (s, 1H) ᅳ 9.16 (s, 1H), 8.14 (d, J-8.8 Hz, 2H) , 7.61 (d, J-8.1 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 4.21 (s, 2H), 3.83 (s, 3H) , 2.71 (s, 3H), 2.70 (s, 3H) Step 3: l- {4-[(dimethylamino) methyl] phenyl} -3- [5- (4-methoxyphenyl) -I pyrazolo [4 , 3-Z>] Pyrazin-3-yl] urea hydrochloride
상기 단계 2에서 제조된 화학식 63A로 표시되는 화합물 (31 mg, 0.074 mmol) 을 ^4—디옥산 (3 )에 용해시키고 0 °C에서 3.7M 염산 (1 ml, 1，4-디옥산용액)을 천천히 첨가 하고， 반응 흔합물을 상온에서 24시간 동안 반응하고， 종결된 흔합물 의 생성된 고체를 여과하여 에틸아세테이트와 디클로로메탄으로 세척하였다. 화합 물을 건조하고 정제 과정 없이 화학식 63으로 표시되는 화합물 (24 mg, 반웅 수 율: 71%， 붉은 고체)을 얻었다.  The compound represented by Chemical Formula 63A (31 mg, 0.074 mmol) prepared in Step 2 was dissolved in ^ 4—dioxane (3) and 3.7 M hydrochloric acid (1 ml, 1,4-dioxane solution) at 0 ° C. Was added slowly, the reaction mixture was reacted at room temperature for 24 hours, and the resulting solid of the terminated mixture was filtered and washed with ethyl acetate and dichloromethane. The compound was dried to give a compound of formula 63 (24 mg, reaction yield: 71%, red solid) without purification.
¾ NMR(400MHz, DMSOo ): δ ll.lKbr, 1H), 10.20(br, 1H), 9.55(br, !H), 9.15(s, 1H), 8.14(d, J^8.8Hz, 2H), 7.57(d, J-8.6Hz, 2H), 7.49(d, 7-β.6Ηζ, 2H), 7.09(d, J=8.8Hz, 2H), 4.18(s, 2H), 3.82(s, 3H), 2.64(s, 3H)， 2.62(s, 3H) 상기 실시예 63과 동일한 방법으로 하기 표 3의 화합물을 제조하였다. ¾ NMR (400 MHz, DMSOo): δ ll.lKbr, 1H, 10.20 (br, 1H), 9.55 (br,! H), 9.15 (s, 1H), 8.14 (d, J ^ 8.8Hz, 2H), 7.57 (d, J-8.6 Hz, 2H), 7.49 (d, 7-β.6Ηζ, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.18 (s, 2H), 3.82 (s, 3H) , 2.64 (s, 3H), 2.62 (s, 3H) The compounds of Table 3 were prepared in the same manner as in Example 63.
【표 3]  [Table 3]
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
ZL ZL
^ίΖ600/ΪΪΟΖΗΜ/Χ3«Ι ZteLLOIZlOZ OAV
Figure imgf000075_0001
Figure imgf000076_0001
^ ίΖ600 / ΪΪΟΖΗΜ / Χ3 «Ι ZteLLOIZlOZ OAV
Figure imgf000075_0001
Figure imgf000076_0001
<실시예 95> 4-[3-(5-{3-[2- (디메틸아미노)에톡시]페닐 }-L¥"피라졸로 [3,4-Z>] 피라진 -3—일)우레이도]벤즈아미드하이드로클로라이드의 제조 Example 95 4- [3- (5- {3- [2- (dimethylamino) ethoxy] phenyl} -L ¥ "pyrazolo [3,4-Z>] pyrazine-3-yl) ureido ] Preparation of Benzamide Hydrochloride
Figure imgf000077_0001
단계 2
Figure imgf000077_0001
Step 2
Figure imgf000077_0002
Figure imgf000077_0002
95A 95A-b 단계 4  95A 95A-b Step 4
Figure imgf000077_0003
Figure imgf000077_0003
95  95
단계 1: l-(4-시아노페닐) -3-[5-(3-하이드록시페닐) -l-(4-메톡시벤질) -IH-피 라졸로 [3, 4-b]피라진 -3-일]우레아의 제조  Step 1: l- (4-cyanophenyl) -3- [5- (3-hydroxyphenyl) -l- (4-methoxybenzyl) -IH-pyrazolo [3, 4-b] pyrazine- 3-yl] Urea Preparation
실시예 72의 중간체 화합물 1-(4-시아노페닐) -3-{1-(4-메록시벤질)— 5-[3-(4- 메톡시벤질 옥시)페닐] -1H-피라졸로 [3,4-b]피라진 -3-일}우레아 화합물 (80 mg, 0.13 mmol)을 3.7M 염산 (2 mi, 1，4-디옥산용액)에 녹이고 상온에서 12시간 동안 교반 하 였다. 반웅종결 후, 반웅물을 감압 여과하여 화학식 95A-a로 표시되는 화합물 (60 mg, 반웅수율: 93%, 노란색 고체)을 얻었다.  Intermediate compound of Example 72 1- (4-cyanophenyl) -3- {1- (4-methoxybenzyl) — 5- [3- (4-methoxybenzyl oxy) phenyl] -1H-pyrazolo [ 3,4-b] pyrazin-3-yl} urea compound (80 mg, 0.13 mmol) was dissolved in 3.7M hydrochloric acid (2 mi, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by the formula (95A-a) (60 mg, reaction yield: 93%, yellow solid).
¾ 匿 (400MHz, DMS0-i¾)； δ 9.83(s, 1H)， 9.54(s, IH), 9.18(s, IH),¾ 匿 (400 MHz, DMS0-i¾); δ 9.83 (s, 1H), 9.54 (s, IH), 9.18 (s, IH),
7.74(d, J=8.8Hz, 2H), 7.66(d, J-8.8Hz, 2H), 7.57-7.54(m, 2H), 7.33(d,7.74 (d, J = 8.8 Hz, 2H), 7.66 (d, J-8.8 Hz, 2H), 7.57-7.54 (m, 2H), 7.33 (d,
MMz, IH), 7.30(d, J-8.8Hz, 2H), 6.91-6.87(m, 3H), 5.58(s, 2H) , 3.70(s, 3H) 단계 2: l-(4-시아노페닐) -3-(5-{3-[2- (디메틸아미노)에톡시]페닐 }-l-(4-메 톡시벤질)— 1H-피라졸로 [3, 4-b]피라진 -3-일)우레아의 제조 MMz, IH), 7.30 (d, J-8.8 Hz, 2H), 6.91-6.87 (m, 3H), 5.58 (s, 2H), 3.70 (s, 3H) Step 2: l- (4-cyanophenyl) -3- (5- {3- [2- (dimethylamino) ethoxy] phenyl} -1- (4-methoxybenzyl) —1H-pyrazolo [3 , 4-b] pyrazin-3-yl) urea
상기 단계 1에서 제조된 화학식 95A-a로 표시되는 화합물 (38 mg, 0.08画 ol) 과 탄산칼륨 (43 mg, 0.31 醒 ol)을 -디메틸포름아미드 (15 에 녹인 후， 상온에 서 2—클로로 디메틸에틸아민 하이드로클로라이드 (22 mg, 0.15 隱 ol)를 첨가하 고 1일 동안 교반 하였다. 디클로로메탄으로 추출하고， 소금물로 세척한 후， 유기 용매층을 무수 황산나트륨으로 건조시킨 다음 용매를 감압 농축하였다. 잔여물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =30:1)로 정제하여 화학식 95A— b로 표시 되는 화합물 (26 mg, 반웅수율 :60%, 노란색 고체)을 얻었다.  The compound represented by the formula 95A-a prepared in Step 1 (38 mg, 0.08 μl ol) and potassium carbonate (43 mg, 0.31 μl ol) were dissolved in -dimethylformamide (15), followed by 2-chloro at room temperature. Dimethylethylamine hydrochloride (22 mg, 0.15 μl) was added and stirred for 1 day, extracted with dichloromethane, washed with brine, the organic solvent layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 30: 1) to give the compound represented by the formula (95A) -b (26 mg, semi-water yield: 60%, yellow solid).
¾ 腿 (400MHz, CDCls); δ 11.23(s, 1H)， 9.03(s, 1H), 7.83(s, 1H),¾ Hz (400 MHz, CDCls); δ 11.23 (s, 1 H), 9.03 (s, 1 H), 7.83 (s, 1 H),
7.54(d, 7=8.8Hz, 2H), 7.49(d, J=8.4Hz, 1H), 7.40(ά, J^.8Hz, 2H),7.54 (d, 7 = 8.8 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.40 (ά, J ^ .8 Hz, 2H),
7.36-7.32(III, 3H), 6.94-6.89(m, 3H), 5.56(s, 2H), 4.69(t, J=7.6Hz, 2H), 3.80(s, 3H), 2.91(t, J^7.6Hz, 2H), 2.41(s, 6H) 단계 3: 4-[3-(5-{3-[2-(디메틸아미노)에특시]페닐}-111-피라졸로[3,4-1)]피라 진 -3ᅳ일)우레이도]벤즈아미드의 제조 7.36-7.32 (III, 3H), 6.94-6.89 (m, 3H), 5.56 (s, 2H), 4.69 (t, J = 7.6 Hz, 2H), 3.80 (s, 3H), 2.91 (t, J ^ 7.6 Hz, 2H), 2.41 (s, 6H) Step 3: 4- [3- (5- {3- [2- (dimethylamino) e] phenyl} -111-pyrazolo [3,4-1) ] Pyrazine-3 yl) ureido] benzamide
상기 단계 2에서 제조된 화학식 95A-a로 표시되는 화합물 (34 mg, 0.06隱 ol) 올 트리플루오로아세트산 (5 )에 녹인 후 100 °C에서 5일 동안 교반 하였다. 상온 으로 냉각 후 차가운 포화 중탄산나트륨 수용액으로 반응을 종결시키고, 반응물을 감압 여과하여 화학식 95A로 표시되는 화합물 (10 mg, 반옹수율: 36.5%， 갈색 고체) 을 얻었다. The compound represented by Chemical Formula 95A-a prepared in Step 2 (34 mg, 0.06 ′ ol) was dissolved in trifluoroacetic acid (5), and stirred at 100 ° C. for 5 days. After cooling to room temperature, the reaction was terminated with a cold saturated aqueous sodium bicarbonate solution, and the reaction product was filtered under reduced pressure to obtain a compound represented by the formula (95A) (10 mg, water repellency: 36.5%, brown solid).
¾ NMR(400MHz, DMS0-*)； 6 13.98(t)r, 1H)ᅳ 9.66(s, 1H), 9.55(br, 1H) , 9.14(s, 1Η), 7.81(s, 1H) , 7.76(d, J=8.8Hz, 2H) , 7.54-7.48(m, 4H), 7.25(t, 8.0Hz, 1H), 7.18(m, 1H), 6.86-6.83 (m, 1H), 4.11(t, J=6.4Hz, 2H), 2.56(t, J-6.8Hz, 2H), 2.16(s, 6H) 단계 4: 4-[3— (5-{3-[2- (디메틸아미노)에톡시]페닐 }-1Η-피라졸로 [3,4-b]피라 진 -3-일)우레이도]벤즈아미드 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0- *); 6 13.98 (t) r, 1H) 9.66 (s, 1H), 9.55 (br, 1H), 9.14 (s, 1Η), 7.81 (s, 1H), 7.76 ( d, J = 8.8 Hz, 2H), 7.54-7.48 (m, 4H), 7.25 (t, 8.0 Hz, 1H), 7.18 (m, 1H), 6.86-6.83 (m, 1H), 4.11 (t, J = 6.4 Hz, 2H), 2.56 (t, J-6.8 Hz, 2H), 2.16 (s, 6H) Step 4: 4- [3— (5- {3- [2- (dimethylamino) ethoxy] phenyl } -1Η-pyrazolo [3,4-b] pyrazin-3-yl) ureido] benzamide hydrochloride
상기 단계 3에서 제조된 화학식 95A로 표시되는 화합물 (9 mg, 0.02 國 ol)을 3.7M 염산 (2 π^, 1,4-디옥산용액)에 녹이고, 상온에서 12시간 동안 교반 하였다. 반웅종결 후， 반응물을 감압 여과하여 화학식 95로 표시되는 화합물 (8 mg, 반웅수 율 :8¾, 갈색 고체)을 얻었다.  The compound represented by Chemical Formula 95A (9 mg, 0.02 Korean ol) prepared in step 3 was dissolved in 3.7 M hydrochloric acid (2 pi ^, 1,4-dioxane solution), and stirred at room temperature for 12 hours. After the reaction was completed, the reaction product was filtered under reduced pressure to obtain a compound of Formula 95 (8 mg, reaction rate: 8¾, brown solid).
¾ 證 (400MHz, DMS0-i¾)； δ 14.16(s, 1H), 9.71(s, 1H)， 9.59(br, 1H), 9.24(s, 1H), 9.21(s, 1H), 7.79-7.77(m, 3H), 7.51-7.47 (m, 4H) , 7.27-7.25(m, 2H), 6.88(m, 1H), 4.34(d, J=6.8Hz, 2H), 2.87(d, J- .8Hz, 6H) , 2.50(m, 2H) ¾ 證 (400 MHz, DMS0-i¾); δ 14.16 (s, 1H), 9.71 (s, 1H), 9.59 (br, 1H), 9.24 (s, 1H), 9.21 (s, 1H), 7.79-7.77 ( m, 3H), 7.51-7.47 (m, 4H), 7.27-7.25 (m, 2H), 6.88 (m, 1H), 4.34 (d, J = 6.8 Hz, 2H), 2.87 (d, J- .8 Hz , 6H), 2.50 (m, 2H)
<제조예 5> 4- (피리딘 -4-일)부탄알의 제조 Preparation Example 5 Preparation of 4- (pyridin-4-yl) butanal
Figure imgf000079_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0002
a-5  a-5
단계 1:( )-4-[3-(1,3-디옥솔란 -2-일)프로프 -1-엔일]피리딘의 제조  Step 1: Preparation of () -4- [3- (1,3-dioxolan-2-yl) prop-1-enyl] pyridine
(2-(1，3-디옥솔란 -2-일)에틸)트라이페닐포스포늄 브로마이드 (500 mg, 4.67 睡 ol)를 테트라히드라퓨란 (10 에 녹인 후， -30 °C에서 2.5 M 부틸리튬 (2.8 mi 핵산용액)을 천천히 첨가한 후， ᅳ 30 °C로 1시간 동안 교반한 후， 테트라히드라퓨란 (10 에 녹인 화학식 b-5로 표시되는 화합물 이소니코틴알데히드 (100 mg, 0.44 mmol)를 천천히 첨가하고, 실온에서 3시간 동안 교반 하였다. 반웅 종결 후， 염화 암모늄과 클로로포름을 가하고 유기 용매층을 무수 황산마그네슴으로 건조시켜 용 매를 감압 농축한 다음 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =3:1)로 정제하여 화학식 c-5로 표시되는 화합물 (630 mg, 반옹수율: 72%, 무색 액체)로 얻 었다. (2- (1,3-dioxolan-2-yl) ethyl) triphenylphosphonium bromide (500 mg, 4.67 睡 ol) was dissolved in tetrahydrafuran (10, and then 2.5M butyllithium at -30 ° C 2.8 mi nucleic acid solution) was added slowly, followed by stirring at ᅳ 30 ° C for 1 hour, followed by slowly adding tetrahydrafuran (compound isonicotinaldehyde (100 mg, 0.44 mmol) represented by formula b-5 dissolved in 10). After the reaction was complete, ammonium chloride and chloroform were added, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (nucleic acid: ethyl acetate). = 3: 1) to obtain a compound represented by the formula (c-5) (630 mg, water repellency: 72%, colorless liquid).
¾ 匿 (400MHz, DMSO-ώ)； δ 8.55(d, J=6.0Hz, 2H), 7.21(d, /-6.0Hz, 2H), 6.52(d, J=l 1.6Hz, 1H), 5.96(t, J-8.0Hz, 1H), 5.00(t, J=4.4Hz, 1H) , 4.12-3.85(m, 4H) , 2.73-2.69(m, 2H) 단계 2: 4-[3-(1，3-디옥솔란— 2—일)프로필]피리딘의 제조 ¾ 匿 (400 MHz, DMSO-ώ); δ 8.55 (d, J = 6.0 Hz, 2H), 7.21 (d, /-6.0 Hz, 2H), 6.52 (d, J = l 1.6 Hz, 1H), 5.96 ( t, J-8.0 Hz, 1H), 5.00 (t, J = 4.4 Hz, 1H), 4.12-3.85 (m, 4H), 2.73-2.69 (m, 2H) Step 2: 4- [3- (1, Preparation of 3-dioxolane— 2—yl) propyl] pyridine
상기 단계 1에서 제조된 화학식 c-5로 표시되는 화합물 (630 mg, 3.30 隱 ol) 에 에탄을을 가하여 녹인 후， 10%-팔라듐 (30 mg, 5 wt¾ 을 첨가하고 수소가스 하에 서 1시간 동안 교반 하였다. 종결된 반응 흔합물을 셀라이트 필터를 통해 팔라듐을 제거하고 용매를 감압 농축하여 정제 과정 없이 화학식 d-5로 표시.되는 화합물 (515 mg, 반웅수율: 85%， 무색 액체)을 얻었다.  After adding ethane to the compound represented by Formula c-5 (630 mg, 3.30 隱 ol) prepared in Step 1, 10% -palladium (30 mg, 5 wt¾ was added and dissolved in hydrogen gas for 1 hour. The terminated reaction mixture was removed with palladium through a celite filter and the solvent was concentrated under reduced pressure to obtain the compound (515 mg, semi-water yield: 85%, colorless liquid) represented by Chemical Formula d-5 without purification. .
¾匿 (400MHz, DMS0-i¾)； δ 8.46(d, J=6.0Hz, 2H), 7.10(d, J-6.4Hz, 2H), 4.86(t, J-4.8Hz, 1H), 3.96-3.81 (ra, 4H), 2.64(t, J^7.2Hz, 2H), 1.78-1.65(m, 4H) 단계 3: 4- (피리딘 -4-일)부탄알의 제조 ¾ 匿 (400MHz, DMS0-i¾); δ 8.46 (d, J = 6.0Hz, 2H), 7.10 (d, J-6.4Hz, 2H), 4.86 (t, J-4.8Hz, 1H), 3.96-3.81 (ra, 4H), 2.64 (t, J ^ 7.2 Hz, 2H), 1.78-1.65 (m, 4H) Step 3: Preparation of 4- (pyridin-4-yl) butanal
상기 단계 2에서 제조된 화학식 d-5로 표시되는 화합물 (200 mg, 1.04 隱 ol) 에 1 염산을 가하여 녹인 후 2시간 동안 교반 하였다. 반응 종결 후, 클로로포름 으로 세척하고 남은 용액을 수산화나트륨을 이용하여 염기성 (pH=12)으로 만든 후, 에틸아세테이트를 가하고， 유기 용매층을 무수 황산마그네슘으로 건조시키고 감압 농축하여 화학식 a-5로 표시되는 화합물 (115 mg, 반응수율: 75%, 무색 액체)을 얻었 다. 1 hydrochloric acid was added to the compound represented by Chemical Formula d-5 (200 mg, 1.04 μl ol) prepared in Step 2, and then stirred for 2 hours. After completion of the reaction, the resultant was washed with chloroform and the remaining solution was made basic with sodium hydroxide (pH = 12), ethyl acetate was added, the organic solvent layer was dried over anhydrous magnesium sulfate, Concentration gave a compound represented by Chemical Formula a-5 (115 mg, reaction yield: 75%, colorless liquid).
¾ 證 (400MHz, O SO-de)； δ 9.78(s, 1H) , 8.50(d, J^.OHz, 2H), 7.11(d, J-5.6, 2H), 2.65(t, 7^7.2Hz, 2H), 2.49(t, J=7.6Hz, 2H), 2.01-1.93(m, 2H) ¾ 證 (400 MHz, O SO-de); δ 9.78 (s, 1H), 8.50 (d, J ^ .OHz, 2H), 7.11 (d, J-5.6, 2H), 2.65 (t, 7 ^ 7.2Hz , 2H), 2.49 (t, J = 7.6 Hz, 2H), 2.01-1.93 (m, 2H)
<실시예 96> 2-{3-[4- (피리딘 -4-일)부틸아미노] -L^-피라졸로 [3,4-b]피라진 -5-일}페놀 하이드로클로라이드의 제조 Example 96 Preparation of [3,4-b] pyrazin-5-yl} phenol hydrochloride with 2- {3- [4- (pyridin-4-yl) butylamino] -L ^ -pyrazolo
Figure imgf000080_0001
Figure imgf000080_0001
96  96
단계 1: 1-(4-메톡시벤질) -5-[2-(4-메톡시벤질옥시)페닐] -7H4- (피리딘 -4- 일)부틸] 피라졸로 [3,4-Z>]피라진 -3-아민의 제조  Step 1: 1- (4-methoxybenzyl) -5 [2- (4-methoxybenzyloxy) phenyl] -7H4- (pyridin-4-yl) butyl] pyrazolo [3,4-Z>] Preparation of Pyrazine-3-amine
상기 제조예 1에서 제조된 화학식 a-1로 표시되는 화합물 (50 mg, 0.11 mmol) 을 메탄올에 녹인 후， 상기 제조예 5에서 제조된 화학식 a-5로 표시되는 화합물 (25.0 mg, 0.17 瞧 ol)과 소듐시아노보로하이드라이드 (11.3 mg, 0.17 mmol), 염화아 연 (Π)(8.1 mg, 0.06 mmol), 1.25M 염산 (0.75 메탄을 용액)을 순서대로 첨가하 고， 12시간 동안 교반 하였다. 반응 종료 후，， 탄산수소나트륨용액과 에틸아세테이 트를 가한 후, 유기 용매층을 무수 황산마그네슘으로 건조시키고 용매를 감압 농축 한 다음 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =10:1)로 정제하여 화 학삭 96A로 표시되는 화합물 (35.0 mg, 반웅수율: 57%, 상아색 고체)을 얻었다.  Compound (50 mg, 0.11 mmol) represented by Chemical Formula a-1 prepared in Preparation Example 1 was dissolved in methanol, and the compound represented by Chemical Formula a-5 prepared in Preparation Example 5 (25.0 mg, 0.17 μl ol ) And sodium cyanoborohydride (11.3 mg, 0.17 mmol), zinc chloride (Π) (8.1 mg, 0.06 mmol), 1.25M hydrochloric acid (0.75 methane solution) were added in this order and stirred for 12 hours. It was. After the reaction was completed, sodium hydrogen carbonate solution and ethyl acetate were added, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1). Purification with (C) yielded the compound (35.0 mg, semi-water yield: 57%, ivory solid) represented by Chemical Engineering 96A.
¾ 匿 (400MHz, DMSO- ); δ 8.85(S, 1H), 8.39(d, 6.0Hz, 2H), 7.69(d, M.mz, 1H), 7.41(t, /-8.8Hz, 1H), 7.33(d, /-8.4Hz, 2H), 7.27(d, 7-8.4Hz, 1H), 7.18(d, J=8.0Hz, 2H), 7.15(d, J=8.8Hz, 2H), 7.08(d, MMz, 1H), 6.88(d, J-8.8Hz, 2H), 6.81(d, J-8.0Hz, 2H), 6.52(t, J-6.6Hz, 1H), 5.30(s, 2H), 5.10(s, 2H), 3.71(s, 3H) , 3.67(s, 3H) , 2.58(q, J-6.4Hz, 2H), 1.66-1.62(m, 6H) 단계 2: 2-{3-[4- (피리딘 -4-일)부틸아미노] -Ly-피라졸로 [3,4->]피라진 -5-일} 페놀 하이드로클로라이드의 제조 ¾ Hz (400 MHz, DMSO-); δ 8.85 (S, 1H), 8.39 (d, 6.0 Hz, 2H), 7.69 (d, M.mz, 1H), 7.41 (t, /-8.8 Hz, 1H), 7.33 (d, /-8.4 Hz, 2H), 7.27 (d, 7-8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.08 (d, MMz, 1H), 6.88 ( d, J-8.8 Hz, 2H), 6.81 (d, J-8.0 Hz, 2H), 6.52 (t, J-6.6 Hz, 1H), 5.30 (s, 2H), 5.10 (s, 2H), 3.71 ( s, 3H), 3.67 (s, 3H), 2.58 (q, J-6.4 Hz, 2H), 1.66-1.62 (m, 6H) Step 2: 2- {3- [4- (pyridin-4-yl) Butylamino] -Ly-pyrazolo [3,4->] pyrazin-5-yl} Preparation of Phenolic Hydrochloride
상기 1단계에서 제조된 화학식 96A로 표시되는 화합물 (35 mg, 0.06 画 ol)을 3.7M 염산 (2 , 1,4-디옥산용액)에 녹이고 상온에서 12시간 동안 교반 하였다. 반 응종결 후， 반웅물을 감압 여과하여 화학식 96으로 표시되는 화합물 (11.2 mg, 반응 수율: 48¾， 상아색 고체)을 얻었다.  The compound represented by Chemical Formula 96A (35 mg, 0.06 μl) prepared in step 1 was dissolved in 3.7 M hydrochloric acid (2,1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 96 (11.2 mg, reaction yield: 48¾, ivory solid).
JH NMR(400MHz, DMS0-o ; δ 12.48(br, 1H), 11.17(br, 1H), 9.16(s, 1H), 8.83(d, J^.8Hz, 2H), 8.00-7.96(m, 3H), 7.29(t, J^7.2Hz, 1H) , 7.02-6.94(m, 2H), 3.38(t, J-6.8Hz, 2H), 2.96(t, J=6.8Hz, 2H), 1.79-1.70(m, 4H) 상기 실시예 96과 동일한 방법으로 하기 표 4의 화합물을 제조하였다. J H NMR (400 MHz, DMS0-o; δ 12.48 (br, 1H), 11.17 (br, 1H), 9.16 (s, 1H), 8.83 (d, J ^ .8 Hz, 2H), 8.00-7.96 (m, 3H), 7.29 (t, J ^ 7.2 Hz, 1H), 7.02-6.94 (m, 2H), 3.38 (t, J-6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 1.79- 1.70 (m, 4H) The compound of Table 4 was prepared in the same manner as in Example 96.
【표 4】  Table 4
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000081_0001
Figure imgf000082_0001
〈실시예 105> Λ 6—아미노 -5- [(디메틸아파노)메틸] 피라졸로 [3 , 피리 딘 -3-일}니코틴아미드 디하이드로클로라이드의 제조 Example 105 Preparation of Λ 6—Amino-5-[(dimethylamino) methyl] pyrazolo [3, pyridin-3-yl} nicotinamide dihydrochloride
Figure imgf000083_0001
Figure imgf000083_0001
37A-a 105A-a 단계 2  37A-a 105A-a Step 2
Figure imgf000083_0002
Figure imgf000083_0002
105A-C 105A-b  105A-C 105A-b
Figure imgf000083_0003
Figure imgf000083_0003
105A 105 단계 1: 7 6—아미노 -5- (하이드록시메틸) -l-(4-메톡시벤질) -l^피라졸로 105A 105 Step 1: 7 6—Amino-5- (hydroxymethyl) -1- (4-methoxybenzyl) -1 ^ pyrazolo
[3.4— b]피리딘 -3—일]니코틴아미드의 제조 Preparation of [3.4—b] pyridin-3-yl] nicotinamide
리튬 알루미늄하이드라이드 (150 mg, 3.95 mmol)에 테트라히드라퓨란 (16 ml) 을 첨가한 후, 0 °C에서 교반하고， 상기 실시예 37에서 제조된 화학식 37A-a로 표 시되는 중간체 화합물 (570 mg, 1.27 mmol)을 천천히 첨가한 후， 30동안 교반 하였 다. 반웅 종료 후, 수산화나트륨 (10 )을 넣고 상온에서 1시간 동안 교반하고 여 과하여 얻은 반응물을 에틸아세테이트로 추출한 후， 유기 용매층을 무수 황산마그 네슘으로 건조시키고 용매를 감압 농축한 다음 잔류물을 컬럼 크로마토그래피 (디클 로로메탄:메탄올 =10:1)로 정제하여 화학식 105A-a로 표시되는 화합물 (464 mg, 반응 수율: 90%, 흰색 고체)을 얻었다. Tetrahydrafuran (16 ml) was added to lithium aluminum hydride (150 mg, 3.95 mmol), followed by stirring at 0 ° C. and an intermediate compound represented by Formula 37A-a prepared in Example 37. mg, 1.27 mmol) was added slowly and stirred for 30 hours. After completion of reaction, sodium hydroxide (10) was added thereto, stirred at room temperature for 1 hour, the reaction mixture was extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column. Purification by chromatography (dichloromethane: methanol = 10: 1) afforded the compound represented by the formula 105A-a (464 mg, reaction yield: 90%, white solid).
¾ 羅(400匪 z, DMS0-o ; δ ll.lKs, 1H), 9.16(s, 1H) , 8.75(d, 세 , 1H), 8.36(d, M. z, 1H), 7.95(s, 1H), 7.54(q, J-4.8Hz, 1H)， 7.16(d, /-8.8Hz, 2H), 6.87(d, J=8.4Hz, 2H), 6.35(br, 2H), 5.33(s, 2H), 5.26(t, J- .8Hz, 1H), 4.42(d, J=5.2Hz, 2H) , 3.70(s, 3H) 단계 2: -[6-아미노-5-포밀—1-(4-메톡시벤질)-1 -피라졸로[3，4—>]피리딘-3- 일]니코틴아미드의 제조 ¾ 羅 (400 匪 z, DMS0-o; δ ll.lKs, 1H), 9.16 (s, 1H), 8.75 (d, three, 1H), 8.36 (d, M.z, 1H), 7.95 (s, 1H), 7.54 (q, J-4.8 Hz, 1H), 7.16 (d, /-8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.35 (br, 2H), 5.33 (s, 2H), 5.26 (t, J- .8 Hz, 1H), 4.42 (d, J = 5.2 Hz, 2H), 3.70 (s, 3H ) Step 2: Preparation of-[6-amino-5-formyl—1- (4-methoxybenzyl) -1 -pyrazolo [3,4 —>] pyridin-3-yl] nicotinamide
상기 1단계에서 제조된 화학식 105A-a로 표시되는 화합물 (410 mg, 1.02 mmol)을 디클로로메탄 (20 m ^에 녹인 후， 데스 -마틴 퍼아이오딘 (Dess-Martin period inane )(730 mg, 1.72 隱 ol)을 첨가하고 2시간 동안 교반 하였다. 반웅 종료 후 탄산수소나트륨용액과 에틸아세테이트를 가한 후， 유기 용매층을 무수 황산마그 네슘으로 건조시키고 용매를 감압 농축한 다음 잔류물을 컬럼 크로마토그래피 (디클 로로메탄:메탄올 =10:1)로 정제하여 화학식 105A— b로 표시되는 화합물 (144 mg, 반웅 수율 :35%， 흰색 고체)을 얻었다.  The compound represented by Formula 105A-a prepared in step 1 (410 mg, 1.02 mmol) was dissolved in dichloromethane (20 m ^, and then des-Martin period inane (730 mg, 1.72隱 ol) was added and stirred for 2 hours After completion of reaction, sodium hydrogencarbonate solution and ethyl acetate were added, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography ( Purification with dichloromethane: methanol = 10: 1) afforded the compound represented by the formula 105A—b (144 mg, reaction yield: 35%, white solid).
¾ NMR(400MHz, DMSO-ofe); δ 11.47(s, 1H), 9.83(s, 1H), 9.16(s, 1H), 8.77(s, 1H), 8.70(br, 1H), 8.37-8.34(m, 1H), 7.84(br, 2H), 7.55(q, J= .8Hz, 1H), 7.19(d, J-8.8Hz, 2H), 6.88(d, J=8.4Hz, 2H), 5.31(br, 2H), 3.68(s, 3H) 단계 3： 7H6-아미노 -5- [ (디메틸아미노)메틸] -1-(4-메톡시벤질) -Ly—피라졸로 ¾ NMR (400 MHz, DMSO-ofe); δ 11.47 (s, 1H), 9.83 (s, 1H), 9.16 (s, 1H), 8.77 (s, 1H), 8.70 (br, 1H), 8.37-8.34 (m, 1H), 7.84 (br, 2H ), 7.55 (q, J = .8 Hz, 1H), 7.19 (d, J-8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.31 (br, 2H), 3.68 (s, 3H ) Step 3: 7H6-amino-5- [(dimethylamino) methyl] -1- (4-methoxybenzyl) -Ly—pyrazolo
[3,4-Z>]피리딘 -3-일}니코틴아미드의 제조 Preparation of [3,4-Z>] pyridin-3-yl} nicotinamide
상기 2단계에서 제조된 화학식 105A-b로 표시되는 화합물 (200 mg, 0.49 画 ol)을 메탄올에 녹인 후 2M 디메틸아민 (1.6 , 메탄을 용액)과 소듐시아노보로 하이드라이드 (34.4 mg, 0.54 隱 ol), 염화아연 (II)(33.8 mg, 0.25 mmol), 1.25M 염 산 (2.4 ml, 메탄을 용액)을 순서대로 첨가하고， 12시간 동안 교반 하였다. 반웅 종 료 후， 탄산수소나트륨용액과 에틸아세테이트를 가한 후， 유기 용매층을 무수 황산 마그네슴으로 건조시키고 용매를 감압 농축한 다음 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =10:1)로 정제하여 화학식 105A-C로 표시되는 화합물 (25 mg, 반웅수율: 15%， 흰색 고체)을 얻었다.  The compound represented by Formula 105A-b prepared in step 2 (200 mg, 0.49 画 ol) was dissolved in methanol, and then 2M dimethylamine (1.6, methane solution) and sodium cyanoborohydride (34.4 mg, 0.54 隱). ol), zinc (II) chloride (33.8 mg, 0.25 mmol), 1.25M hydrochloric acid (2.4 ml, methane solution) were added sequentially and stirred for 12 hours. After completion of reaction, sodium hydrogencarbonate solution and ethyl acetate were added, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1). Purification gave a compound represented by Chemical Formula 105A-C (25 mg, semi-water yield: 15%, white solid).
¾ NMR(400MHz, DMS0-o¾)； δ 11.13(br, 1H), 9.15(s, 1H), 8.75(d, J=5.2Hz, 1H), 8.36(d, J=8.0Hz, 1H), 7.86(br, 1H), 7.54(q, J^ .4Hz, 1H), 7.18(d, J-8.4Hz, 2H), 6.87(d, J-8.4Hz, 2H), 6.73(br, 2H), 5.32(s, 2H)ᅳ 3.70(s, 3H), 3.24(br, 2H) 단계 4: 아미노 -5- [(디메틸아미노)메틸] -1가피라졸로 [3,4-Z>]피리딘 -3- 일}니코틴아미드의 제조 ¾ NMR (400 MHz, DMS0-o¾); δ 11.13 (br, 1H), 9.15 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.86 (br, 1H), 7.54 (q, J ^ .4 Hz, 1H), 7.18 (d, J-8.4 Hz, 2H), 6.87 (d, J-8.4 Hz, 2H), 6.73 (br, 2H), 5.32 (s, 2H) ᅳ 3.70 (s, 3H), 3.24 (br, 2H) Step 4: Amino-5- [(dimethylamino) methyl] -1gapyrazolo [3,4-Z>] pyridine-3- Preparation of Nicotinamide
상기 단계 3에서 제조된 화학식 105A-C로 표시되는 화합물 (40 mg, 0.09 mmol)을 트리플루오로아세트산 (5 )에 녹인 후 100 °C에서 24시간 동안 교반 하였 다. 상온으로 넁각 후 차가운 얼음물로 반웅을 종결하고 클로로포름으로 추출하였 다. 소금물로 세척하고 유기 용매층을 무수 황산나트륨으로 건조시킨 다음 감압 하 에 농축하였다. 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =10:1)로 정제 하여 화학식 105A로 표시되는 화합물 (22 mg, 반웅수율: 76%, 흰색 고체)을 얻었다. The compound represented by Formula 105A-C (40 mg, 0.09 mmol) prepared in Step 3 was dissolved in trifluoroacetic acid (5) and stirred at 100 ° C. for 24 hours. After cooling to room temperature, the reaction was terminated with cold ice water and extracted with chloroform. The mixture was washed with brine and the organic solvent layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give a compound represented by the formula (105A) (22 mg, semi-water yield: 76%, white solid).
¾ NMR( 400MHz, DMS0-i¾)； δ 12.45(s, 1H), 11.05(s, 1H)， 9.17(s, 1H), 8.76(d, J^.SUz, 1H), 8.38(d, J-7.6Hz, 1H), 7.82(br, 1H) , 7.56(q, J^.8Hz 2H), 6.53(br, 2H), 3.07(br, 2H) , 2.08(s, 6H) 단계 5: VH6-아미노 -5- [(디메틸아미노)메틸] -1 -피라졸로 [3,4-Z>]피리딘 -3- 일}니코틴아미드 디하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0-i¾); δ 12.45 (s, 1H), 11.05 (s, 1H), 9.17 (s, 1H), 8.76 (d, J ^ .SUz, 1H), 8.38 (d, J-7.6 Hz, 1H), 7.82 (br, 1H), 7.56 (q, J ^ .8 Hz 2H), 6.53 (br, 2H), 3.07 (br, 2H), 2.08 (s, 6H) Step 5: VH 6-amino-5-[(dimethylamino) methyl] -1-pyrazolo [3,4-Z>] pyridin-3-yl} nicotinamide di Preparation of Hydrochloride
상기 단계 4에서 제조된 화학식 105A로 표시되는 화합물 (22 mg, 0.07 隱 ol) 을 3.7M 염산 (2 ml, 1，4-디옥산용액)에 녹이고 상온에서 12시간 동안 교반 하였다. 반웅종결 후， 반웅물을 감압 여과하여 화학식 105로 표시되는 화합물 (9.1 mg, 반웅 수율 :34¾， 갈색 고체)을 얻었다.  Compound (22 mg, 0.07 μl) represented by Chemical Formula 105A prepared in Step 4 was dissolved in 3.7 M hydrochloric acid (2 ml, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 105 (9.1 mg, reaction yield: 34¾, brown solid).
¾ NMR(400MHz, DMS0-o ; δ 11.69(br, 1H), 10.10(br 1H), 9.33(s, 8.93(d, J^.6Hz, 1H), 8.69(d, J^7.6Hz, 1H), 8.43(br, 1H) 7.86-7.83 (m, 6.87(br, 2H), 4.38(s, 2H), 2.76(s, 6H) ¾ NMR (400MHz, DMS0-o; δ 11.69 (br, 1H), 10.10 (br 1H), 9.33 (s, 8.93 (d, J ^ .6Hz, 1H), 8.69 (d, J ^ 7.6Hz, 1H) , 8.43 (br, 1H) 7.86-7.83 (m, 6.87 (br, 2H), 4.38 (s, 2H), 2.76 (s, 6H)
<실시예 106> 피리딘 -3 일메틸 6-아미노 -3-(4-메톡시벤즈아미도) -l^피라졸 로 [3, 4—/)]피리딘 -5-카르복실레이트 하이드로클로라이드의 제조 Example 106 Preparation of Pyridine-3-ylmethyl 6-amino-3- (4-methoxybenzamido) -1 ^ pyrazolo [3, 4 — /)] pyridine-5-carboxylate hydrochloride
Figure imgf000085_0001
Figure imgf000085_0001
a-2 106A-a 단계 2  a-2 106A-a Step 2
Figure imgf000085_0002
Figure imgf000085_0002
106A 106 단계 1: 에틸 6-아미노 -3— (4-메록시벤즈아미도) -1-(4-메톡시벤질) 피라졸 로 [3， 4-Z>]피리딘 -5-카복실레이트의 제조 106A 106 Step 1: Preparation of [3,4-Z>] pyridine-5-carboxylate with ethyl 6-amino-3— (4-methoxybenzamido) -1- (4-methoxybenzyl) pyrazole
상기 제조예 2에서 제조된 화학식 a-2로 표시되는 화합물 (2.0 gᅳ 5.85 mmol)을 피리딘 (20 )에 녹인 후 4-메톡시벤조일 클로라이드 (1.2 ml, 8.78 mmol) 을 천천히 첨가한 후， 상온에서 1시간 동안 교반 하였다. 반웅 종결 후， 감압 농축 하여 피리딘을 제거한 후, 에틸아세테이트로 추출하고 유기 용매층을 무수 황산마 그네슘으로 건조시킨 다음 용매를 감압 농축하였다. 감압 농축한 잔류물을 디에틸 에테르로 세척하여 화학식 106A-a로 표시되는 화합물 (1.6 g, 반옹수율: 57%， 흰색고 처 1)을 얻었다.  After dissolving the compound represented by Chemical Formula a-2 (2.0 g ᅳ 5.85 mmol) prepared in Preparation Example 2 in pyridine (20), 4-methoxybenzoyl chloride (1.2 ml, 8.78 mmol) was slowly added thereto, and then at room temperature. Stirred for 1 h. After completion of reaction, the mixture was concentrated under reduced pressure to remove pyridine, extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue concentrated under reduced pressure was washed with diethyl ether to obtain a compound represented by the formula (106A-a) (1.6 g, water absorption: 57%, white solid 1).
¾ NMR(400MHz, OMSO-de) - δ 10.98(s, 1H), 8.92(s, 1H), 8.04(d, 7-6.8Hz, 2H), 7.56(br, 2H) , 7.19(d, J=6.8Hz, 2H), 7.04(d, 7=8.8Hz, 2H), 6.88(d, J=8.8Hz, 2H), 5.75(s, 2H), 4.30(q, J=5.6Hz, 2H), 3.83(s, 3H)， 3.70(s, 3H) , 1.65(1: , J-4.8Hz, 3H) 단계 2: 6-아미노 -3-(4—메톡시벤즈아미도) -l-(4-메록시벤질) -1^피라졸로 ¾ NMR (400 MHz, OMSO-de)-δ 10.98 (s, 1H), 8.92 (s, 1H), 8.04 (d, 7-6.8Hz, 2H), 7.56 (br, 2H), 7.19 (d, J = 6.8 Hz, 2H), 7.04 (d, 7 = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.75 (s, 2H), 4.30 (q, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 1.65 (1:, J-4.8 Hz, 3H) Step 2: 6-amino-3- (4—methoxybenzamido) -l- (4-meth Roxybenzyl) -1 ^ pyrazolo
[3,4-Z>]피리딘 -5-카복실릭 액시드의 제조 Preparation of [3,4-Z>] pyridine-5-carboxylic acid
상기 단계 1에서 제조된 화학식 106A-a로 표시되는 화합물 (1.0 g, 2.10 mmol)을 에탄올 (20 )과 물 (2 m ^에 용해시킨 후 수산화칼륨 (590 mg, 10.50 mmol)을 첨가하고， 80 °C에서 2시간 동안 환류 교반 하였다. 반웅 종결 후， 상온으 로 넁각한 다음 에틸아세테이트로 추출하고 물층을 1 염산 용액을 이용하여 산성 화 시킨 후 다시 에틸아세테이트로 추출하였다. 유기 용매층을 무수 황산마그네슴 으로 건조시킨 다음 용매를 감압 농축하여 화학식 106A-b로 표시되는 화합물 (450 mg, 반응수율: 47%, 흰색고체)을 얻었다. The compound represented by the formula 106A-a prepared in Step 1 (1.0 g, 2.10 mmol) was dissolved in ethanol (20) and water (2 m ^, and then potassium hydroxide (590 mg, 10.50 mmol) was added thereto, and 80 The mixture was stirred at reflux for 2 hours at ° C. After completion of reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, the aqueous layer was acidified with 1 hydrochloric acid solution, and extracted again with ethyl acetate. After drying with magnesium, the solvent was concentrated under reduced pressure to obtain a compound represented by Chemical Formula 106A-b (450 mg, reaction yield: 47%, white solid).
¾ 腿 (400MHz, OUS0-d6)： δ 12.94(s, 1H), 10.96(s, 1H), 8.91(s, 1H) , 8.05(d, J=8.8Hz, 2H) , 7.62(br, 2H), 7.18(d, J-8.4Hz, 2H), 7.03(d, J=8.4Hz, 2H), 6.88(d, J-e.4Hz, 2H), 5.48(s, 2H), 3.87(s, 3H), 3.70(s, 3H) 단계 3: 피리딘 -3—일 메틸 6-아미노 -3-(4-메톡시벤즈아미도) -1-(4-메록시벤 질 )-L 피라졸로 (3， -b]피리딘 -5-카복실레이트의 제조 ¾ 腿 (400MHz, OUS0-d 6 ): δ 12.94 (s, 1H), 10.96 (s, 1H), 8.91 (s, 1H), 8.05 (d, J = 8.8Hz, 2H), 7.62 (br, 2H ), 7.18 (d, J-8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.88 (d, Je.4 Hz, 2H), 5.48 (s, 2H), 3.87 (s, 3H) , 3.70 (s, 3H) Step 3: pyridin-3-yl methyl 6-amino-3- (4-methoxybenzamido) -1- (4-methoxybenzyl) -L pyrazolo (3 ，- b] preparation of pyridine-5-carboxylate
상기 단계 2에서 제조된 화학식 106A-b로 표시되는 화합물 (100 mg, 0.22 mmol)을 씨디메틸포름아미드 (3 에 녹인 후， 피리딘 -3-일-메탄올 (0.03 ml, 0.33 隱 ol)과 1-에틸 -3-(3-디메틸아미노프로필) -카르보디이미드 히드로클로라이드 (EDC, 86 mg, 0.44 mmol)과 1-하이드록시-벤조트리아졸 수화물 (HOBt, 61 mg, 0.44 mmol), 그리고 , _디이소프로필에틸아민 (0.16 ml, 0.89 mmol)을 첨가한 후， 상온 에서 12시간 동안 교반 하였다. 반웅 종결 후, 에틸아세테이트로 추출하고 유기 용 매층을 무수 황산마그네슘으로 건조시킨 다음 용매를 감압 농축하였다. 감압 농축 한 잔류물을 컬럼 크로마토그래피 (헥산：에틸아세테이트 =9:1)로 정제하여 화학식 106A-C로 표시되는 화합물 (39 mg, 반웅수율: 32%, 흰색고체)을 얻었다.  The compound represented by Chemical Formula 106A-b prepared in Step 2 (100 mg, 0.22 mmol) was dissolved in cydimethylformamide (3), and then pyridin-3-yl-methanol (0.03 ml, 0.33 隱 ol) and 1- Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC, 86 mg, 0.44 mmol) and 1-hydroxy-benzotriazole hydrate (HOBt, 61 mg, 0.44 mmol), and Isopropylethylamine (0.16 ml, 0.89 mmol) was added, followed by stirring at room temperature for 12 hours After completion of reaction, the mixture was extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue, which was concentrated under reduced pressure, was purified by column chromatography (hexane: ethyl acetate = 9: 1) to obtain a compound represented by Chemical Formula 106A-C (39 mg, semi-water yield: 32%, white solid).
Έ 腿(400丽 z, DMS0- ί¾)： δ 10.99(s, 1H), 9.01(s, 1H), 8.69(s, 1H) 8.55(d, J-4.8Hz, 1H), 8.02(d, J^8.8Hz, 2H), 7.88(d, J^7.6Hz, 1H), 7.57(br 2H), 7.44-7.41 (m, 1H), 7.18(d, J-β.ΟΗζ, 2H), 7.03(d, J-8.8Hz, 2H), 6.87(d J=8.4Hz, 2H), 5.41(s, 2H), 5.31(s, 2H), 3.83(s, 3H) , 3.70(s, 3H) 단계 4: 피리딘 -3-일 메틸 6-아미노 -3-(4-메톡시벤즈아미도) -1^피라졸로 [3，4ᅳ ]피리딘 -5-카복실레이트의 제조 400 400 (400 δ z, DMS0-ί¾): δ 10.99 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H) 8.55 (d, J-4.8Hz, 1H), 8.02 (d, J ^ 8.8 Hz, 2H), 7.88 (d, J ^ 7.6 Hz, 1H), 7.57 (br 2H), 7.44-7.41 (m, 1H), 7.18 (d, J-β.ΟΗζ, 2H), 7.03 (d , J-8.8 Hz, 2H, 6.87 (d J = 8.4 Hz, 2H), 5.41 (s, 2H), 5.31 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) Step 4: pyridin-3-yl methyl 6-amino-3- Preparation of (4-methoxybenzamido) -1 ^ pyrazolo [3,4 ′] pyridine-5-carboxylate
상기 단계 3에서 제조된 화학식 106A-C로 표시되는 화합물 (35 mg, 0.06 睡 ol)을 트리플루오로아세트산 (3 i )에 녹인 후 실드 -튜브 (sealed tube)에 넣고 90 °C에서 2시간 동안 교반 하였다. 상온으로 냉각한 후， 감압 농축하였다. 에틸 아세 테이트를 첨가하고 생성된 고체를 여과하여 다시 에틸아세테이트로 세척하여 화학 식 106A로 표시되는 화합물 (20 mg, 반응수율: 82%, 흰색고체)을 얻었다.  The compound represented by Chemical Formula 106A-C prepared in Step 3 (35 mg, 0.06 μl) was dissolved in trifluoroacetic acid (3 i), and then placed in a shielded tube for 2 hours at 90 ° C. Stirred. After cooling to room temperature, the mixture was concentrated under reduced pressure. Ethyl acetate was added and the resulting solid was filtered and washed again with ethyl acetate to obtain the compound represented by the chemical formula 106A (20 mg, reaction yield: 82%, white solid).
¾ NMR(400MHz, DMS0-a : δ 12.68(s, 1H) , 10.91(s, 1H), 8.97(s, 1H), 8.83(s, 1H), 8.68(s, 1H) , 8.18(d, J-7.6Hz, 1H), 8.02(d, J=10.0Hz, 2H), 7.68(t, J^7.6Hz, 1H), 7.05(d, J^.8Hz, 1H), 5.46(s, 2H)， 4.02(s, 3H) 단계 5: 피리딘 -3-일 메틸 6-아미노 -3-(4-메톡시벤즈아미도) -L 피라졸로 [3, 4-Z>]피리딘 -5-카르복실레이트 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0-a: δ 12.68 (s, 1H), 10.91 (s, 1H), 8.97 (s, 1H), 8.83 (s, 1H), 8.68 (s, 1H), 8.18 (d, J -7.6 Hz, 1H), 8.02 (d, J = 10.0 Hz, 2H), 7.68 (t, J ^ 7.6 Hz, 1H), 7.05 (d, J ^ .8 Hz, 1H), 5.46 (s, 2H), 4.02 (s, 3H) Step 5: Pyridin-3-yl methyl 6-amino-3- (4-methoxybenzamido) -L pyrazolo [3, 4-Z>] pyridine-5-carboxylate hydro Preparation of Chloride
상기 단계 4에서 제조된 화학식 106A로 표시되는 화합물 (20 mg, 0.04 隱 ol) 을 1>4-디옥산 Q ιη£)에 녹인 후 3/7Μ 염산 1，4-다옥산 용액 (1 을 첨가하였다. 24시간 동안 교반 후 용매를 감압 농축하였다. 감압 농축한 잔류물에 에틸아세테이 트와 디에틸에테르를 가하고 30분 동안 교반하고 여과한 후， 디에틸에테르로 세척 하여 화학식 106으로 표시되는 화합물 (17 mg, 반웅수율: 79%， 녹색 고체)을 얻었다. The compound represented by Chemical Formula 106A prepared in Step 4 (20 mg, 0.04 隱 ol) was dissolved in 1> 4 -dioxane Q ηη £), and 3 / 7M hydrochloric acid 1,4-dioxane solution (1 was added thereto). After stirring for 24 hours, the solvent was concentrated under reduced pressure, and ethyl acetate and diethyl ether were added to the residue, which was then stirred for 30 minutes, filtered, and washed with diethyl ether to obtain a compound represented by Chemical Formula 106 ( 17 mg, reaction yield: 79%, green solid).
¾ NMR( 400MHz, DMSO-flfe)： δ 11.00(s, 1H)， 9.03(s, 1H)， 8.86(s, 1H) , 8.58(d, J^IMz, 1H), 8.07-8.00 (m, 3H), 7.45(br, 2H)， 7.06(d, J=8.4Hz, 2H), 5.54(s, 2H), 3.84(s, 2H) 상기 실시예 106과 동일한 방법으로 하기 표 5의 화합물을 제조하였다.  ¾ NMR (400MHz, DMSO-flfe): δ 11.00 (s, 1H), 9.03 (s, 1H), 8.86 (s, 1H), 8.58 (d, J ^ IMz, 1H), 8.07-8.00 (m, 3H ), 7.45 (br, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.54 (s, 2H), 3.84 (s, 2H) The compounds of Table 5 were prepared in the same manner as in Example 106 above. .
【표 5】 Table 5
Figure imgf000088_0001
Figure imgf000088_0001
<실시예 112> 6-아미노 디메틸 -3- (니코틴아미도) -L^-피라졸로 [3，4-/?]피 리딘 -5-카복사아미드 하이드로클로라이드의 제조
Figure imgf000089_0001
Example 112 Preparation of 6-amino Dimethyl-3- (nicotinamido) -L ^ -pyrazolo [3,4-/?] Pyridine-5-carboxamide hydrochloride
Figure imgf000089_0001
112A-a 112A-b  112A-a 112A-b
단계 2
Figure imgf000089_0002
Step 2
Figure imgf000089_0002
112A 112A-C  112A 112A-C
단계 4  Step 4
Figure imgf000089_0003
Figure imgf000089_0003
112  112
단계 1: 6- -부톡시카보닐아미노 )-l-(4-메톡시벤질) -3- (니코틴아미도) -Ly- 피라졸로 [3, 4-Z>]피리딘 -5-카복실릭 액시드의 제조  Step 1: 6-Butoxycarbonylamino) -l- (4-methoxybenzyl) -3- (nicotinamido) -Ly-pyrazolo [3,4-Z>] pyridine-5-carboxylic solution Preparation of Seeds
제조예 3의 단계 2의 화학식 c-3으로 표시되는 화합물을 실시예 37의 단계 1 의 방법으로 제조된 화학식 112A-a로 표시되는 화합물 (300 mg, 0.55 隱 ol)을 에탄 올 (7 )에 녹인 후， 물 (1.2 O를 첨가하고 수산화칼륨 (92.4 mg, 1.65 mmol)첨가 후 80 °C에서 2시간 동안 교반 하였다. 물 (5 과 에틸아세테이트 (10 ι )를 첨가 하고 물로 추출하였다. I 염산으로 산성화시키고， 에틸아세테이트로 추출하였다. 소금물로 세척하고 무수 황산나트륨으로 건조 후 여과하여 화학식 112A-b로 표시되 는 화합물 (251 mg, 반응수율 :88%, 흰색 고체)을 얻었다. Compound (300 mg, 0.55 μl) represented by Chemical Formula 112A-a prepared by the method of Step 1 of Example 37 was prepared in ethanol (7). After dissolving, water (1.2 O was added and potassium hydroxide (92.4 mg, 1.65 mmol) was added and stirred for 2 hours at 80 ° C. Water (5 and ethyl acetate (10 ι) were added and extracted with water. The resulting mixture was acidified with ethyl acetate, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered to give the compound represented by the formula (112A-b) (251 mg, reaction yield: 88%, white solid).
¾ NMR(400MHz, DMS0-i¾); δ 13.69(s, 1H), 11.58(s, 1H), 10.89(s, 1H), 9.18(s, 2H), 8.77(d, J-3.6Hz, 1H) , 8.39(d, J^7.6Hz, 1H), 7.57-7.54(m, 1H), 7.31(d, J-8.4Hz, 2H), 6.89(d, J=8.0Hz, 2H) , 5.45(s, 2H) , 3.70(s, 3H), l,51(s, 9H) 단계 2: -부틸 5- (디메틸카바모일) -l-(4-메특시벤질) -3- (니코틴아미도) 피라졸로 [3,4-Z>]피리딘 -6—일카바메이트의 제조 ¾ NMR (400 MHz, DMS0-i¾); δ 13.69 (s, 1H), 11.58 (s, 1H), 10.89 (s, 1H), 9.18 (s, 2H), 8.77 (d, J-3.6 Hz, 1H), 8.39 (d, J ^ 7.6 Hz, 1H), 7.57-7.54 (m, 1H), 7.31 (d, J-8.4 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.45 (s, 2H), 3.70 (s, 3H), l, 51 (s, 9H) Step 2: -Butyl 5- (dimethylcarbamoyl) -l- (4-methoxybenzyl) -3- (nicotinamido) Preparation of Pyrazolo [3,4-Z>] pyridine-6-ylcarbamate
상기 단계 1에서 제조된 화학식 112A-b로 표시되는 화합물 (100 mg, 0.19 mmol)을 -디메틸포름아미드 (3 )에 녹인 후 디메틸아민 (145/ , 0.29 隱 ol)과 1-에틸 -3-(3-디메틸아미노프로필) -카르보디이미드 히드로클로라이드 (EDC, 56 mg, 0.28 隱 ol)과 디메틸아미노피리딘 (4.7 mg, 0.04 隱 ol)을 첨가한 후, 상온에서 24시 간 동안 교반 하였다. 반응 종결 후， 에틸아세테이트로 추출하고 유기 용매층을 감 압 하에 농축하고 디에틸에테르와 에틸아세테이트로 세척하여 화학식 112A-C로 표 시되는 화합물 (67 mg, 반응수율 :63¾， 흰색고체)을 얻었다.  The compound represented by Formula 112A-b prepared in Step 1 (100 mg, 0.19 mmol) was dissolved in -dimethylformamide (3), and then dimethylamine (145 /, 0.29 μl) and 1-ethyl-3- ( 3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC, 56 mg, 0.28 μl ol) and dimethylaminopyridine (4.7 mg, 0.04 μl ol) were added and stirred at room temperature for 24 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and the organic solvent layer was concentrated under reduced pressure and washed with diethyl ether and ethyl acetate to obtain a compound represented by Chemical Formula 112A-C (67 mg, reaction yield: 63¾, white solid). .
¾ NMR( 400MHz, DMSO-cfe); δ 11.84(s, 1Η), 9.92(s, 1H), 9.17(s, 1H), 8.76(d, J¾.2Hz, 1H), 8.38(d, J^7.6Hz, 1H)， 8.33(s, 1H)， 7.57-7.54(m, 1H), 7.28(d, 세 ' 2H), 6.88(d, J=8AEz, 2H), 5.46(s, 2H), 3.70(s, 3H), 2.99(s, 3H), 2.92(s, 3H), 1.44(s, 9H) 단계 3: 6-아미노 디메틸 -3— (니코틴아미도)—Ly-피라졸로 [3,4-b]피리딘 -5-카복사아미드의 제조  ¾ NMR (400 MHz, DMSO-cfe); δ 11.84 (s, 1Η), 9.92 (s, 1H), 9.17 (s, 1H), 8.76 (d, J¾.2Hz, 1H), 8.38 (d, J ^ 7.6Hz, 1H), 8.33 (s, 1H ), 7.57-7.54 (m, 1H), 7.28 (d, three '2H), 6.88 (d, J = 8AEz, 2H), 5.46 (s, 2H), 3.70 (s, 3H), 2.99 (s, 3H ), 2.92 (s, 3H), 1.44 (s, 9H) Step 3: 6-amino dimethyl-3— (nicotinamido) —Ly-pyrazolo [3,4-b] pyridine-5-carboxamide Produce
상기 단계 2에서 제조된 화학식 112A-C로 표시되는 화합물 (35 mg, 0.06 mmol)을 트리플루오로아세트산 (5 에 녹인 후， 100 °C에서 48시간 동안 교반 하 였다. 상온으로 냉각한 후， 차가운 얼음물로 반응을 종결시키고 클로로포름으로 추 출하였다. 소금물로 세척하고 유기 용매층을 무수 황산나트륨으로 건조시킨 다음 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =10:1) 로 정제하여 화학식 112A로 표시되는 화합물 (16 mg, 반웅수율: 80%, 흰색 고체)을 얻었다. The compound represented by Chemical Formula 112A-C (35 mg, 0.06 mmol) prepared in Step 2 was dissolved in trifluoroacetic acid (5) and stirred for 48 hours at 100 ° C. After cooling to room temperature, cold The reaction was terminated with ice water and extracted with chloroform, washed with brine, the organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) Compound (16 mg, semi-water yield: 80%, white solid) represented by Chemical Formula 112A was obtained.
¾ NMR( 400MHz, DMS0-i¾); δ 12.60(s, 1Η), 11.17(s, 1H), 9.17(s, 1H), 8.76-8.75(m, 1H), 8.37(d, J=8.0Hz, 1H), 8.00s, 1H), 7.57-7.54(m, 1H)， 6.35(br, 2H), 2.95(s, 6H) 단계 4: 6—아미노 U-디메틸 -3- (니코틴아미도 )ᅳ1 -피라졸로 [3,4-Z>]피리딘 -5-카복사아미드 하이드로클로라이드의 제조  ¾ NMR (400 MHz, DMS0-i¾); δ 12.60 (s, 1Η), 11.17 (s, 1H), 9.17 (s, 1H), 8.76-8.75 (m, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.00s, 1H), 7.57 -7.54 (m, 1H), 6.35 (br, 2H), 2.95 (s, 6H) Step 4: 6—Amino U-dimethyl-3- (nicotinamido) ᅳ 1-pyrazolo [3,4-Z> ] Preparation of Pyridine-5-Carboxamide Hydrochloride
상기 단계 3에서 제조된 화학식 112A로 표시되는 화합물 (16 mg, 0.05 mmol) 올 3.7M 염산 (2 1，4-디옥산용액)에 녹이고 상온에서 12시간 동안 교반 하였다. 반웅종결 후， 반웅물을 감압 여과하여 화학식 112로 표시되는 화합물 (6.3 mg, 반웅 수율 :35%， 갈색 고체)을 얻었다.  The compound represented by Chemical Formula 112A prepared in Step 3 (16 mg, 0.05 mmol) was dissolved in 3.7M hydrochloric acid (2 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 112 (6.3 mg, reaction yield: 35%, brown solid).
¾ NMR(400MHz, DMS0-i¾)； δ 12.68(s, 1H), 11.32(s, 1H), 9.22(br, 1H), 8.81(br, 1H), 8.48(br, 1H), 8.03(br, 1H), 7.65-7.62(m, 1H), 2.08(s, 6H)  ¾ NMR (400 MHz, DMS0-i¾); δ 12.68 (s, 1H), 11.32 (s, 1H), 9.22 (br, 1H), 8.81 (br, 1H), 8.48 (br, 1H), 8.03 (br, 1H), 7.65-7.62 (m, 1H), 2.08 (s, 6H)
<실시예 113> 에틸 6-아미노 -3-{4-[2- (디메틸아미노)에틸]벤즈아미도 }-l -피 라졸로 [3,4—>]피리딘 -5-카복실레이트 하이드로클로라이드의 제조
Figure imgf000091_0001
Example 113 Ethyl 6-amino-3- {4- [2- (dimethylamino) ethyl] benzamido} -l-pyrazolo [3,4 —>] pyridine-5-carboxylate hydrochloride Produce
Figure imgf000091_0001
c-3 113A-a 단계 2  c-3 113A-a step 2
Figure imgf000091_0002
Figure imgf000091_0002
단계 1: 에틸 부특시카보닐아미노 )-3-[4-(2—클로로에틸)벤즈아미 도] -1-(4—메톡시벤질) -Ly-피라졸로 [3 ,4-b]피리딘 -5-카복실레이트의 제조  Step 1: ethyl secondary carbonylamino) -3- [4- (2—chloroethyl) benzamido] -1- (4—methoxybenzyl) -Ly-pyrazolo [3,4-b] pyridine- Preparation of 5-carboxylate
상기 제조예 3의 단계 2에서 제조한 화학식 c-3으로 표시되는 화합물 (500 mg, 1.13 匪 ol)을 피리딘 (10 )에 녹인 후， 실시예 1의 단계 1과 같은 방법으로 얻은 4-(2-클로로에틸)벤조일 클로라이드를 (320 mg, 1.57 mmol) \천 첨가한 후， 70 °C로 3시간 동안 교반 하였다. 반웅 종결 후, 반응흔합물을 감압 농축한 다음 에틸아세테이트로 세척하여 화학식 113A-a로 표시되는 화합물 (580 mg, 반웅수율: 74%, 노란색고체)을 얻었다. After dissolving the compound represented by Chemical Formula c-3 prepared in Step 2 of Preparation Example 3 (500 mg, 1.13 匪 ol) in pyridine (10), 4- (2) obtained by the same method as in Step 1 of Example 1 -Chloroethyl) benzoyl chloride (320 mg, 1.57 mmol) was added, followed by stirring at 70 ° C for 3 hours. After completion of reaction, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain a compound represented by Formula 113A-a (580 mg, reaction yield: 74%, yellow solid).
¾ NMR(400MHz, DMS0-o ; δ 11.31(s, 1H), 10.52(s, 1H) , 9.03(s, 1H), 8.02(d, J=8.0Hz, 2H), 7.44(d, J=8.4Hz, 2H) , 7.30(d, J=8.8Hz, 2H), 6.89(d, J-8.8Hz, 2H), 5.45(s, 2H), 4.32(q, J^7.2Hz, 2H), 3.92(t, J=QMz, 2H), 3.71(s, 3H), 3.12(t, J-6.8Hz, 2H), 1.50(s, 9H), 1.32(t, Jd , 3H) 단계 2: 에틸 6- ~부톡시카보닐아미노 )-3-{4-[2- (디메틸아미노)에틸]벤즈아 미도 }— 1-(4—메톡시벤질) 피라졸로 [3， 4- ]피리딘 -5-카복실레이트의 제조  ¾ NMR (400 MHz, DMS0-o; δ 11.31 (s, 1H), 10.52 (s, 1H), 9.03 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.89 (d, J-8.8 Hz, 2H), 5.45 (s, 2H), 4.32 (q, J ^ 7.2 Hz, 2H), 3.92 ( t, J = QMz, 2H), 3.71 (s, 3H), 3.12 (t, J-6.8 Hz, 2H), 1.50 (s, 9H), 1.32 (t, Jd, 3H) Step 2: ethyl 6- to Butoxycarbonylamino) -3- {4- [2- (dimethylamino) ethyl] benzamido} — of 1- (4—methoxybenzyl) pyrazolo [3,4-] pyridine-5-carboxylate Produce
상기 단계 1에서 제조한 화학식 113A-a로 표시되는 화합물 (100 mg, 0.16 隱 ol)을 yV V-디메틸포름아미드 (10 ι )에 녹인 후, 디메틸아민을 과량 첨가한 후， 실드-류브를 이용하여 70 °C로 12시간 동안 교반 하였다. 반웅 종결 후， 반응 흔합 물을 감압 농축한 다음 에틸아세테이트로 세척하여 화학식 113A로 표시되는 화합물 (36 mg, 반응수율: 32%， 노란색고체)을 얻었다. After dissolving the compound represented by Chemical Formula 113A-a prepared in Step 1 (100 mg, 0.16 단계 ol) in yV V-dimethylformamide (10 ι), an excess of dimethylamine was added, followed by shield-leuve. Stir at 70 ° C for 12 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain a compound of formula 113A (36 mg, reaction yield: 32%, yellow solid).
¾ 證 (400MHz, DMS0-o¾); δ 11.27(s, 1H), 10.52(s, 1H), 9.02(s, 1H), 7.97(d, /-8.4Hz, 2H), 7.37(d, J-6.8Hz, 2H)， 7.29(d, J=8.8Hz, 2H), 6.88(d, J-8.8Hz, 2H), 5.45(s, 2H), 4.32(q, Μ.ΊΆζ, 2H)， 4.12(q, J=1.8Hz, 2H), 3.71(s, 3H), 3.17(s, 3H), 3.16(s, 3H), 2.78(t, J^7.6Hz, 2H), 1.50(s, 9H), 1.32(t, J=6.8Hz, 3H) 단계 3: 에틸 6—아미노 -3-{4-[2- (디메틸아미노)에틸]벤즈아미도 피라졸 로 [3,4 - ]피리딘 -5-카복실레이트 하이드로클로라이드의 제조 ¾ Hz (400 MHz, DMS0-o¾); δ 11.27 (s, 1H), 10.52 (s, 1H), 9.02 (s, 1H), 7.97 (d, /-8.4 Hz, 2H), 7.37 (d, J-6.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.88 (d, J-8.8 Hz, 2H), 5.45 (s, 2H), 4.32 (q, Μ.ΊΆζ, 2H), 4.12 (q, J = 1.8 Hz, 2H), 3.71 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H), 2.78 (t, J ^ 7.6 Hz, 2H), 1.50 (s, 9H), 1.32 (t, J = 6.8 Hz, 3H ) Step 3: Preparation of [3,4-] pyridine-5-carboxylate hydrochloride with ethyl 6-amino-3- {4- [2- (dimethylamino) ethyl] benzamido pyrazole
상기 2단계에서 제조한 화학식 113A로 표시되는 화합물 (36 mg, 0.06 mmol)을 실시예 37의 단계 2~3의 반응을 이용하여 화학식 113으로 표시되는 화합물 (15 mg, 반웅수율: 58%， 상아색 고체)을 얻었다.  The compound represented by the formula 113A (36 mg, 0.06 mmol) prepared in the step 2 was represented by the formula 113 using the reactions of Steps 2 to 3 of Example 37 (15 mg, the semi-water yield: 58%, ivory color) Solid).
¾ NMR(400MHz, DMS0-o ; δ 12.76(br, 1H), 11.13(br, 1H), 10.60(br, 1H), 8.94(br, 1H), 8.05(d, J-8.0Hz, 2H) , 7.46(d, J-8.4Hz, 2H) , 4.32(q, J^7.6Hz, 2H), 3.36-3.30(m, 2H), 3.14-3.10(m, 2H), 2.82(s, 3H), 2.81(s, 3H), 1.31(t, J=6.8Hz, 3H) 상기 실시예 113과 동일한 방법으로 하기 표 6의 화합물을 제조하였다.  ¾ NMR (400 MHz, DMS0-o; δ 12.76 (br, 1H), 11.13 (br, 1H), 10.60 (br, 1H), 8.94 (br, 1H), 8.05 (d, J-8.0 Hz, 2H), 7.46 (d, J-8.4 Hz, 2H), 4.32 (q, J ^ 7.6 Hz, 2H), 3.36-3.30 (m, 2H), 3.14-3.10 (m, 2H), 2.82 (s, 3H), 2.81 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H) The compounds of Table 6 were prepared in the same manner as in Example 113.
【표 6】 Table 6
Figure imgf000093_0001
Figure imgf000093_0001
<실시예 119> 에틸 6-아미노 -3-{3-[3- (디메틸아미노)프로판아미도]벤즈아 ' 도}-1 -피라졸로 [3,4-b]피리딘 -5-카복실레이트 하이드로클로라이드의 제조
Figure imgf000094_0001
단계 1: 에틸 6- -부톡시카보닐아미노 )-3-[3-(3-클로로프로판아미도)벤즈아 미도] -1— (4-메톡시벤질) -I 피라졸 [3，4-/>]피리딘 -5-카복실레이트의 제조 <Example 119> Ethyl 6-amino-3- {3- [3- (dimethylamino) propane amido] benzamide oh "Fig} -1-pyrazolo [3,4-b] pyridine-5-carboxylate hydro Preparation of Chloride
Figure imgf000094_0001
Step 1: Ethyl 6-butoxycarbonylamino) -3- [3- (3-chloropropaneamido) benzamido] -1— (4-methoxybenzyl) -I pyrazole [3,4- />] Preparation of Pyridine-5-carboxylate
제조예 3의 단계 2의 화학식 c-3으로 표시되는 화합물을 실시예 37의 단계 1 의 방법을 이용하여 제조한 화학식 119A-a로 표시되는 화합물 에틸 3-(3-아미노벤 즈아미도) -6-( -부록시카보닐아미노 )-1-(4-메록시벤질) -1^피라졸로 [3 , 4-b]피리딘 -5-카복실레이트 (340 mg, 0.61 匪 ol)를 피리딘 (10 )에 녹인 후， 4-(2-클로로에 틸)벤조일 클로라이드 (116 mg, 0.92 瞧 ol)를 천천히 첨가한 후， 70 °C로 3시간 동 안 교반 하였다. 반응 종결 후， 반응흔합물을 감압 농축한 다음 에틸아세테이트로 세척하여 화학식 119A-b로 표시되는 화합물 (300 mg, 반응수율: 76%， 흰색고체)을 얻었다. Compound ethyl 3- (3-aminobenzamido) represented by Chemical Formula 119A-a, prepared by using the method of Step 1 of Example 37, of the compound represented by Chemical Formula c-3 of Step 2 of Preparation Example 3 6-(-Buroxycarbonylamino) -1- (4-methoxybenzyl) -1 ^ pyrazolo [3,4-b] pyridine-5-carboxylate (340 mg, 0.61 匪 ol) to pyridine (10 ), 4- (2-chloroethyl) benzoyl chloride (116 mg, 0.92 瞧 ol) was added slowly, followed by stirring at 70 ° C for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain a compound represented by the formula (119A-b) (300 mg, reaction yield: 76%, white solid).
¾ 匿 (400MHz, DMS0-*); δ 12.52(s, 1H), 11.36(s, 1H) , 10.53(s, 1H) , 10.30(s, 1H), 9.03(s, 1H), 8.23(s, 1H), 7.84(d, J^7.6Hz, 1H), 7.77(d, M.2Yiz, 1)， 7.46(t, J=8.0Hz, 1H), 7.30(d, J=8.4Hz, 2H), 6.89(d, J^.OHz, 2H), 5.46(s, 2H), 4.33(q, J-7.6Hz, 2H), 3.90(t, J=6.0Hz, 2H), 3.71(s, 3H), 2.85(t, J-6.4Hz, 2H), 1.50(s, 9H), 1.32(t, J^7.2Hz, 3H) 단계 2: 에틸 6-(f-부특시카보닐아미노 )-3-{3-[3- (디메틸아미노)프로판아미 도]벤즈아미도}-1-(4-메특시벤질) 피라졸 [3， 4-b]피리딘 -5-카복실레이트의 제조 상기 단계 1에서 제조한 화학식 119A-b로 표시되는 화합물 (50 mg, 0.08 mmol)을 에탄올 (10 에 녹인 후， 디메틸아민을 과량 첨가한 후, 실드 -튜브 (sealed tube)를 이용하여 70 °C로 12시간 동안 교반 하였다. 반응 종결 후， 반웅 흔합물을 감압 농축한 다음 에틸아세테이트로 세척하여 표제 화합물 (32 mg, 반웅수 율: 62%， 노란색고체)을 얻었다 ¾ Hz (400 MHz, DMS0- *); δ 12.52 (s, 1H), 11.36 (s, 1H), 10.53 (s, 1H), 10.30 (s, 1H), 9.03 (s, 1H), 8.23 (s, 1H), 7.84 (d, J ^ 7.6 Hz, 1H), 7.77 (d, M.2Yiz, 1), 7.46 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.89 (d, J ^ .OHz, 2H ), 5.46 (s, 2H), 4.33 (q, J-7.6 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.71 (s, 3H), 2.85 (t, J-6.4 Hz, 2H ), 1.50 (s, 9H), 1.32 (t, J ^ 7.2 Hz, 3H) Step 2: ethyl 6- (f-butoxycarbonylamino) -3- {3- [3- (dimethylamino) propaneami FIG.] Preparation of benzamido} -1- (4-mesoxybenzyl) pyrazole [3,4-b] pyridine-5-carboxylate Compound represented by Formula 119A-b prepared in Step 1 (50 mg) , 0.08 mmol) was dissolved in ethanol (10), dimethylamine was added in excess, and then stirred at 70 ° C. for 12 hours using a sealed tube. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Then washed with ethyl acetate to obtain the title compound (32 mg, semi-water ratio: 62%, yellow solid).
¾ NMR(400MHz, DMS0-i¾) '； δ 11.34(s, 1H), 10.50(s, 1H), 10.39(s, 1H), 9.00(s, 1H), 8.22(s, 1H), 7.79(t, J-8.0Hz, 2H), 7.44(t, J^7.6Hz, 1H), 7.28(d, J=8.8Hz, 2H), 6.87(d, J-8.0Hz, 2H) , 5.44(s, 2H), 4.30(q, J=6.8Hz, 2H)， 3.69(s, 3H), 3.20(br, 2H), 2.76(t, J-6.8Hz, 2H) , 2.67(s, 6H), 1.48(s, 9H), 1.30(t, J=6Mz, 3H) 단계 3: 에틸 6-아미노 -3-{3-[3- (디메틸아미노)프로판아미도]벤즈아미 도}-1^"-피라졸로 [3,4-Z>]피리딘 -5-카복실레이트 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0-i¾) ' ; δ 11.34 (s, 1H), 10.50 (s, 1H), 10.39 (s, 1H), 9.00 (s, 1H), 8.22 (s, 1H), 7.79 (t , J-8.0 Hz, 2H), 7.44 (t, J ^ 7.6 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.87 (d, J-8.0 Hz, 2H), 5.44 (s, 2H ), 4.30 (q, J = 6.8 Hz, 2H), 3.69 (s, 3H), 3.20 (br, 2H), 2.76 (t, J-6.8 Hz, 2H), 2.67 (s, 6H), 1.48 (s, 9H), 1.30 (t, J = 6Mz, 3H) Step 3: Ethyl 6-amino-3- {3- [3- (dimethylamino) propaneamido] benzamido} -1 ^ " -pyrazolo [3,4-Z>] pyridine-5-carboxylate hydro Preparation of Chloride
상기 2단계에서 제조한 화학식 119A로 표시되는 화합물 (32 mg, 0.06隱 ol)을 실시예 37의 단계 2~3의 방법으로 화학식 119로 표시되는 화합물 (10.2 mg, 반웅수 율: 44%， 회색 고체)을 얻었다  The compound represented by the formula (119A) prepared in the step 2 (32 mg, 0.06 μl) was represented by the formula (119) by the method of Steps 2 to 3 of Example 37 (10.2 mg, the semi-shallow rate: 44%, gray Solid)
¾ NMR(400MHz, O S0-d6)； δ 12.72(br, 1H), 11.13(br, 1H)， 10.62(s, 1H)， 10.30(br, 1H), 8.92(br, 1H), 8.23(s, 1H), 7.82(d, J-8.4Hz, 1H), 7.76(d, J^.6Hz, 1H), 7.46(t, J^IMz, 1H), 4.30(q, J^.2Hz, 2H), 3.35(q, J=6.8Hz, 2H), 2.92(t, J-7.2Hz, 2H), 2.77(s, 3H), 2.76(s, 3H), 1.29(t, J=6.8Hz, 3H) ¾ NMR (400 MHz, O S0-d 6 ); δ 12.72 (br, 1H), 11.13 (br, 1H), 10.62 (s, 1H), 10.30 (br, 1H), 8.92 (br, 1H), 8.23 ( s, 1H), 7.82 (d, J-8.4 Hz, 1H), 7.76 (d, J ^ .6 Hz, 1H), 7.46 (t, J ^ IMz, 1H), 4.30 (q, J ^ .2 Hz, 2H ), 3.35 (q, J = 6.8 Hz, 2H), 2.92 (t, J-7.2 Hz, 2H), 2.77 (s, 3H), 2.76 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H )
<실시예 120> 에틸 6-아미노 -3-[3-(3-모폴리노프로판아미도)벤즈아미도] 피라졸로 [3,4 -Z>]피리딘 -5-카복실레이트 하이드로클로라이드의 제조 Example 120 Preparation of Ethyl 6-amino-3- [3- (3-morpholinopropaneamido) benzamido] pyrazolo [3,4-Z>] pyridine-5-carboxylate hydrochloride
Figure imgf000095_0001
Figure imgf000095_0001
상기 실시예 119와 동일한 방법으로 수행하여 화학식 120으로 표시되는 화합 물을 제조하였다. In the same manner as in Example 119, a compound represented by Chemical Formula 120 was prepared.
¾ NMR(400MHz, DMS0-*); δ 12.73(br, 1H), 11.59(br, 1H), ll.lKbr, 1H) , 10.72(s, 1H), 8.84(br, 1H), 7.84(d, /-β.4Ηζ, 1H) , 7.76(d, J^JMz, 1H)， 7.45(t, /-7.6Hz, 1H), 4.30(q, ^. Hz, 2H), 3.94(d, J-10.4Hz, 2H)， 3.82(t, J=l 1.6Hz, 2H), 3.42-3.37(m, 4H), 3.12-3.00(m, 4H), 1.29(t, J-6.8Hz, 3H)  ¾ NMR (400 MHz, DMS0- *); δ 12.73 (br, 1H), 11.59 (br, 1H), ll.lKbr, 1H), 10.72 (s, 1H), 8.84 (br, 1H), 7.84 (d, /-β.4Ηζ, 1H), 7.76 (d, J ^ JMz, 1H), 7.45 (t, /-7.6 Hz, 1H), 4.30 (q, ^. Hz, 2H), 3.94 (d, J-10.4 Hz, 2H), 3.82 (t, J = l 1.6 Hz, 2H), 3.42-3.37 (m, 4H), 3.12-3.00 (m, 4H), 1.29 (t, J-6.8 Hz, 3H)
<실시예 121>피리딘 -3-일 메틸 6-아미노 -3- [4- (피리딘 -3-일메특시 )벤즈아미 도] -1H-피라졸로 [3,4-b]피리딘 -5-카복실레이트 하이드로클로라이드의 제조 Example 121 Pyridin-3-yl Methyl 6-amino-3- [4- (pyridin-3-ylmethoxy) benzamido] -1H-pyrazolo [3,4-b] pyridine-5-carboxyl Preparation of Rate Hydrochloride
Figure imgf000096_0001
Figure imgf000096_0001
단계  step
Figure imgf000096_0002
단계 3
Figure imgf000096_0002
Step 3
Figure imgf000096_0003
단계 5
Figure imgf000096_0003
Step 5
Figure imgf000096_0004
단계 1: 에틸 6-아미노 -1-(4-메톡시벤질) -3-(4- (피리딘 -3-일메톡시)벤즈아미 도)— 피라졸로 [3 , -M피리딘 -5-카복실레이트의 제조
Figure imgf000096_0004
Step 1: Ethyl 6-amino-1- (4-methoxybenzyl) -3- (4- (pyridin-3-ylmethoxy) benzamido) —pyrazolo [3, -Mpyridine-5-carboxylate Produce
4- (피리딘 -3-일-메톡시)벤조산 (134 mg, 0.58 mmol)을 디클로로메탄 (10 )에 녹인 후， 0 °C에서 옥살릴클로라이드 (0.08 mi, 0.75 mmol)와 씨디메틸포름아미드 (촉매량)를 차례로 첨가하고 상온에서 1시간 동안 교반 하였다. 감압 농축 후 잔류 물을 디클로로메탄 (10 i )에 용해시키고, 상온에서 제조예 2의 단계 5에서 제조한 e-2로 표시되는 화합물 (100 mg, 0.28 薩 ol)을 피리딘 (3 m«에 녹인 후 1시간 동안 교반 하였다. 반웅 종결 후, 에틸아세테이트로 추출하고 유기 용매층을 무수 황산 마그네슘으로 건조시킨 다음 용매를 감압 농축하였다. 감압 농축한 잔류물을 디에 틸에테르로 세척하여 화학식 121A-a로 표시되는 화합물 (120 mg, 반웅수율: 74%, 흰 색고체)을 얻었다. Έ NMR( 400MHz, DMSO-o : δ 11.00(s, 1H), 8.92(s, 1H), 8.70(s, 1H), 8.57(dd, J^1.8, 1.2Hz, 1H), 8.04(d, J=9.2Hz, 2H), 7.94-7.89(m, 2H), 7.57(br, 2H), 7.46-7.43 Cm, 1H), 7.20-7.13(m, 4H) , 6.88(d, J=8.8Hz, 2H) , 5.31(s, 2H) , 5.25(s, 2H), 4.31(q, J^7.6Hz, 2H), 3.81(s, 3H), 1.30(t, J^7.6Hz, 3H) 단계 2: 6-아미노 -l-(4-메톡시벤질) -3-[4- (피리딘 -3-일메특시)벤즈아미 도 ]-L 피라졸로 [3,4->]피리딘 -5-카복실릭 액시드의 제조 4- (pyridin-3-yl-methoxy) benzoic acid (134 mg, 0.58 mmol) in dichloromethane (10) chloride (0.08 mi, 0.75 mmol) and CD-methyl formamide then oxalyl at 0 ° C dissolved in ( Catalyst amount) was added sequentially and stirred for 1 hour at room temperature. After concentration under reduced pressure, the residue was dissolved in dichloromethane (10 i), and the compound represented by e-2 prepared in Step 5 of Preparation Example 2 (100 mg, 0.28 薩 ol) was dissolved in pyridine (3 m «at room temperature. After completion of reaction, the reaction mixture was extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was concentrated under reduced pressure, and then washed with ethyl ether. The compound represented by (120 mg, half-water yield: 74%, white solid) was obtained. NMR (400MHz, DMSO-o: δ 11.00 (s, 1H), 8.92 (s, 1H), 8.70 (s, 1H), 8.57 (dd, J ^ 1.8, 1.2Hz, 1H), 8.04 (d, J = 9.2 Hz, 2H), 7.94-7.89 (m, 2H), 7.57 (br, 2H), 7.46-7.43 Cm, 1H), 7.20-7.13 (m, 4H), 6.88 (d, J = 8.8 Hz, 2H ), 5.31 (s, 2H), 5.25 (s, 2H), 4.31 (q, J ^ 7.6Hz, 2H), 3.81 (s, 3H), 1.30 (t, J ^ 7.6Hz, 3H) Step 2: 6 -Amino-l- (4-methoxybenzyl) -3- [4- (pyridin-3-ylmexico) benzamido] -L pyrazolo [3,4->] pyridine-5-carboxylic acid Manufacture
상기 단계 1에서 제조한 화학식 121A-a로 표시되는 화합물 (120 mg, 0.21 隱 ol)올 에탄올 (10 )와 물 (1.5 )에 용해시킨 후 수산화칼륨 (76 mg, 1.35 醒 ol) 을 첨가 후 80 °C에서 2시간 동안 환류 교반 하였다. 반웅 종결 후， 상온으로 넁각 한 다음 에틸아세테이트로 추출하고 물층을 1 염산 용액을 이용하여 산성화 시킨 후 다시 에틸아세테이트로 추출하였다. 유기 용매층을 무수 황산마그네슘으로 건조 시킨 다음 용매를 감압 농축하여 화학식 121A-b로 표시되는 화합물 (82 mg, 반웅수 율: 74¾， 흰색고체)을 얻었다. The compound represented by Chemical Formula 121A-a prepared in Step 1 (120 mg, 0.21 隱 ol) ol was dissolved in ethanol (10) and water (1.5), followed by addition of potassium hydroxide (76 mg, 1.35 醒 ol) 80 It was stirred at reflux for 2 hours at ° C. After completion of reaction, the mixture was cooled to room temperature, extracted with ethyl acetate, the aqueous layer was acidified with 1 hydrochloric acid solution, and extracted again with ethyl acetate. The organic solvent layer was dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure to obtain a compound represented by Chemical Formula 121A-b (82 mg, half-water yield: 74 ¾, white solid).
¾ NMR( 400MHz, DMS0-*)： δ 10.98(s, 1H), 8.91(s, 1H), 8.75(s, 1H), 8.61(s, 2H), 8.07-8.00(m, 2H), 7.90(d, 7-6.8Hz, 1H), 7.54(br, 2H), 7.19-7. ll(m, 4H), 6.85(d, J=L4.0Hz, 2H), 5.30-5.26(m, 4H), 3.70(s, 3H) 단계 3: 피리딘 -3-일 메틸 6-아미노 -1-(4-메톡시벤질) -3-[4- (피리딘 -3-일메 특시)벤즈아미도] -ly 피라졸로 [3,4- ]피리딘 -5-카복실레이트의 제조 ¾ NMR (400MHz, DMS0- *): δ 10.98 (s, 1H), 8.91 (s, 1H), 8.75 (s, 1H), 8.61 (s, 2H), 8.07-8.00 (m, 2H), 7.90 ( d, 7-6.8 Hz, 1H), 7.54 (br, 2H), 7.19-7. ll (m, 4H), 6.85 (d, J = L4.0 Hz, 2H), 5.30-5.26 (m, 4H), 3.70 (s, 3H) Step 3: Pyridin-3-yl methyl 6-amino-1- Preparation of (4-methoxybenzyl) -3- [4- (pyridin-3-ylme special) benzamido] -ly pyrazolo [ 3 , 4- ] pyridine-5-carboxylate
상기 단계 2에서 제조한 화학식 121A-b로 표시되는 화합물 (80.0 mg, 0.13 瞧 ol)을 그디메틸포름아미드 (3 )에 녹인 후 피리딘 -3-일 메탄올 (0.02 m^, 0.19 mmol)과 1-에틸— 3— (3-디메틸아미노프로필) -카르보디이미드 히드로클로라이드 (EDC, 58 mg, 0.30 mmol)과 1-하이드톡시-벤조트리아졸 수화물 (HOBt, 41 mg, 0.30 mmol), 그리고 디이소프로필에틸아민 (0.11 0.61 隱 ol)을 첨가한 후， 상온에서 12 시간 동안 교반 하였다. 반응 종결 후， 에틸아세테이트로 추출하고 유기 용매층을 무수 황산마그네슴으로 건조시킨 다음 용매를 감압 농축하였다. 감압 농축한 잔류 물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =7:3)로 정제하여 화학식 121A-C로 표시되는 화합물 (24 mg, 반응수율 :30%， 흰색고체)을 얻었다.  The compound represented by Chemical Formula 121A-b prepared in Step 2 (80.0 mg, 0.13 μl) was dissolved in dimethylformamide (3), and then pyridin-3-yl methanol (0.02 m ^, 0.19 mmol) and 1- Ethyl— 3— (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC, 58 mg, 0.30 mmol) and 1-hydroxy-benzotriazole hydrate (HOBt, 41 mg, 0.30 mmol), and diisopropyl Ethylamine (0.11 0.61 Pa ol) was added, followed by stirring at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue concentrated under reduced pressure was purified by column chromatography (nucleic acid: ethyl acetate = 7: 3) to obtain a compound represented by Chemical Formula 121A-C (24 mg, reaction yield: 30%, white solid).
¾ NMR( 400MHz, W&-d6)： δ ll.OKs, 1H), 9.00(s, 1H), 8.69(s, 2H) , 8.55(t, /-4.8Hz, 2H), 8.02(d, J-8.8Hz, 2H), 7.89(t, J-6.4Hz, 2H), 7.57(br, 2H), 7.46-7.41(m, 2H), 7.19-7.12(m, 2H)， 6.87(d, /-β.8Ηζ, 2H), 5.48(s, 2H)， 5.31(s, 2H), 5.25(s, 2H) , 3.70(s, 3H) 단계 4: 피리딘 -3-일 메틸 6-아미노 -3— [4- (피리딘 -3-일메톡시)벤즈아미 도 피라졸로 [3,4- ]피리딘 -5-카복실레이트의 제조 ¾ NMR (400MHz, W & -d 6 ): δ ll.OKs, 1H, 9.00 (s, 1H), 8.69 (s, 2H), 8.55 (t, /-4.8Hz, 2H), 8.02 (d, J -8.8 Hz, 2H), 7.89 (t, J-6.4 Hz, 2H), 7.57 (br, 2H), 7.46-7.41 (m, 2H), 7.19-7.12 (m, 2H), 6.87 (d, /- β.8Ηζ, 2H), 5.48 (s, 2H), 5.31 (s, 2H), 5.25 (s, 2H), 3.70 (s, 3H) Step 4: Pyridin-3-yl methyl 6-amino-3— [ Preparation of 4- (pyridin-3-ylmethoxy) benzamido pyrazolo [3,4-] pyridine-5-carboxylate
상기 단계 3에서 제조한 화학식 121A-C로 표시되는 화합물 (20 mg, 0.03 mmol)을 트리플루오로아세트산 (3 mO에 녹인 후 실드 -튜브 (sealed tube)에 넣고 90 °C에서 1시간 동안 교반 하였다. 상온으로 넁각한 후， 감압 농축 하였다. 에틸 아 세테이트를 첨가하고 생성된 고체를 여과하여 다시 에틸아세테이트로 세척하여 화 학식 121A로 표시되는 화합물 (12 mg, 반응수율 :75%, 흰색고체)을 얻었다. The compound represented by Chemical Formula 121A-C prepared in Step 3 (20 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (3 mO, and then put in a shielded tube, followed by stirring at 90 ° C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure, ethyl acetate was added, and the produced solid was filtered and washed again with ethyl acetate (12 mg, reaction yield: 75%, white solid). Got.
¾ NMR(400MHz, DMS0-*)： δ 12.65(s, 1H) , 10.94(s, 1H), 8.96(s, 1H), 8.81(d, J-9.2Hz, 2H) , 8.67(d, J-6.4Hz, 2H), 8.16— 8.10(m, 2H) , 8.05(d, H , 2H), 7.68-7.63(m, 2H), 7.29(br, 2H), 7.04(d, J=7.2Hz, 2H), 5.44(s, 2H), 4.82(s, 2H) 단계 5: 피리딘 -3-일 메틸 6-아미노 -3-[4— (피리딘 -3-일메특시)벤즈아미 도] -1H-피라졸로 [3,4-b]피리딘 -5-카복실레이트 하이드로클로라이드의 제조 ¾ NMR (400 MHz, DMS0- *): δ 12.65 (s, 1H), 10.94 (s, 1H), 8.96 (s, 1H), 8.81 (d, J-9.2Hz, 2H), 8.67 (d, J- 6.4 Hz, 2H), 8.16— 8.10 (m, 2H), 8.05 (d, H, 2H), 7.68-7.63 (m, 2H), 7.29 (br, 2H), 7.04 (d, J = 7.2 Hz, 2H), 5.44 (s, 2H), 4.82 (s, 2H) Step 5: pyridine Preparation of 3-ylmethyl 6-amino-3- [4— (pyridin-3-ylmethoxy) benzamido] -1H-pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride
상기 단계 4에서 제조한 화학식 121A로 표시되는 화합물 (12 mg, 0.02 mmol) 을 1!4-디옥산 α ιη ^에 녹인 후 3.7 Μ 염산 (2 1,4-디옥산용액)을 첨가하였다. 24시간 동안 교반 후 용매를 감압 농축하였다. 감압 농축한 잔류물에 에틸아세테이 트와 디에틸에테르를 가하고 30분 동안 교반하고 여과한 후， 디에틸에테르로 세척 하여 화학식 121로 표시되는 화합물 (9.0 mg, 반응수율 :65¾， 녹색 고체)을 얻었다. The compound represented by Chemical Formula 121A (12 mg, 0.02 mmol) prepared in Step 4 was dissolved in 1! 4 -dioxane α ηη , and then 3.7 M hydrochloric acid (2 1,4-dioxane solution) was added. After stirring for 24 hours, the solvent was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, which was then concentrated under reduced pressure, stirred for 30 minutes, filtered and washed with diethyl ether to obtain the compound represented by Chemical Formula 121 (9.0 mg, reaction yield: 65¾, green solid). Got it.
¾ NMR(400MHz, DMSO-o^)： δ ll.OKs, IH), 9.02(s, 3H), 8.87(d, J=l 1.2Hz, 2H), 8.55(t, J=8.0Hz, 2H) , 8.09(d, /죈.0Hz, 2H), 8.04-7.97(m, 4H), 7.19(d, J-9.2Hz, 2H), 5.53(s, 2H), 5.43(s, 2H) 상기 실시예 121과 동일한 방법으로 하기 표 7의 화합물을 제조하였다.  ¾ NMR (400 MHz, DMSO-o ^): δ ll.OKs, IH), 9.02 (s, 3H), 8.87 (d, J = l 1.2 Hz, 2H), 8.55 (t, J = 8.0 Hz, 2H) , 8.09 (d, / 죈 .0 Hz, 2H), 8.04-7.97 (m, 4H), 7.19 (d, J-9.2 Hz, 2H), 5.53 (s, 2H), 5.43 (s, 2H) In the same manner as 121, the compound of Table 7 was prepared.
【표 7]  [Table 7]
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000098_0001
Figure imgf000099_0001
<제조예 6> 2-(4-메특시페닐) -Λ45-(4-메록시페닐) -1 -피라졸로 [3,4- ]피라 진 -3-일] -2-옥소아세트아미드의 합성의 제조  Preparation Example 6 Synthesis of 2- (4-methoxyphenyl) -Λ45- (4-methoxyphenyl) -1-pyrazolo [3,4-] pyrazin-3-yl] -2-oxoacetamide Manufacture
Figure imgf000099_0002
Figure imgf000099_0002
4-메록시아세토페논 (500 mg, 3.33 隱 ol)을 피리딘 (3 에 녹인 후， 셀레늄 디옥사이드 (968 mg, 8.72 mmol)을 첨가 후 80 °C에서 5시간 동안 교반시킨다. 용매 를 감압 하에 제거하고 잔류물을 컬럼 크로마토그래피 (에틸아세테이트:핵산 =3:1)로 정제하여 표제 화합물 (376 mg, 반응수율: 63%， 하얀색 고체)을 얻었다. 4-methoxyacetophenone (500 mg, 3.33 隱 ol) was dissolved in pyridine (3), and then selenium dioxide (968 mg, 8.72 mmol) was added and stirred at 80 ° C for 5 hours. The residue was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate: nucleic acid = 3: 1) to obtain the title compound (376 mg, reaction yield: 63%, white solid).
¾ NMR(400MHz, DMS()-^); δ 14.46(br, 1H), 7.90(d, J=8.4Hz, 2H), 7.14(d, J=8.8Hz, 2H)  ¾ NMR (400 MHz, DMS () − ^); δ 14.46 (br, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H)
<실시예 129> 아미노 -5-(4-메록시페닐) 피라졸로 [3,4-Z>]피라진 -3- 일] -2-(4-메특시페닐) - 2ᅳ옥소아세트아미드의 제조 Example 129 Preparation of Amino-5- (4-Methoxyphenyl) pyrazolo [3,4-Z>] pyrazin-3-yl] -2- (4-methoxyphenyl) -2-ioxoacetamide
Figure imgf000100_0001
Figure imgf000100_0001
129A 단계 1: -[6—아미노 -1-(4-메톡시벤질) -5— (4-메톡시페닐)— 1 -피라졸로  129A Step 1:-[6—Amino-1- (4-methoxybenzyl) -5— (4-methoxyphenyl) — 1-pyrazolo
[3,4->]피라진 -3-일] -2-(4-메톡시페닐)— 2-옥소아세트아미드의 제조 [3,4->] pyrazin-3-yl] -2- (4-methoxyphenyl) — Preparation of 2-oxoacetamide
상기 제조예 6에서 제조한 화학식 a-6으로 표시되는 화합물 (37 mg, 0.21 隱 ol)를 디클로로메탄 (2.0 에 녹인 후， 0 °C에서 옥살릴크로라이드 (63.2^， 0.41 mmol)와 vV,V-디메틸포름아미드 (2방울)를 천천히 첨가하고 1시간 동안 교반 후 용매를 감압 하에 제거하고 상기 제조에 1의 단계 7에서 제조한 화학식 a-1 '로 표 시되는 화합물 (50 mg, 0.14 mmol)을 피리딘 (3 에 녹여 반웅 흔합물에 첨가하고 2시간 동안 교반 하였다. 디클로로메탄으로 추출 후 소금물로 세척하고， 유기 용 매층을 무수 황산나트륨으로 건조시킨 다음 용매를 감압 농축하였다. 잔류물을 컬 럼 크로마토그래피 (디클로로메탄:메탄올 =50:1)로 정제하여 화학식 129A로 표시되는 화합물 (23 mg, 반웅수율: 32%, 하얀색 고체)을 얻었다. The compound represented by Chemical Formula a-6 prepared in Preparation Example 6 (37 mg, 0.21 예 ol) was dissolved in dichloromethane (2.0, and then oxalyl chloride (63.2 ^, 0.41 mmol) and vV, at 0 ° C. Slowly adding V-dimethylformamide (2 drops), stirring for 1 hour, and then removing the solvent under reduced pressure, and preparing the compound represented by Chemical Formula a-1 ′ prepared in Step 7 of 1 (50 mg, 0.14 mmol ) Was dissolved in pyridine (3) and added to the reaction mixture and stirred for 2 hours. The mixture was extracted with dichloromethane, washed with brine, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Purification by chromatography (dichloromethane: methanol = 50: 1) gave a compound represented by the formula 129A (23 mg, semi-abundance: 32%, white solid).
¾ NMR(400MHz, DMS0-o ; δ 9.75(s, 1H), 8.94(s, 1H), 8.60(d, J-8.8Hz, 2H), 8.02(d, J-8.8Hz, 2H), 7.39(d, J^8.4Hz, 2H), 7.04(d, J-8.4Hz, 2H), 6.99(d, J^.8Hz, 2H), 6.84(d, J-8.8Hz, 2H), 5.65(br, 2H), 3.91(s, 3H), 3.88(s, 3H), 3.75(s, 3H) 단계 2: 46-아미노 -5-(4_메톡시페닐) 피라졸로 [3,4-Z>]피라진 -3- 일] -2-(4-메특시페닐) - 2-옥소아세트아미드의 제조  ¾ NMR (400MHz, DMS0-o; δ 9.75 (s, 1H), 8.94 (s, 1H), 8.60 (d, J-8.8Hz, 2H), 8.02 (d, J-8.8Hz, 2H), 7.39 ( d, J ^ 8.4Hz, 2H), 7.04 (d, J-8.4Hz, 2H), 6.99 (d, J ^ .8Hz, 2H), 6.84 (d, J-8.8Hz, 2H), 5.65 (br, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H) Step 2: 46-amino-5- (4_methoxyphenyl) pyrazolo [3,4-Z>] pyrazine -3-yl] -2- (4-methoxyphenyl)-2-oxoacetamide
상기 단계 1에서 제조한 화학식 129A로 표시되는 화합물 (23 mg, 0.04 画 ol) 을 트리플루오로아세트산 (5 )에 녹인 후 100 °C에서 48시간 동안 교반 하였다. 상온으로 넁각 후 차가운 얼음물로 반응을 종결시키고 클로로포름으로 추출하였다. 소금물로 세척하고 유기 용매층을 무수 황산나트륨으로 건조시킨 다음 감압 농축하 였다. 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =10:1)로 정제하여 화학 식 129로 표시되는 화합물 (7.2 mg, 반웅수율: 40%, 노란색 고체)을 얻었다. After the compound (23 mg, 0.04画ol) represented by a formula 129A prepared in the above step 1 was dissolved in acetic acid (5) trifluoromethyl was stirred at 100 ° C for 48 hours. After cooling to room temperature, the reaction was terminated with cold ice water and extracted with chloroform. The organic solvent layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give the compound represented by the formula (129) (7.2 mg, semi-water yield: 40%, yellow solid).
¾ NMR(400MHz, CDC13); δ 10.00(s, 1H), 9.01(s, 1H), 8.59(d, J=%Mz, 2H), 8.05(d, J^8.8Hz, 2H), 7.06(d, J=8.8Hz, 2H), 7.00(d, J^.8Hz, 2H), 3.91(s, 3H), 3.89(s, 3H) 상기 실시예 129와 동일한 방법으로 하기 표 8의 화합물을 제조하였다. ¾ NMR (400 MHz, CDC1 3 ); δ 10.00 (s, 1H), 9.01 (s, 1H), 8.59 (d, J =% Mz, 2H), 8.05 (d, J ^ 8.8Hz, 2H), 7.06 (d, J = 8.8Hz, 2H) , 7.00 (d, J ^ 8 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H) The compounds of Table 8 were prepared in the same manner as in Example 129.
【표 8】 Table 8
Figure imgf000101_0001
Figure imgf000101_0001
<실시예 132> 에틸 6-아미노 -3-[3- (핵실옥시술포닐)벤즈아미도] 피라졸로 [3,4-/>]피리딘 -5-카복실레이트의 제조 Example 132 Preparation of ethyl 6-amino-3- [3- (nuxyloxysulfonyl) benzamido] pyrazolo [3,4-/>] pyridine-5-carboxylate
Figure imgf000102_0001
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000102_0002
단계 1: 에틸 6- ( 부톡시카보닐아미노) -3-[3- (핵실옥시술포닐)벤즈아미 도 ] 1-(4-메톡시벤질 )— L—피라졸 [3， 4 ->]피리딘 -5-카복실레이트의 제조  Step 1: Ethyl 6- (butoxycarbonylamino) -3- [3- (nuxyloxysulfonyl) benzamido] 1- (4-methoxybenzyl) — L—pyrazole [3, 4->] Preparation of Pyridine-5-carboxylate
상기 제조예 5의 단계 2에서 제조한 화학식 c-5로 표시되는 화합물 (100 mg, 0.23 mmol)을 피리딘 (10 에 녹인 후， 실시예 1의 단계 8과 같은 제조방법으로 얻은 3- (클로로술포닐)벤조일 클로라이드 (82 mg, 0.35 隱 ol)를 천천히 첨가한 후, 70 °C로 3시간 동안 교반 하였다. 반웅흔합물을 감압 농축한 다음 핵산올과 함께 1 시간 동안 교반 하였다. 반웅 종결 후, 감압 농축한 다음 에틸아세테이트로 세척하 여 화학식 132A로 표시되는 화합물 (42.5 mg, 반웅수율: Ί？ > , 회색 고체)을 얻었다. Compound (100 mg, 0.23 mmol) represented by Chemical Formula c-5 prepared in Step 2 of Preparation Example 5 was dissolved in pyridine (10, and 3- (chlorosulfur obtained by the same method as in Step 8 of Example 1). Phenyl) benzoyl chloride (82 mg, 0.35 μl) was added slowly and stirred for 3 hours at 70 ° C. The reaction mixture was concentrated under reduced pressure and then stirred with the nucleic acid for 1 hour. The mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain a compound represented by the formula (132A) (42.5 mg, half-water yield:??>, Gray solid).
¾ 匿 (400腿 z, DMS0- ); δ 11.73(br, 1H)， 10.49(s, 1H), 9.05(s, 1H) , 8.54(s, 1H), 8.40(d, J=6.8Hz, 1H), 8.10(d, J^7.6Hz, 1H) , 7.82(t, J=7.6Hz, 1H), 7.28(d, J-8.0Hz, 2H), 6.87(d, J^7.6Hz, 2H) , 5.44(s, 2H) , 4.31(q, J^.8Hz, 2H), 4.09(t, J=6.4Hz, 2H), 3.69(s, 3H), 1.55(t, J-6.4Hz, 2H), 1.48(s, 9H), 1.30(t, J^7.6Hz, 3H), 1.21-1.14(m, 6H), 0.77(t, 7-6.0Hz, 3H) 단계 2: 에틸 6-아미노—3-[3- (핵실옥시술포닐)벤즈아미도] -1 -피라졸로 [3，4-/>]피리딘 -5-카복실레이트의 제조  ¾ kPa (400 k z, DMS0-); δ 11.73 (br, 1H), 10.49 (s, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 8.40 (d, J = 6.8 Hz, 1H), 8.10 (d, J ^ 7.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.28 (d, J-8.0 Hz, 2H), 6.87 (d, J ^ 7.6 Hz, 2H), 5.44 (s, 2H), 4.31 (q, J ^ .8 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 3.69 (s, 3H), 1.55 (t, J-6.4 Hz, 2H), 1.48 (s, 9H), 1.30 (t, J ^ 7.6 Hz, 3H), 1.21-1.14 (m, 6H), 0.77 (t, 7-6.0 Hz, 3H) Step 2: Ethyl 6-amino—3- [3- (nucleooxyoxysulfonyl) benzamido Preparation of -1 -pyrazolo [3,4-/>] pyridine-5-carboxylate
상기 1단계에서 제조한 화학식 132A로 표시되는 화합물 (42.5 mg, 0.06隱 ol) 을 실시예 37의 단계 1과 같은 방법으로 화학식 132로 표시되는 화합물 (10.2 mg, 반웅수율: 21%, 갈색 고체)을 얻었다.  Compound represented by the formula (132A) prepared in step 1 (42.5 mg, 0.06 隱 ol) in the same manner as in step 1 of Example 37, the compound represented by formula 132 (10.2 mg, semi-water yield: 21%, brown solid) Got.
.¾ NMR( 400MHz, DMS0-o¾; δ 12.73(s, 1Η) , 11.45(s, 1H)ᅳ 8.90(s, 1H) , 8.53(s, 1H), 8.41(d, .0Hz, 1H) , 8.12(d, M. z, 1H), 7.84(d, J^.OHz, 1H), 7.42(br, 2H)， 4.29(q, J=6AEz, 2H), 4.11(t, J-6.0Hz, 2H), 1.56(t, J-6.8Hz, 2H), 1.29U, 세 , 3H), 1.21-1. ll(m, 6H) , 0.78(t, J-6.4H, 3H) 상기 실시예 132와 동일한 방법으로 하기 표 9의 화합물을 제조하였다.  .¾ NMR (400MHz, DMS0-o¾; δ 12.73 (s, 1Η), 11.45 (s, 1H) ᅳ 8.90 (s, 1H), 8.53 (s, 1H), 8.41 (d, .0Hz, 1H), 8.12 (d, M. z, 1H), 7.84 (d, J ^ .OHz, 1H), 7.42 (br, 2H), 4.29 (q, J = 6AEz, 2H), 4.11 (t, J-6.0 Hz, 2H ), 1.56 (t, J-6.8 Hz, 2H), 1.29U, three, 3H), 1.21-1. ll (m, 6H), 0.78 (t, J-6.4H, 3H) The compound of Table 9 was prepared in the same manner as in Example 132.
【표 9】
Figure imgf000103_0001
Table 9
Figure imgf000103_0001
<실시예 136> 소듐 3-{3-[5-(4-메톡시페닐) 피라졸로 [3,4-Z>]피라진 -3-일] 이도 }프로파노에이트의 제조 Example 136 Preparation of Sodium 3- {3- [5- (4-methoxyphenyl) pyrazolo [3,4-Z>] pyrazin-3-yl] ido} propanoate
Figure imgf000104_0001
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000104_0002
Figure imgf000104_0003
Figure imgf000104_0003
단계 1: 에틸 3ᅳ{3-[1-(4-메톡시벤질) -5-(4-메톡시페닐) -Ly-피라졸로 [3,4-;] 피라진 -3-일]우레이도}프로파노에이트의 제조 Step 1: ethyl 3 '{3- [1- (4-methoxybenzyl) -5 (4-methoxyphenyl) -Ly-pyrazolo [3,4-;] pyrazin-3-yl] ureido} Preparation of Propanoate
실시예 1의 단계 1의 방법을 이용하여 제조한 화학식 a-1 '로 표시되는 화합 물 1-(4-메록시벤질 )-5-(4-메록시페닐) -l^피라졸로 [4,3-b]피라진 -3—아민 (55 mg, 0.23 mmol)을 디클로로메탄 (3 에 용해시키고 0 °C로 낮춘 후， 트리에틸아민 (0.16 1.14 mmol)과 트리포스젠 (23 mg, 0.08 隱 ol)을 첨가하여 동일한 은도에 서 30분 동안 반웅하였다. 반웅 흔합물에 에틸 3ᅩ아미노프로파노에이트와 과량의 피리딘 (2 을 넣고 실온에서 12시간 동안 교반하였다. 종결된 반응 흔합물의 용 매를 감압 농축하고 건조하여 얻은 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메 탄올 =8:1)하여 화학식 136A-a로 표시되는 화합물 (24 mg, 반웅 수율 :21%, 노란 고 체)을 얻었다. Example compounds 1-one represented by the formula 1 a-1 'manufactured by the method of Step 1 of (4-hydroxy-methoxy-benzyl) - 5 - (4-hydroxyphenyl) -l ^ pyrazolo [4, 3-b] pyrazine-3-amine (55 mg, 0.23 mmol) was dissolved in dichloromethane (3 and lowered to 0 ° C), then triethylamine (0.16 1.14 mmol) and triphosphene (23 mg, 0.08 μl ol The reaction mixture was reacted for 30 minutes at the same degree of silver, and the reaction mixture was added with ethyl 3 ᅩ aminopropanoate and excess pyridine (2) and stirred for 12 hours at room temperature. The solvent of the reaction mixture was terminated under reduced pressure. The residue obtained by concentration and drying was subjected to column chromatography (dichloromethane: methanol = 8: 1) to give a compound represented by the formula (136A-a) (24 mg, reaction yield: 21%, yellow solid).
¾ 證 (400MHz, DMSO-ok); 6 9.87(s, 1H), 9.23(s, 1H), 8.16(d, J-8.8Hz, 2H), 7.28(d, /-β.ΟΗζ, 2H), 7.04(d, J=8.4Hz, 2H) , 6.87(d, J^7.6Hz, 2H), 5.57(S, 2H), 4.06(q, 7^7.2Hz, 2H), 3.83(s, 3H), 3.81(s, 3H), 3.41(q, J-6.0Hz, 2H), 2.54(t, /-6.4Hz, 2H), 1.21(t, J-7.2Hz, 3H) 단계 2: 3-{3-[l-(4-메톡시벤질) -5-(4-메톡시페닐) -L¥-피라졸로 [3,4_Z>]피라 진 -3—일]우레이도}프로파논산의 제조  ¾ Hz (400 MHz, DMSO-ok); 6 9.87 (s, 1H), 9.23 (s, 1H), 8.16 (d, J-8.8Hz, 2H), 7.28 (d, /-β.ΟΗζ, 2H), 7.04 (d, J = 8.4Hz, 2H ), 6.87 (d, J ^ 7.6 Hz, 2H), 5.57 (S, 2H), 4.06 (q, 7 ^ 7.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.41 (q , J-6.0 Hz, 2H), 2.54 (t, /-6.4 Hz, 2H), 1.21 (t, J-7.2 Hz, 3H) Step 2: 3- {3- [l- (4-methoxybenzyl) Preparation of 5-5- (4-methoxyphenyl) -L-pyrazolo [3,4_Z>] pyrazine-3-yl] ureido} propanoic acid
상기 단계 1에서 제조한 화학식 136A-a로 표시되는 화합물 (26 mg, 0.05 mmol)을 에탄올 (7 m«에 녹인 후， 물 (1.2 m«을 첨가하고 수산화칼륨 (6.3 mg, 0.16 瞧 ol)첨가 후 80 °C에서 2시간 동안 교반 하였다. 물 (5 m£)과 에틸아세테이트 (10 )를 첨가하고 물로 추출하였다. LV염산으로 산성화시키고 에틸아세테이트로 추 출하였다. 소금물로 세척하고 무수 황산나트륨으로 건조 후 여과하여 건조하여 화 학식 136A-b로 표시되는 화합물 (20 mg, 반응수율 :80%, 흰색 고체)을 얻었다. The compound represented by Formula 136A-a prepared in Step 1 (26 mg, 0.05 mmol) was dissolved in ethanol (7 m «, followed by addition of water (1.2 m« and potassium hydroxide (6.3 mg, 0.16). 瞧 ol) and then stirred at 80 ° C for 2 hours. Water (5 m £) and ethyl acetate (10) were added and extracted with water. Acidified with LV hydrochloric acid and extracted with ethyl acetate. Washed with brine, dried over anhydrous sodium sulfate, filtered and dried to obtain the compound represented by the chemical formula 136A-b (20 mg, reaction yield: 80%, white solid).
¾ 丽 (400MHz, DMSO-oy; δ 9.86(s, 1H)， 9.23(s, 1H), 8.16(d, J-8.8Hz, 2H), 7.29(d, J^8.8Hz, 2H), 7.04(d, J-8.8Hz, 2H), 6.87(d, J^.SHz, 2H), 5.57(S, 2H), 3.81(s, 3H) , 3.68(s, 3H) , 3.34(br, 3H),2.53(br, 3H) 단계 3: 3-{3-[5-(4-메특시페닐) 피라졸로 [3,4-Z>]피라진 -3-일]우레이도} 프로파논산의 제조  ¾ δ (400MHz, DMSO-oy; δ 9.86 (s, 1H), 9.23 (s, 1H), 8.16 (d, J-8.8Hz, 2H), 7.29 (d, J ^ 8.8Hz, 2H), 7.04 ( d, J-8.8 Hz, 2H), 6.87 (d, J ^ .SHz, 2H), 5.57 (S, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.34 (br, 3H), 2.53 (br, 3H) Step 3: Preparation of 3- {3- [5- (4-methoxyphenyl) pyrazolo [3,4-Z>] pyrazin-3-yl] ureido} propanoic acid
상기 단계 2에서 제조한 화학식 136A-b로 표시되는 화합물 (20 mg, 0.04 瞧 ol)을 트리플루오로아세트산 (5 에 녹인 후 100 °C에서 48시간 동안 교반 하였 다. 상온으로 넁각 후 차가운 얼음물로 반웅을 종결시키고 클로로포름으로 추출하 였다. 소금물로 세척하고 유기 용매층올 무수 황산나트륨으로 건조시킨 다음 감압 농축하였다. 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄올 =10:1)로 정제하여 화학식 136A로 표시되는 화합물 (3.4 mg, 반응수율 :23%， 흰색 고체)을 얻었다. The compound represented by Chemical Formula 136A-b prepared in Step 2 (20 mg, 0.04 瞧 ol) was dissolved in trifluoroacetic acid (5) and stirred for 48 hours at 100 ° C. After cooling to room temperature, the mixture was cooled with cold ice water. The reaction was terminated and extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, anhydrous sodium sulfate, and then concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1) and represented by Chemical Formula 136A. To obtain a compound (3.4 mg, reaction yield: 23%, white solid).
¾ NMR(400MHz, DMS0-o ; δ 13.36(s, 1H), 12.30(s, 1H), 9.25(s, 1H) , 9.10(s, 1H), 8.17(d, J-8.8Hz, 2H) , 7.51(br, 1H), 7.14(d, J-β.δΗζ, 2H), 3.83(S, 3H), 3.69(br, 2H), 2.54(br, 2H) 단계 4: 소듐 3-{3_[5-(4-메톡시페닐) -Ly-피라졸로 [3,4-Z>]피라진 -3-일]우레 이도 }프로파노에이트의 제조  ¾ NMR (400 MHz, DMS0-o; δ 13.36 (s, 1H), 12.30 (s, 1H), 9.25 (s, 1H), 9.10 (s, 1H), 8.17 (d, J-8.8Hz, 2H), 7.51 (br, 1H), 7.14 (d, J-β.δΗζ, 2H), 3.83 (S, 3H), 3.69 (br, 2H), 2.54 (br, 2H) Step 4: Sodium 3- {3_ [5 Preparation of [3,4-Z>] pyrazin-3-yl] ureido} propanoate with-(4-methoxyphenyl) -Ly-pyrazolo
상기 단계 3에서 제조한 화학식 136A로 표시되는 화합물 (8.8 mg, 0.03誦 ol) 을 메탄올에 녹이고 수산화나트륨 (24//£， 0.03 mmol)을 첨가하고 상온에서 12시 간 동안 교반 하였다. 반응종결 후, 반웅물을 감압 여과하여 화학식 136로 표시되 는 화합물 (9.2 mg, 반웅수율: 98%， 노란색 고체)을 얻었다.  The compound represented by Chemical Formula 136A (8.8 mg, 0.03 μl) prepared in Step 3 was dissolved in methanol, sodium hydroxide (24 // £, 0.03 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 136 (9.2 mg, reaction yield: 98%, yellow solid).
¾ NMR( 400MHz, CD30D)； δ 8.99(s, 1H) , 8.06(d, J=8.8Hz, 2H), 7.07(d, 세 z, 2H), 3.86(S, 3H), 3.59(t, J^7.2Hz, 2H), 2.47(d, J=6.4Hz, 2H) ¾ NMR (400 MHz, CD 3 0D); δ 8.99 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.07 (d, three z, 2H), 3.86 (S, 3H), 3.59 (t , J ^ 7.2 Hz, 2H), 2.47 (d, J = 6.4Hz, 2H)
<실시예 137> 에틸 6-아미노 -l-(2-아미노아세틸 )-3- (니코틴아미도) -1H-피라 졸로 [3, 4-b]피리딘 -5-카복실레이트 디하이드로클로라이드의 제조 Example 137 Preparation of ethyl 6-amino-l- (2-aminoacetyl) -3- (nicotinamido) -1H-pyrazolo [3,4-b] pyridine-5-carboxylate dihydrochloride
Figure imgf000106_0001
Figure imgf000106_0001
Figure imgf000106_0002
단계 1: 에틸 6-아미노 -1-(2- (^부톡시카보닐아미노)아세틸 )-3- (니코틴아미 도) 피라졸로 [3 , 4->]피리딘 -5-카복실레이트의 제조
Figure imgf000106_0002
Step 1: Preparation of ethyl 6-amino-1- (2- (^ butoxycarbonylamino) acetyl) -3- (nicotinamido) pyrazolo [3, 4->] pyridine-5-carboxylate
실시예 37 단계 2에서 제조한 화학식 37A로 표시되는 화합물 (50 mg, 0.15 圆 ol)을 ^가디메틸포름아미드 (5 에 녹인 후, 1-에틸 -3— (3-디메틸아미노프로 필) -카르보디이미드 히드로클로라이드 (EDC, 39 mg, 0.20 mmol)과 1-하이드록시-벤 조트리아졸 수화물 (27 mg, 0.20 瞧 ol) 및 씨디메틸에틸렌디아민 (22 ᅳ, 0.20 画 ol)을 첨가하고 15시간 동안 교반 하였다. 포화 중탄산나트륨 수용액으로 반웅 을 종결시키고 클로로포름으로 추출 후， 소금물로 세척하였다. 무수 황산나트륨으 로 건조 후 여과하고 용매를 감압 농축하였다. 소량의 디에틸에테르를 첨가한 후， 잔여물을 감압 여과하여 화학식 137A로 표시되는 화합물 (12.3 mg, 반응수율: 22%， 상아색 고체)을 얻었다.  Example 37 The compound represented by the formula (37A) prepared in step 2 (50 mg, 0.15 μl) was dissolved in ^ dimethyldimethylformamide (5, and then 1-ethyl-3— (3-dimethylaminopropyl) -carr Bodyimide hydrochloride (EDC, 39 mg, 0.20 mmol), 1-hydroxy-benzotriazole hydrate (27 mg, 0.20 μl ol) and cdimethylethylenediamine (22 μg, 0.20 μl ol) were added and 15 hours The reaction was terminated with a saturated aqueous sodium bicarbonate solution, extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and a small amount of diethyl ether was added to the residue. Filtration under reduced pressure gave a compound represented by Chemical Formula 137A (12.3 mg, reaction yield: 22%, ivory solid).
¾ NMR(400MHz, DMS0-i¾); δ 11.74(s, IH), 9.17(s, IH), 8.98(s, IH), 8.78(d, J=5.2Hz, IH), 8.38(d, J-8.0Hz, IH), 7.91(br, 2H) , 7.57(t, J-6.4Hz, IH), 7.25(t, J-5.6Hz, IH), 4.56(d, J-6.4Hz, 2H), 4.32(q, J-6.8Hz, 2H), 1.40(s, 9H), 1.30(t, J=5.2Hz, 3H) 단계 2: 에틸 6-아미노 -l-(2-아미노아세틸 )-3- (니코틴아미도) -Ly-피라졸로 [3， 4 ->]피리딘 -5-카복실레이트 디하이드로클로라이드의 제조  ¾ NMR (400 MHz, DMS0-i¾); δ 11.74 (s, IH), 9.17 (s, IH), 8.98 (s, IH), 8.78 (d, J = 5.2 Hz, IH), 8.38 (d, J-8.0 Hz, IH), 7.91 (br, 2H), 7.57 (t, J-6.4 Hz, IH), 7.25 (t, J-5.6 Hz, IH), 4.56 (d, J-6.4 Hz, 2H), 4.32 (q, J-6.8 Hz, 2H) , 1.40 (s, 9H), 1.30 (t, J = 5.2 Hz, 3H) Step 2: ethyl 6-amino-l- (2-aminoacetyl) -3- (nicotinamido) -Ly-pyrazolo [3 , 4->] pyridine-5-carboxylate dihydrochloride
상기 1단계에서 제조한 화학식 137A로 표시되는 화합물 (10.2 mg, 0.02 瞧 ol) 을 실시예 37의 단계 3과 같은 방법으로 반응을 수행하여 화학식 137로 표시되는 화합물 (6.7 mg, 반응수율: 70%, 갈색 고체)을 얻었다.  The compound represented by the formula (137A) prepared in step 1 (10.2 mg, 0.02 단계 ol) was reacted in the same manner as in Step 3 of Example 37, wherein the compound represented by the formula 137 (6.7 mg, reaction yield: 70% , Brown solid).
¾ NMR(400MHz, W&)~d6)； δ 11.90(s, IH), 9.24(s, IH) , 9.02(s, IH) , 8.87(s, IH), 8.51(t, J-8.0Hz, 3H) , 7.99(s, 2H) , 7.72(t, 세 , IH), 4.56(s, 2H), 4.33(q, J^7.2H, 2H), 1.30(t, 7.2Hz, 3H) 상기 실시예 137과 동일한 방법으로 하기 표 10의 화합물을 제조하였다. 【표 10】 ¾ NMR (400MHz, W &) ~ d 6); δ 11.90 (s, IH), 9.24 (s, IH), 9.02 (s, IH), 8.87 (s, IH), 8.51 (t, J-8.0Hz, 3H), 7.99 (s, 2H), 7.72 (t, three, IH), 4.56 (s, 2H), 4.33 (q, J ^ 7.2H, 2H), 1.30 (t, 7.2Hz, 3H) In the same manner as 137, the compound of Table 10 was prepared. Table 10
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000107_0001
Figure imgf000108_0001
<실시예 147> 5-에틸 1-페닐 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-A] 피리딘 -1,5-디카복실레이트 하이드로클로라이드의 제조 Example 147 Preparation of 5-ethyl 1-phenyl 6-amino-3- (nicotinamido) pyrazolo [3,4-A] pyridine-1,5-dicarboxylate hydrochloride
Figure imgf000109_0001
Figure imgf000109_0001
Figure imgf000109_0002
Figure imgf000109_0002
147  147
단계 1: 5-에틸 1-페닐 6-아미노 -3- (니코틴아미도) 피라졸로 [3， 4->]피리 딘 -1,5-디카복실레이트의 제조  Step 1: Preparation of [3,4->] pyridine-1,5-dicarboxylate with 5-ethyl 1-phenyl 6-amino-3- (nicotinamido) pyrazolo
실시예 37의 단계 7에서 제조한 화합물 (300 mg, 0.55誦 ol)을 에탄올 (7 mi) 에 녹인 후 물 (1.2 ι )과 수산화칼륨 (92.4 mg, 1.65誦 ol)을 첨가 후 80 °C에서 2 시간 동안 교반시킨다. 물 (5 과 에틸아세테이트 (10 )를 첨가하고 물로 추출하 였다. 1 염산으로 산성화시키고 에틸아세테이트로 추출하였다. 소금물로 세척하고 무수 황산나트륨으로 건조 후 여과하여 건조하여 표제 화합물 (251 mg, 반웅수 율 :88¾， 흰색 고체)을 얻었다. The compound prepared in step 7 of Example 37 (300 mg, 0.55 誦 ol) was dissolved in ethanol (7 mi), and then water (1.2 ι) and potassium hydroxide (92.4 mg, 1.65 誦 ol) were added at 80 ° C. Stir for 2 hours. Water (5 and ethyl acetate (10) were added and extracted with water. 1 Acidified with hydrochloric acid and extracted with ethyl acetate. Washed with brine, dried over anhydrous sodium sulfate, filtered and dried to give the title compound (251 mg, semiungsu) : 88¾, white solid).
¾ NMR(400MHz, DMSO-o ; δ 13.69(s, 1H)， 11.58(s, 1H), 10.89(s, 1H), 9.18(s, 2H), 8.77(d, J=3.6Hz, 1H), 8.39(d, J^7.6Hz, 1H), 7.57-7.54(m, 1H) , 7.31(d, J-6.4Hz, 2H), 6.89(d, J-8.0Hz, 2H), 5.45(s, 2H)， 3.70(s, 3H) , 1.51(s, 9H) 단계 2: 5-에틸 1-페닐 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-Z>]피리 딘 -1,5—디카복실레이트 하이드로클로라이드의 제조  ¾ NMR (400MHz, DMSO-o; δ 13.69 (s, 1H), 11.58 (s, 1H), 10.89 (s, 1H), 9.18 (s, 2H), 8.77 (d, J = 3.6Hz, 1H), 8.39 (d, J ^ 7.6 Hz, 1H), 7.57-7.54 (m, 1H), 7.31 (d, J-6.4 Hz, 2H), 6.89 (d, J-8.0 Hz, 2H), 5.45 (s, 2H ), 3.70 (s, 3H), 1.51 (s, 9H) Step 2: 5-ethyl 1-phenyl 6-amino-3- (nicotinamido) pyrazolo [3,4-Z>] pyridine-1, 5—Preparation of Dicarboxylate Hydrochloride
상기 단계 1에서 제조한 화합물 (45 mg, 0.10隱 ol)을 3.7M 염산 (2 ml, 1,4- 디옥산용액)에 녹이고 상은에서 12시간 동안 교반 하였다. 반응종결 후， 반응물을 감압 여과하여 표제 화합물 (34 mg, 반웅수율 :34%， 회색 고체)을 얻었다.  The compound (45 mg, 0.10 mg ol) prepared in step 1 was dissolved in 3.7M hydrochloric acid (2 ml, 1,4-dioxane solution) and stirred for 12 hours at silver. After completion of the reaction, the reaction mixture was filtered under reduced pressure to obtain the title compound (34 mg, semi-water yield: 34%, gray solid).
¾ NMR( 400MHz, DMS으^)； δ 11.84(s, 1H)ᅳ 9.92(s, 1H), 9.17(s, 1H), 8.76(d, J=5.2Hz, 1H) , 8.38(d, J^.6Hz, 1H), 8.33(s, 1H), 7.57-7.54(m, 1H), 7.28(d, J-8.8Hz, 2H), 6.88(d, J=8.4Hz, 2H), 5.46(s; 2H)， 3.70(s, 3H), 2.99(s, 3H), 2.92(s, 3H), 1.44(s, 9H) 상기 실시예 147과 동일한 방법으로 하기 표 11의 화합물을 제조하였다. 【표 11】
Figure imgf000110_0001
¾ NMR (400MHz, DMS); δ 11.84 (s, 1H) ᅳ 9.92 (s, 1H), 9.17 (s, 1H), 8.76 (d, J = 5.2Hz, 1H), 8.38 (d, J ^ .6 Hz, 1H), 8.33 (s, 1H), 7.57-7.54 (m, 1H), 7.28 (d, J-8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.46 (s; 2H), 3.70 (s, 3H), 2.99 (s, 3H), 2.92 (s, 3H), 1.44 (s, 9H) The compounds of Table 11 were prepared in the same manner as in Example 147. Table 11
Figure imgf000110_0001
도) 피라졸로 [3,4 피리딘 -5-카복실레이트 디하이드로클로라이드의 제조 Fig.) Preparation of pyrazolo [3,4 pyridine-5-carboxylate dihydrochloride
Figure imgf000110_0002
Figure imgf000110_0002
단계 1: 에틸 6-아미노 -1— (3— (디메틸아미노)프로필 )-3- (니코틴아미도) 라졸로 [3, 4-b]피리딘 -5-카복실레이트의 제조  Step 1: Preparation of ethyl 6-amino-1 — (3— (dimethylamino) propyl) -3- (nicotinamido) lazolo [3, 4-b] pyridine-5-carboxylate
실시예 37 단계 1에서 제조한 화학식 37A로 표시되는 화합물 (100 mg, 0.31 mmol)을 ^ -디메틸포름아미드 (2 )에 녹인 후, 3ᅳ클로로프로필 (디메틸)아민 (41 mg, 0.34 mmol)과 탄산칼슘 (128 mg, 0.93 瞧 ol)을 천천히 첨가한 후, 70 °C로 5시 간 동안 교반 하였다. 반웅 종결 후， 반웅흔합물에 물과 디클로로메탄을 가하고， 분리한 유기층을 무수 황산마그네슘으로 건조한 후, 용매를 감압 농축하여 에틸아 세테이트로 세척하여 화학식 150A로 표시되는 화합물 (41 mg, 반응수율: 33%, 갈색 고체)을 얻었다. Ή NMR(400MHz, DMSO-^); δ 11.38(s, 1H), 9.16(s, 1H), 8.94(s, 1H),Example 37 The compound represented by Chemical Formula 37A (100 mg, 0.31 mmol) prepared in Step 1 was dissolved in ^ -dimethylformamide (2), and then 3 ᅳ chloropropyl (dimethyl) amine (41 mg, 0.34 mmol) was used. Calcium carbonate (128 mg, 0.93 μl) was added slowly and then stirred at 70 ° C. for 5 hours. After completion of reaction, water and dichloromethane were added to the reaction mixture, and the separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure and washed with ethyl acetate (41 mg, reaction yield). : 33%, brown solid). NMR (400 MHz, DMSO- ^); δ 11.38 (s, 1 H), 9.16 (s, 1 H), 8.94 (s, 1 H),
8.75(d, J=4.4Hz, 1H), 8.36(d, J^8.0Hz, 1H), 7.55(dd, J^.O, 3.9Hz, 3H)ᅳ8.75 (d, J = 4.4 Hz, 1H), 8.36 (d, J ^ 8.0 Hz, 1H), 7.55 (dd, J ^ .O, 3.9 Hz, 3H)
4.29(q, /^7.2Hz, 2H), 4.18(t, J=6.8Hz, 2H), 2.21(t, 7=6.8Hz, 2H), 2.10(s, 6H), 1.91(t, J-6.8Hz, 2H), 1.28(t, J^.8Hz, 3H) 단계 2: 에틸 6-아미노 -l-[3- (디메틸아미노)프로필 ]-3- (니코틴아미도) 피 라졸로 [3,4 - ]피리딘 -5-카복실레이트 디하이드로클로라이드의 제조 4.29 (q, /^7.2 Hz, 2H), 4.18 (t, J = 6.8 Hz, 2H), 2.21 (t, 7 = 6.8 Hz, 2H), 2.10 (s, 6H), 1.91 (t, J-6.8 Hz, 2H), 1.28 (t, J ^ 8 Hz, 3H) Step 2: ethyl 6-amino-l- [3- (dimethylamino) propyl] -3- (nicotinamido) pyrazolo [3,4 Preparation of Pyridine-5-carboxylate Dihydrochloride
상기 1단계에서 제조한 화학식 150A로 표시되는 화합물 (41.0 mg, 0.10瞧 ol) 을 실시예 37의 단계 8의 반웅올 이용하여 화학식 150으로 표시되는 화합물 (22.0 mg, 반웅수율: 46%, 갈색 고체)을 얻었다.  The compound represented by the formula 150 (41.0 mg, 0.10) ol) prepared in step 1 was reacted with the reaction product of Step 8 of Example 37 to give the compound represented by the formula 150 (22.0 mg, semi-water yield: 46%, brown solid. )
¾ NMR(400MHz, DMS0-o ; δ 11.68(s, 1H) , 10.67(br, 1H) , 9.31(s, 1H), 8.99(s, 1H), 8.92(d, J- .0Hz, 1H), 8.70(d, J^7.6Hz, 1H), 7.86(dd, J^A, 4.1Hz, 1H), 4.30(d, J^7.6Hz, 2H), 3.12-3.07(m, 2H), 2.72(s, 3H), 2.7l(s, 3H) , 2.24-2.17(m, 2H)， 1.29(1: , J-5.2Hz, 3H)  ¾ NMR (400 MHz, DMS0-o; δ 11.68 (s, 1H), 10.67 (br, 1H), 9.31 (s, 1H), 8.99 (s, 1H), 8.92 (d, J-0.0 Hz, 1H), 8.70 (d, J ^ 7.6 Hz, 1H), 7.86 (dd, J ^ A, 4.1 Hz, 1H), 4.30 (d, J ^ 7.6 Hz, 2H), 3.12-3.07 (m, 2H), 2.72 (s , 3H), 2.7l (s, 3H), 2.24-2.17 (m, 2H), 1.29 (1:, J-5.2Hz, 3H)
<실시예 151> 6-(4-하이드록시페닐) _1 ^피라졸로 [3 ,4- ]피리딘 -3-아민의 Example 151 of 6- (4-hydroxyphenyl) _1 ^ pyrazolo [3,4-] pyridin-3-amine
Figure imgf000111_0001
Figure imgf000111_0001
in situ  in situ
151A-a 단계 2  151A-a Step 2
Figure imgf000111_0002
Figure imgf000111_0002
151 151A 151A-b 단계 1: 6-(4-메톡시페닐) -2-옥소 -1,2-디히드로피리딘 -3-카보니트릴의 제조 4-메록시아세토페논 (1.0 g, 6.66腿 ol)에 vV, V-디메틸포름아미드 디메틸 아세 탈 (4.4 ιη , 33.30 画 ol)을 상온에서 가한 후， 12시간 동안 환류 교반 하였다. 반웅 종료 후 반응물을 상온으로 넁각하고 감압 농축하였다. 잔류물을 디메틸포름아 미드 (15 ) 녹이고， 시아노아세트아미드 (620 mg, 7.33 圆 ol)와 소듐하이드라이드 (530 mg, 13.32 瞧 ol)를 0 °C에서 차례로 첨가한 후, 100 °C에서 5시간 동안 교반 하였다. 반웅물을 상온으로 넁각하고, 감압 농축하여 과량의 용매를 제거한 후， 잔 류물에 소량의 물을 천천히 첨가하였다. 아세트산으로 산성화 (pH 5.0)한 후， 침전 된 고체를 감압 여과하여 화학식 151A-a로 표시되는 화합물 (1.4 g, 반웅수율: 93%， 노란색 고체)을 얻었다. 151 151A 151A-b Step 1: Preparation of 6- (4-methoxyphenyl) -2-oxo-1,2-dihydropyridine-3-carbonitrile 4-methoxyacetophenone (1.0 g, 6.66 'ol) To vV, V-dimethylformamide dimethyl acetal (4.4 ιη, 33.30 画 ol) was added at room temperature, followed by stirring under reflux for 12 hours. After completion of reaction, the reaction was cooled to room temperature and concentrated under reduced pressure. Dissolve the residue in dimethylformamide (15), add cyanoacetamide (620 mg, 7.33 圆 ol) and sodium hydride (530 mg, 13.32 瞧 ol) in turn at 0 ° C, then at 100 ° C Stir for 5 hours. The reaction product was cooled to room temperature, concentrated under reduced pressure to remove excess solvent, and a small amount of water was slowly added to the residue. After acidification with acetic acid (pH 5.0), the precipitated solid was filtered under reduced pressure to obtain a compound represented by the formula (151A-a) (1.4 g, semi-water yield: 93%, yellow solid).
¾ 醒 (400MHz, CDCls); δ 12.64(br, 1H)， 8.14(d, /-8.0Hz, 1H), 7.80(d, J-8.8Hz, 2H), 7.07(d, J^8.8Hz, 2H), 6.71(br, 1H), 3.82(s, 3H) 단계 2: 2-클로로 -6-(4-메특시페닐)니코티노니트릴의 제조 ¾ Hz (400 MHz, CDCls); δ 12.64 (br, 1H), 8.14 (d, /-8.0 Hz, 1H), 7.80 (d, J-8.8 Hz, 2H), 7.07 (d, J ^ 8.8 Hz, 2H), 6.71 (br, 1H), 3.82 (s, 3H) Step 2: 2-chloro-6- (4-methoxyphenyl) nico Preparation of Tinonitrile
상기 단계 1에서 제조한 화학식 151A-a로 표시되는 화합물 (300 mg, 1.33 mmol)에 염화 포스포릴 (5 )을 상온에서 첨가한 후， 12시간 동안 환류 교반 하였 다. 반응종료 후 반웅물을 상온으로 넁각하고 차가운 얼음물로 반응을 종결하였다. 클로로포름으로 추출 후 소금물로 세척하고， 무수 황산나트륨으로 건조시킨 다음 용매를 감압 농축하였다. 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =4:1) 로 정제하여 화학식 151A-b로 표시되는 화합물 (240 mg, 반웅수율: 74%， 흰색 고체) 을 얻었다.  Phosphoryl chloride (5) was added to the compound represented by Formula 151A-a (300 mg, 1.33 mmol) prepared in Step 1 at room temperature, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction product was cooled to room temperature and the reaction was terminated with cold ice water. After extraction with chloroform, washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (nucleic acid: ethyl acetate = 4: 1) to obtain a compound represented by the general formula (151A-b) (240 mg, semi-water yield: 74%, white solid).
¾ 證 (400MHz, CDCls); δ 8.03(d, J쐰.6Hz, 2H)， 7.96(d, /-8.8Hz, 1H)， 7.70(d, J-8.8Hz, 1H), 7.01(d, J=9.2Hz, 2H), 3.88(s, 3H) 단계 3: 6-(4-메톡시페닐) -1^피라졸로 [3,4-Z>]피리딘— 3-아민의 제조  ¾ Hz (400 MHz, CDCls); δ 8.03 (d, J 쐰 .6 Hz, 2H), 7.96 (d, /-8.8 Hz, 1H), 7.70 (d, J-8.8 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 3.88 (s, 3H) Step 3: Preparation of [3,4-Z>] pyridin— 3-amine with 6- (4-methoxyphenyl) -1 ^ pyrazolo
상기 단계 2에서 제조한 화학식 151A-b로 표시되는 화합물 (30 mg, 0.12 mmol)을 에탄올 (5 )에 녹인 후， 히드라진 수화물 (24 ， 0.49 醒 ol)을 첨가하고 3 일 동안 환류 교반 하였다. 반웅물을 상온으로 넁각하고 감압 농축한 후， 잔류물을 컬럼 크로마토그래피 (디클로로메탄:메탄을 =20:1)로 정제하여 화학식 151A로 표시되 는 화합물 (25 mg, 반웅수율 :85%, 노란색 고체)을 얻었다.  After dissolving the compound represented by Formula 151A-b prepared in step 2 (30 mg, 0.12 mmol) in ethanol (5), hydrazine hydrate (24, 0.49 醒 ol) was added and stirred under reflux for 3 days. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methane = 20: 1) to give the compound represented by the following formula (151A) (25 mg, reaction yield: 85%, yellow) Solid).
¾ NMR( 400MHz, DMSO-cfe)； δ 11.89(s, 1H), 8.12(d, J-8.4Hz, 1H), 8.07(d, J-8.8Hz, 2H), 7.50(d, J-8.0Hz, 1H), 7.04(d, J=8.8Hz, 2H) , 5.55(s, 2H), 3.82(s, 3H) 단계 4: 6-(4-하이드록시페닐) -l^피라졸로 [3,4-Z>]피리딘 -3-아민의 제조 상기 단계 3에서 제조한 화학식 151A로 표시되는 화합물 (18 mg, 0.07 醒 ol) 을 디클로로메탄 (1 과 1M 보론트리브로마이드 디클로로메탄 용액 (0.6 m£)에 녹 이고 상온에서 12시간 동안 교반 하였다. 얼음물로 반웅을 종결시키고 수산화나 트륨 수용액으로 중화한 후, 반웅물을 감압 여과하여 화학식 151로 표시되는 화합 물 (12 mg, 반응수율 :71¾>, 노란색 고체)을 얻었다.  ¾ NMR (400 MHz, DMSO-cfe); δ 11.89 (s, 1H), 8.12 (d, J-8.4 Hz, 1H), 8.07 (d, J-8.8 Hz, 2H), 7.50 (d, J-8.0 Hz , 1H), 7.04 (d, J = 8.8Hz, 2H), 5.55 (s, 2H), 3.82 (s, 3H) Step 4: 6- (4-hydroxyphenyl) -1 ^ pyrazolo [3,4 -Z>] Preparation of Pyridin-3-amine The compound represented by the formula (151A) prepared in Step 3 (18 mg, 0.07 μl) was added to dichloromethane (1 and 1M borontribromide dichloromethane solution (0.6 m £). After dissolution, the reaction mixture was stirred at room temperature for 12 hours.The reaction was terminated with ice water, neutralized with an aqueous solution of sodium hydroxide, and the reaction product was filtered under reduced pressure to give the compound represented by Chemical Formula 151 (12 mg, reaction yield: 71¾>, yellow solid). )
¾ 證 (400MHz, DMS0-c¾)； 6 11.85(s, 1H), 9.76(s, 1H), 8.09(d, 세 ， 1H), 7.95(d, 7=8.8Hz, 2H) , 7.45(d, J-8.8Hz, 1H) , 6.85(d, 7-8.8Hz, 2H), 5.52(s, 2H)  ¾ 證 (400 MHz, DMS0-c¾); 6 11.85 (s, 1H), 9.76 (s, 1H), 8.09 (d, three, 1H), 7.95 (d, 7 = 8.8Hz, 2H), 7.45 (d, J-8.8 Hz, 1H), 6.85 (d, 7-8.8 Hz, 2H), 5.52 (s, 2H)
<실시예 152> 6-(4-메록시페닐) -3- (피를리딘 -1-일) -L 피라졸로 [3,4-b]피리 딘의 제조 Example 152 Preparation of 6- (4-methoxyphenyl) -3- (pyridin-1-yl) -L pyrazolo [3,4-b] pyridine
Figure imgf000113_0001
Figure imgf000113_0001
152 152A 단계 1: l-(4-메톡시벤질) -6-(4-메톡시페닐) -L¥~피라졸로 [3,4-Z>]피리딘 -3-아 민의 제조  152 152A Step 1: Preparation of l- (4-methoxybenzyl) -6- (4-methoxyphenyl) -L-pyrazolo [3,4-Z>] pyridine-3-amine
실시예 151의 단계 2에서 제조한 화학식 151A-a로 표시되는 화합물 (200 mg, 0.82 mmol)을 에탄올 (25 )에 녹인 후， 4-메특시벤질 히드라진 (375 mg, 2.45 mmol)을 첨가하고 12시간 동안 환류 교반 하였다. 상온으로 넁각 한 후, 감압 농축 하고 디클로로메탄으로 추출하였다. 소금물로 세척하고 무수 황산나트륨으로 건조 후 여과하였다. 감압 농축하고 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =3 :2)로 정제하여 화학식 152A-a로 표시되는 화합물 (140 mg, 반응수율: 48%, 노란색 고체)을 얻었다.  Compound (200 mg, 0.82 mmol) represented by Formula 151A-a prepared in step 2 of Example 151 was dissolved in ethanol (25), and 4-methoxybenzyl hydrazine (375 mg, 2.45 mmol) was added thereto. It was stirred at reflux for an hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and extracted with dichloromethane. Washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure and the residue was purified by column chromatography (nucleic acid: ethyl acetate = 3: 2) to obtain a compound represented by the formula (152A-a) (140 mg, reaction yield: 48%, yellow solid).
JH NMR(400MHz, CDC13); δ '8.11(d, 7=8.8Hz, 2Η), 7.87(d, 7=8.4Hz, 1H), 7.42(d, J=8.0Hz, 1H) , 7.32(d, J=8.4Hz, 2H), 7.02(d, J=8.4Hz, 2H)， 6.82(d, J^8.4Hz, 2H), 5.49(s, 2H), 4.06(s, 2H) , 3.88(s, 3H), 3.75(s, 3H) 단계 2: l-(4-메톡시벤질) -6-(4-메톡시페닐) -3- (피를리딘 -1-일) -L 피라졸로 J H NMR (400 MHz, CDC1 3 ); δ ' 8.11 (d, 7 = 8.8 Hz, 2Η), 7.87 (d, 7 = 8.4 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4Hz, 2H), 6.82 (d, J ^ 8.4Hz, 2H), 5.49 (s, 2H), 4.06 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H Step 2: l- (4-methoxybenzyl) -6- (4-methoxyphenyl) -3- (pyridin-1-yl) -L pyrazolo
[3,4-Z> ]피리딘의 제조 Preparation of [3,4-Z>] pyridine
상기 단계 1에서 제조한 화학식 152A-a로-표시되는 화합물 (70 mg, 0.19 mmol)을 -디메틸포름아미드 (5 에 녹인 후에 0 °C로 넁각시키고 소듐하이드라 이드 (31 mg, 0.78 mmol)을 첨가하고 30분간 교반한다. 1,4-디브로모부탄(23//£， 0.19 隱 ol)을 0 °C에서 천천히 첨가하고 90 °C로 가열하여 24시간 동안 교반 하였 다. 얼음물을 가하여 반응을 종결시키고 에틸아세테이트로 추출한 후, 소금물로 세 척하였다. 유기 용매 층을 무수 황산 마그네슘으로 건조 후 여과하고 용매를 감압 농축하였다. 잔류물을 컬럼 크로마토그래피 (핵산：에틸아세테이트 =4:1)로 정제하여 화학식 152A로 표시되는 화합물 (20 mg, 반웅수율: 25%, 노란색 고체)을 얻었다. The compound represented by Chemical Formula 152A-a (70 mg, 0.19 mmol) prepared in Step 1 was dissolved in -dimethylformamide (5), and then stirred at 0 ° C to give sodium hydride (31 mg, 0.78 mmol). was added and the mixture was stirred for 30 minutes C. was slowly added 1,4-dibromobutane (23 // £, 0.19隱ol ) at 0 ° C and stirred for 24 hours then heated to 90 ° C. Ice water was added to the reaction The mixture was extracted with ethyl acetate, washed with brine, the organic solvent layer was dried over anhydrous magnesium sulfate, filtered and the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (nucleic acid: ethyl acetate = 4: 1). Purification gave a compound represented by Formula 152A (20 mg, semi-abundance: 25%, yellow solid).
匿 (400MHz, CDCls); δ 8.09(d, J=8.8Hz, .2H)， 8.03(d, J=8.0Hz, 1H), 7.34(d, J-8.4Hz, 2H) , 7.30(d, J=8.4Hz, 1H), 7.09(d, J-8.4Hz, 2H), 6.80(d, J-8.4Hz, 2H), 5.51(s, 2H), 3.87(s, 3H) , 3.74(s, 3H) , 3.63-3.60(m, 4H) , 2.03-1.99(111， 4H) 단계 3： 6-(4-메톡시페닐) -3- (피를리딘 -1-일 )-L 피라졸로 [3 , 4-b]피리딘의 제조 匿 (400 MHz, CDCls); δ 8.09 (d, J = 8.8Hz ,. 2H), 8.03 (d, J = 8.0Hz, 1H), 7.34 (d, J-8.4Hz, 2H), 7.30 (d, J = 8.4Hz, 1H), 7.09 (d, J-8.4 Hz, 2H), 6.80 (d, J-8.4 Hz, 2H), 5.51 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.63-3.60 (m , 4H), 2.03-1.99 (111, 4H) Step 3: 6- (4-methoxyphenyl) -3- (pyridin-1-yl) -L pyrazolo [3,4-b] pyridine Produce
상기 단계 2에서 제조한 화학식 152A로 표시되는 화합물 (30 mg, 0.08 mmol) 을 트리플루오로아세트산 (5 )에 녹인 후 50 °C에서 1시간 동안 교반 하였다. 상 온으로 넁각 후 얼음물로 반응을 종결시키고 클로로포름으로 추출하였다. 소금물로 세척하고 유기 용매층을 무수 황산나트륨으로 건조시킨 다음 감압 농축하였다. 잔 류물을 컬럼 크로마토그래피 (디클로로메탄:메탄을 =30:1)로 정제하여 화학식 152로 표시되는 화합물 (14 mg, 반응수율: 99%, 노란색 고체)을 얻었다. Compound (30 mg, 0.08 mmol) represented by Chemical Formula 152A prepared in Step 2 was dissolved in trifluoroacetic acid (5), and then stirred at 50 ° C. for 1 hour. After cooling to room temperature, the reaction was terminated with ice water and extracted with chloroform. The organic solvent layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methane = 30: 1) to obtain a compound represented by Chemical Formula 152 (14 mg, reaction yield: 99%, yellow solid).
¾ NMR( 400MHz, CDC13); δ 9.41(br, 1H)， 8.11(d, J-8.0Hz, 1H), 8.01(d, J-9.2Hz, 2H), 7.36(d, J-8.8Hz, 1H) , 7.01(d, 7-8.8Hz, 2H), 3.87(s, 3H) , 3.68-3.65(m, 4H), 2.07-2.04(m, 4H) ¾ NMR (400 MHz, CDC1 3 ); δ 9.41 (br, 1H), 8.11 (d, J-8.0 Hz, 1H), 8.01 (d, J-9.2 Hz, 2H), 7.36 (d, J-8.8 Hz, 1H), 7.01 (d, 7- 8.8 Hz, 2H), 3.87 (s, 3H), 3.68-3.65 (m, 4H), 2.07-2.04 (m, 4H)
<실시예 153> 6-(4-하이드록시페닐) -3- (피를리딘— 1-일) -L 피라졸로 [3,4-Z>] Example 153 6- (4-hydroxyphenyl) -3- (pyridin— 1-yl) -L pyrazolo [3,4-Z>]
Figure imgf000114_0001
Figure imgf000114_0001
152 153  152 153
상기 실시예 152에서 얻은 화학식 152로 표시되는 화합물 (13 mg, 0.04隱 ol) 을 디클로로메탄 (2 과 1M 보론트리브로마이드 디클로로메탄 용액 (0.2 )에 녹 이고 상온에서 12시간 동안 교반 하였다. 얼음물로 반웅을 종결시키고 2 수산화나 트륨 수용액으로 중화한 후, 반웅물을 감압 여과하여 화학식 153으로 표시되는 화 합물 (9 mg, 반웅수율: 76%, 노란색 고체)을 얻었다.  The compound represented by Chemical Formula 152 (13 mg, 0.04 μl) obtained in Example 152 was dissolved in dichloromethane (2 and 1M borontribromide dichloromethane solution (0.2) and stirred at room temperature for 12 hours. The reaction mixture was terminated and neutralized with an aqueous solution of sodium hydroxide, and the reaction product was filtered under reduced pressure to obtain a compound represented by Chemical Formula 153 (9 mg, reaction yield: 76%, yellow solid).
¾ NMR(400MHz, DMS으^)； 5 12.15(s, 1H), 9.79(s, 1H), 8.20(d, J-8.4Hz, 1H), 7.97(d, J=8.0Hz, 2H), 7.43(d, J-8.4Hz, 1H) , 6.87(d, J^.4Hz, 2H), 3.52(ni, 4H), 1.95(m, 4H)  ¾ NMR (400MHz, DMS); 5 12.15 (s, 1H), 9.79 (s, 1H), 8.20 (d, J-8.4Hz, 1H), 7.97 (d, J = 8.0Hz, 2H), 7.43 (d, J-8.4Hz, 1H), 6.87 (d, J ^ .4Hz, 2H), 3.52 (ni, 4H), 1.95 (m, 4H)
<실험예 1>글리코겐 합성효소 키나아제 3b[GSK-3P] 효소 저해 시험 Experimental Example 1 Glycogen Synthase Kinase 3b [GSK-3P] Enzyme Inhibition Test
상기 실시예에서 제조된 화합물들의 GSK-3P 효소 저해 활성은 upstate 사에 서 구입한 재조합 인간 GSK-3P (Cat No. 14-306 )및 인산화된 GSK-3 기질 (GS2, Cat No. 12-241)을 사용하여 제조사의 프로토콜을 참조로 다음과 같이 검정하였다. 실온에서 Corning사의 96 well round bottom plate (Cat No. 3365)에 최종농 도 1% DMS0로 다양한 농도의 실시예의 화합물에 GSK-3P 효소 (lng/well), 6.67uM 포스포-글리코겐 신타제 펩티드 -2 (GS2, YRRMVPPSPSLSRHSSPHQ(pS)EDEEE)를 함유하 는 반응 완층액 (12mM MOPS (pH7.0), ImM DTT, ImM EDTA, lOmM MgCl2] 과 효소 완충 액 (2mM MOPS (pH7.0), O.OlmM EDTA, 0.001% Brij-35, 0.5% glycerol, O.lmg BSA, 0.01% 2-mercaptoethanol] 첨가하여 30 °C에서 10분간 예비 반웅을 시켰다. 10분 후, 0.2uCi(33P_ATP] 및 라벨링 되지 않은 luM ATP를 넣고 30 °C에서 30분 동안 반 응시켰다. 그 후， 플레이트에 3% 인산을 첨가하여 반웅을 종결시켰다. GSK-3I3효 소에 의해 형성된 인산화의 양^ cell harvester (IN0TECH사， 모델명 IH— 110)를 이 용하여 P81 양이온 교환 여과지 (Whatman사, Cat No. 3698-915) 로 전달하고 0.5% 인산으로 4회 세척하고 마지막으로 아세톤으로 세척한 후 Liquid Scintillation counter (Wallac 사， 모델명 1409)에서 3 ml의 신틸레이션 칵테일 (PerkinElmer사， Cat No. 1205-440)로 계수된다. GSK-3P enzyme inhibitory activity of the compounds prepared in the above examples was obtained from recombinant human GSK-3P (Cat No. 14-306) and phosphorylated GSK-3 substrate (GS2, Cat No. 12-241) purchased from Upstate. ) Was assayed as follows with reference to the manufacturer's protocol. GSK-3P enzyme (lng / well), 6.67 uM phospho-glycogen synthase peptide, in various concentrations of Example compounds at a final concentration of 1% DMS0 in Corning's 96 well round bottom plate (Cat No. 3365) at room temperature. Reaction buffer containing 2 (GS2, YRRMVPPSPSLSRHSSPHQ (pS) EDEEE) (12 mM MOPS (pH 7.0), ImM DTT, ImM EDTA, 100 mM MgCl 2 ] and enzyme buffer (2 mM MOPS (pH 7.0), O .OlmM EDTA, 0.001% Brij-35, 0.5% glycerol, O.lmg BSA, 0.01% 2-mercaptoethanol] was preliminarily reacted for 10 minutes at 30 ° C. After 10 minutes, 0.2 uCi ( 33 P_ATP] and labeling Uncoated luM ATP was added and reacted for 30 minutes at 30 ° C. The reaction was then terminated by adding 3% phosphoric acid to the plate Amount of phosphorylation formed by GSK-3I3 enzyme ^ cell harvester (IN0TECH Co., Ltd.) ， Model name IH— 110) 3 ml of scintillation cocktail on a Liquid Scintillation counter (Wallac, Model 1409), then delivered to P81 cation exchange filter paper (Whatman, Cat No. 3698-915), washed four times with 0.5% phosphoric acid and finally with acetone. (PerkinElmer, Cat No. 1205-440).
상기 실시예의 화합물에 대해서 각각의 농도별로 수득된 결과는 3개의 웰에 서 얻어진 평균값이고， 결과 분석은 SigmaPlot 10(Systat Software Inc., USA)을 사용하여 화합물의 IC50 값을 계산하였다. 또한 상기의 방법으로 상용으로 구입할 수 있는 AR-A014418 (Calbiochem사， Cat No. 361549)를 대조물질로 사용하여 비교 실험을 수행하였다. 실험결과를 하기 표 12에 나타내었다 (표에서 AM는 IC50's< 0.1 μΜ, ΑΑ는 IC50's< 0.3μΜ, Α는 IC50's< Ι.ΟμΜ 및 Β는 IC50's>1.0yM을 의미한다). 【표 12] The results obtained at each concentration for the compounds of the above examples are the average values obtained in three wells, and the result analysis was calculated using SigmaPlot 10 (Systat Software Inc., USA) to calculate the IC 50 values of the compounds. In addition, a comparative experiment was performed using AR-A014418 (Calbiochem, Cat No. 361549), which is commercially available by the above method, as a control. The experimental results are shown in Table 12 (wherein AM is IC 50 's <0.1 μΜ, ΑΑ is IC 50 's <0.3 μΜ, Α is IC 50 's <Ι.ΟμΜ and Β is IC 50 's>). 1.0yM). Table 12
GSK-3 GSK-3J3 GSK-3 GSK-3J3
실시예 실시예  EXAMPLE EXAMPLE
효소저해활성 효소저해활성  Enzyme inhibitory activity enzyme inhibitory activity
1 AA 2 B  1 AA 2 B
3 A 4 B  3 A 4 B
5 B 6 B  5 B 6 B
7 B 8 B  7 B 8 B
9 B 10 B  9 B 10 B
11 B 12 B  11 B 12 B
13 B 14 B  13 B 14 B
15 A 16 A  15 A 16 A
17 B 18 B  17 B 18 B
19 B 20 B  19 B 20 B
21 B 22 B  21 B 22 B
23 B 24 B  23 B 24 B
25 B 26 B  25 B 26 B
27 AAA 28 A  27 AAA 28 A
29 AA 30 B  29 AA 30 B
31 AA 32 A  31 AA 32 A
33 A 34 AA  33 A 34 AA
35 B 36 B  35 B 36 B
37 AA 38 AA  37 AA 38 AA
39 B 40 AA  39 B 40 AA
41 AA 42 AA  41 AA 42 AA
43 AA 44 A  43 AA 44 A
45 A 46 AA  45 A 46 AA
47 B 48 B  47 B 48 B
49 A 50 AAA  49 A 50 AAA
51 A 52 AAA  51 A 52 AAA
53 AA 54 AA  53 AA 54 AA
55 A 56 AA  55 A 56 AA
57 AA 58 A  57 AA 58 A
59 A 60 A  59 A 60 A
61 B 62 B  61 B 62 B
63 B 64 AAA  63 B 64 AAA
65 AA 66 AA  65 AA 66 AA
67 AAA 68 A  67 AAA 68 A
69 AA 70 AAA 71 A 72 AAA 69 AA 70 AAA 71 A 72 AAA
73 A 74 A  73 A 74 A
75 B 76 AA  75 B 76 AA
77 B 78 A  77 B 78 A
79 B 80 AA  79 B 80 AA
81 AA 82 A  81 AA 82 A
83 AA 84 B  83 AA 84 B
85 B 86 A  85 B 86 A
87 AA 88 B  87 AA 88 B
89 AA 90 AAA  89 AA 90 AAA
91 AA 92 AA  91 AA 92 AA
93 A 94 A  93 A 94 A
95 B 96 A  95 B 96 A
97 B 98 B  97 B 98 B
99 B 100 B  99 B 100 B
101 A 102 A  101 A 102 A
103 B 104 B  103 B 104 B
105 B 106 AAA  105 B 106 AAA
107 A 108 A  107 A 108 A
109 A 110 AA  109 A 110 AA
111 AAA 112 B  111 AAA 112 B
113 AA 114 A  113 AA 114 A
115 A 116 AA  115 A 116 AA
117 AAA 118 AAA  117 AAA 118 AAA
119 A 120 A  119 A 120 A
121 AAA 122 A  121 AAA 122 A
123 AAA 124 B  123 AAA 124 B
125 A. 126 AAA  125 A. 126 AAA
127 AA 128 AAA  127 AA 128 AAA
129 A 130 A  129 A 130 A
131 B 132 A  131 B 132 A
133 AA 134 A  133 AA 134 A
135 AA 136 B  135 AA 136 B
137 AA 138 AA  137 AA 138 AA
139 AA 140 A  139 AA 140 A
141 B 142 AA  141 B 142 AA
143 A 144 A  143 A 144 A
145 AA 146 A  145 AA 146 A
147 A 148 B  147 A 148 B
149 B 150 B  149 B 150 B
151 B 152 B  151 B 152 B
153 B 상기 표 12에 나타낸 바와 같이， 본 발명에 따른 피라졸로 피리딘 유도체 중 실시예 1, 27, 29, 31, 34， 37, 38， 40， 41-43, 46， 50, 53-57, 64-67, 69， 70, 76, 78， 80， 81, 83, 87, 89-92, 110, 111, 113, 116-118, 121, 123, 126-128, 133, 135, 137-139, 142 및 145의 화합물이 IC50 값이 0.3 μΜ 이하로 나타났고, 그 중 실시예 27, 50, 52, 64, 67, 70, 78， 90, 106, 111, 117, 118, 121， 123， 126 및 128의 화합물의 IC50 값이 0.1 μΜ 이하로 매우 우수한 억제작용이 나타나는 것 으로 확인되었다. 따라서 본 발명의 유도체는 GSK-3JP를 억제함으로써, 치매, 알츠하이머 병, 파킨슨 병， 전두측두 (Frontotemporal) 치매 파킨슨 유형， 괌 (Guam) 파킨슨 치매 복 합증 HIV 치매 또는 신경섬유 얽힘 병리학과 관련된 질환을 예방 또는 치료하는데 유용하게 사용될 수 있다. 153 B As shown in Table 12, Examples 1, 27, 29, 31, 34, 37, 38, 40, 41-43, 46, 50, 53-57, 64 of pyrazolopyridine derivatives according to the present invention. -67, 69, 70, 76, 78, 80, 81, 83, 87, 89-92, 110, 111, 113, 116-118, 121, 123, 126-128, 133, 135, 137-139, 142 And the compound of 145 has an IC 50 value of 0.3 μΜ or less, of which Examples 27, 50, 52, 64, 67, 70, 78, 90, 106, 111, 117, 118, 121, 123, 126 and It was confirmed that the IC 50 value of the compound of 128 was 0.1 μΜ or less, indicating a very good inhibitory effect. Thus, the derivatives of the present invention inhibit GSK-3JP to prevent or prevent dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam's Parkinson's dementia complications, HIV dementia or neurofibrillary pathology. It can be usefully used for treatment.
<실험예 2>세포 -기제 글루코스 생성 억제 분석을사용한 GSK-30 저해 활성 스크리닝 실험 Experimental Example 2 GSK-30 Inhibitory Activity Screening Experiment Using Cell-Based Glucose Production Inhibition Assay
H4IIE(ATCC, CRL154) 세포를 96웰 조직 배양 플레이트에 웰 당 0.1 의 세 포배양 배지 (DMEM 배지 /10%투석된 소 태아 혈청) 중에 100,000 세포 /웰로 파종한 후 37 °C, 5% C02 배양 조건 하에서 3시간 배양하였다. 3시간 후 0.1 의 PBS (인 산염 완충 용수)로 한번 세척하고， 0.1 의 글루코스 생성 배지 (글루코스와 혈청 이 없고， 20 mM 소디움 락테이트와 2 mM 소디움 파이루베이트가 포함된 DMEM 배지) 로 교환한 후 21시간 동안 배양되었다. 다음날， 90 ^의 새로운 글루코스 생성 배 지로 교환하였고, 각각의 농도로 회석된 화합물들은 글루코스 생성배지에 녹여 10 ^씩 첨가한 후, 24시간 동안 배양하였다. 다음날 상등액 10 ^와 ½plex Red 반응 액 (Amplex Red Glucose Assay Kit; Invitrogen) 10 ^를 흔합하여 384웰 플레이트 에서 30분간 실온에서 반응시킨 후 형광값 (Ex 560nm, Em 615nm)을 Wallac EnVision™(PerkinElmer Oy, Turku, Finland)을 이용하여 측정하였다. 이 같은 값은 화합물의 6 가지 상이한 농도 및 DMS0 단독에 대하여 삼중으로 측정되고， 그 값은 그 다음 농도의 로그값에 대하여 그래프로 나타내었다. 글루코스 생성 활성을 DMS0 단독의 50%로 억제시키는 화합물의 농도 (IC50)는 그래프화 된 데이터에 대한 S자형 곡선에 적합화 함으로써 측정되었다. 또한 상기와 방법으로 상용으로 구입할 수 있 는 SB415286 (Sigma사)을 대조물질로 사용하여 비교실험을 수행하였다. 실험결과를 하기 표 13에 나타내었다 (표에서 M는 IC50's<5.0yM, A는 IC50's<10yM 및 B는 IC50's>10yM을 의미한다). 하기 표 13(실험예 2)에 나타난 바와 본 발명의 화합물 들이 우수한 GSK-3P 에 대한 억제작용을 가짐을 확인할 수 있었다. H4IIE (ATCC, CRL154) cells were seeded in 96 well tissue culture plates at 100,000 cells / well in 0.1 cell culture medium (DMEM medium / 10% dialyzed fetal bovine serum) per well at 37 ° C, 5% C0 2 Incubated for 3 hours under the culture conditions. After 3 hours, washed once with 0.1 PBS (phosphate buffered water) and exchanged with 0.1 glucose producing medium (DMEM medium without glucose and serum, containing 20 mM sodium lactate and 2 mM sodium pyruvate). Then incubated for 21 hours. The next day, the cells were exchanged for 90 ^ fresh glucose producing medium, and the compounds diluted at each concentration were dissolved in glucose producing medium, added 10 ^ each, and incubated for 24 hours. Next day, the supernatant 10 ^ and the ½plex Red reaction solution (Amplex Red Glucose Assay Kit; Invitrogen) were mixed and reacted in a 384 well plate for 30 minutes at room temperature, followed by fluorescence (Ex 560 nm, Em 615 nm). , Turku, Finland). These values are measured in triplicates for six different concentrations of compound and DMS0 alone, and the values are graphically plotted against the logarithm of the next concentration. The concentration of compound (IC 50 ) that inhibits glucose producing activity to 50% of DMS0 alone was determined by fitting to the sigmoidal curve for the graphed data. In addition, a comparative experiment was performed using SB415286 (Sigma), which is commercially available as described above, as a control. The experimental results are shown in Table 13 below (where M represents IC 50 's <5.0yM, A represents IC 50 's <10yM and B represents IC 50 's> 10yM). As shown in Table 13 (Experimental Example 2), it was confirmed that the compounds of the present invention had an excellent inhibitory effect on GSK-3P.
【표 13】 Table 13
GSK一 3β GSK-3P GSK 一 3β GSK-3P
실시예 실시예  EXAMPLE EXAMPLE
효소 저해 활성 효소 저해 활성  Enzyme inhibitory activity enzyme inhibitory activity
1 A 16 B  1 A 16 B
27 A 31 B  27 A 31 B
33 A 34 B  33 A 34 B
35 B 36 A .  35 B 36 A.
37 A 39 B  37 A 39 B
40 A 41 AA  40 A 41 AA
44 B 45 B  44 B 45 B
46 A 50 AA  46 A 50 AA
52 B 53 A  52 B 53 A
54 A 57 A  54 A 57 A
59 A 60 AA  59 A 60 AA
61 B 64 A  61 B 64 A
65 B 67 A  65 B 67 A
69 B 70 A  69 B 70 A
73 AA 80 B  73 AA 80 B
81 AA 82 B  81 AA 82 B
84 A 89 B  84 A 89 B
90 AA 92 B  90 AA 92 B
93 AA 94 A  93 AA 94 A
96 B 100 B  96 B 100 B
101 B 102 B  101 B 102 B
103 AA 104 B  103 AA 104 B
107 B 108 B  107 B 108 B
110 B 113 A  110 B 113 A
114 B 115 B  114 B 115 B
116 AA 117 AA  116 AA 117 AA
118 AA 122 B  118 AA 122 B
123 A 126 AA  123 A 126 AA
127 B 128 AA  127 B 128 AA
129 B 135 AA  129 B 135 AA
137 AA 138 AA  137 AA 138 AA
139 AA 140 AA  139 AA 140 AA
141 A 142 A  141 A 142 A
143 AA 144 A .  143 AA 144 A.
145 A 146 A  145 A 146 A
147 A 148 A  147 A 148 A
149 A 150 B  149 A 150 B
153 AA  153 AA
상기 표 13에 나타낸 바와 같이, 본 발명에 따른 피라졸로 피리딘 유도체 중 실시예 37， 40, 41, 50, 60, 73， 81, 90， 93， 103, 116-118, 126, 128， 135， 137-140, 143 및 153의 화합물의 IC50 값이 5.0 μΜ 이하로 매우 우수한 억제작용이 나타나는 것으로 확인되었다. As shown in Table 13, Examples 37, 40, 41, 50, 60, 73, 81, 90, 93, 103, 116-118, 126, 128, 135, 137 of pyrazolopyridine derivatives according to the present invention. It was found that the IC 50 values of the compounds of -140, 143 and 153 showed a very good inhibitory effect of 5.0 μΜ or less.
따라서 본 발명의 유도체는 GSK-3I3를 억제함으로써, 치매， 알츠하이머 병, 파킨슨 병, 전두측두 (Frontotemporal) 치매 파킨슨 유형, 괌 (Guam) 파킨슨 치매 복 합증, HIV 치매 또는 신경섬유 얽힘 병리학과 관련된 질환을 예방 또는 치료하는데 유용하게 사용될 수 있다. 한편， 본 발명에 따른 상기 화학식 1로 표시되는 피라졸로 피리딘 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식Thus, the derivatives of the present invention inhibit GSK-3I3 to prevent diseases associated with dementia, Alzheimer's disease, Parkinson's disease, Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complications, HIV dementia or neurofibrillary pathology. Or may be usefully used for treatment. On the other hand, the pyrazolo pyridine derivative represented by Formula 1 according to the present invention According to the purpose, it can be formulated in various forms. Below is the chemical formula according to the invention
1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다. Some formulation methods in which the compound represented by 1 is included as an active ingredient are illustrated, but the present invention is not limited thereto.
<제제예 1>산제의 제조 Preparation Example 1 Preparation of Powder
화학식 1의 피라졸로 피리딘 유도체 2 g 유당 1 g 상기의 성분을 흔합하고 기밀포에 층진하여 산제를 제조하였다.  2 g of pyrazolopyridine derivatives of formula (1) Lactose 1 g The above components were mixed and layered in an airtight cloth to prepare a powder.
<제제예 2> 정제의 제조 Preparation Example 2 Preparation of Tablet
화학식 1의 피라졸로 피리딘 유도체 100 rag 옥수수전분 100 mg 유당 100 rag 스테아린산 마그네슴 2 rag 상기의 성분을 흔합한 후， 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.  Pyrazolopyridine derivative of Formula 1 100 rag Corn starch 100 mg Lactose 100 rag Magnesium stearate 2 rag After the above components were mixed, tablets were prepared according to a conventional method for preparing tablets.
<제제예 3> 캡슐제의 제조 Preparation Example 3 Preparation of Capsule
화학식 1의 피라졸로 피리딘 유도체 100 rag 옥수수전분 100 rag 유당 100 mg 스테아린산 마그네슘 2 rag 상기의 성분을 흔합한후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 층전하여 캡술제를 제조하였다.  Pyrazolopyridine derivative of Formula 1 100 rag Corn starch 100 rag Lactose 100 mg Magnesium stearate 2 rag After the above components were mixed, the capsule was prepared by layering on gelatin capsules according to a conventional method for preparing capsules.
<제제예 4>주사제의 제조  Preparation Example 4 Preparation of Injection
화학식 1의 피라졸로 피리딘 유도체 100 mg 만니를 180 rag Pyrazolopyridine Derivatives of Formula 1 180 mg rag 100 mg Manni
Na2HP04 · 2 0 26 rag Na 2 HP0 4 · 2 0 26 rag
"δ Γ丁 2974 mg 통상적인 주사제의 제조방법에 따라 7장기 성분 -을 제지된 함량으로 함유시 켜 주사제를 제조하였다. "Δ Γ丁2974 mg according to the method for producing a conventional injection seven long component was prepared on an injection when containing an amount of the paper.

Claims

【청구의 범위】 【청구항 11 하기 화학식 1로 표시되는 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염： [화학식 1] (상기 화학식 1에서, A는 질소 (N) 또는 탄소 (C)이고; R1은 수소; 비치환 또는 아민 및 OR5로 이루어지는 군으로부터 선택되는 1 이 상의 치환기로 치환된 C5-10 아릴; 고리 내 질소 (N) 원자를 1 이상 포함하는 5~L0 원 헤테로아릴; 비치환 또는 -NR6R7 및 — 0H로 이루어지는 군으로부터 선택되는 1 이상 의 치환기로 치환된 d~4 직쇄 또는 측쇄 알킬; -C00R8 또는 -C0R8이고; 이때， 상기 R5는 수소， d-4 직쇄 알킬， 또는 고; R6 및 R7은 각각 수소 또는 Cw 직쇄 또는 측쇄 알킬이고; R8은 수소， N¾, 비치환 또는 NR6R7로 치환된 d-4 직쇄 또는 측쇄 알킬; 5-8 원 헤테로아릴 d-4알킬 또는 C5-10 아릴이고; R2는 수소， NR¾7또는; 비치환또는 1 이상의 OR5로 치환된 C5~10 아릴이고; R3는 수소, 또는 -(C )n-NRbR7이고; 이고; n은 0 내지 15이고 이때, R10은 NR6R7; -(CH2)n-C00R5; -(CH2)n-NR6R7; C5-12아릴; 5~12원 해테로아 릴; 5~L2원 헤테로사이클로알킬이고， -(C¾)n-C5-12아릴 ，- (CH2)n-5~L2원 헤테로아릴ᅳ -(CH2)n-5~L2원 헤테로사이클로알킬; 이때， 상기 아릴， 헤테로아릴 또는 헤테로사이클로알킬은 비치환 또는 직쇄 또는 측쇄 알킬, OR5, NR6R7, -(CH2)n-NR6R7, C00R5, 할로겐， N02, CN, PMB, f 또는 로 이루어지는 군으로부 터 선택되는 하나 이상의 치환기로 치환 가능하고, 상기 헤테로아릴 또는 헤테로사 이클로알킬은 고리내 N또는 0를 1이상 포함한다). 【청구항 2] 제 1항에 있어서, 상기 R1은 수소; 비치환 또는 아민 및 OR5로 이루어지는 군 으로부터 선택되는 1이상의 치환기로 치환된 페닐; 피리딘, -(CH2)n-NR6R7, -(CH2)n-0H( -C00R8 또는 -COR8이고; 이때， 상기 R5는 H, CH3, 이고; 상기 R6 및 R7은 각각 H 또는 c 이고; 상기 R8은 H, NH2l N(CH3)2, 메틸, 에틸 페닐 또는 이고; η은 1 또는 2인 것을 특징으로 하는 피라졸로 피리딘 유도체 및 이의 약학적 으로 허용 가능한 염 . 【청구항 3】 제 1항에 있어서 , 상기 R2는 수소, NH2, NH(CH3) , N(CH3)2 또는; 비치환 또는 OH, 0C¾로 치환된 페닐인 것을 특징으로 하는 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염 . 【청구항 4】 제 1항에 있어서， 상기 R3는 수소， 또는 _(CH2)m-NR6R7이고, 0 때， m은 1 내지 7이고; 또 이고; 이때 , 상기 «은 0 내지 5인 것을 특징으로 하는 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염 . 【청구항 5】 제 1항에 있어서， 상기 R4는 NH2, -NH-(CH2)n-R 또는 이고; 이때 , n은 0 ~ 4이고; 상기 R10은 비치환 또는 메틸， 에틸， 프로필, -OH, -OMe, -NH2l -N02-N(CH3)2> -CH2N(C¾)2, -(CH2)2N(CH3)2, -0(C¾)2N(CH3)2, -COOH, -COOMe, -(CH3)2C00H, -C0NH2) -CN, -F, -CI, -PMB, —SOOOH -S000CH2CH3> -S000(CH2)2CH3, -S000(CH2)5CH3, 또는 로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환된; 페닐， 피리딘， 피페라진, 피페리딘, 이소인돌린, 벤즈0 나프탈렌 i 인 것을 특징으로 하는 피라졸 피리딘 유도체 및 이의 약학적으로 허용 가능한 염. 【청구항 6] ο ο入 / HO—/ 제 1항에 있어서, 상기 R1은 수소， 又/ ᅳ 으로 이루어지는 군으로부터 선택되는 1종이고; ^ΖΖ600/ΐΐΟΖΗΜ/Χ3<Ι ZC6..0/ZT0Z OAV ^ΖΖ600/ΐΐΟΖΗΜ/Χ3<Ι ZC6..0/ZT0Z OAV 로 이루어진 군으로부터 선택되는 1종을 특징으로 하는 피라졸 로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염. 【청구항 7】 제 1항에 있어서， 상기 화학식 1의 유도체는, Claims [Claim 11] Pyrazolo pyridine derivatives represented by the following general formula (1) and pharmaceutically acceptable salts thereof: (In Formula 1, A is nitrogen (N) or carbon (C); R1 is hydrogen; unsubstituted or C5-10 aryl substituted with one or more substituents selected from the group consisting of amines and OR5; 5- to 0-membered heteroaryl containing one or more nitrogen (N) atoms in the ring; unsubstituted or D-4 straight chain or branched alkyl substituted with one or more substituents selected from the group consisting of -NR6R7 and -0H, -C00R8 or -C0R8, wherein R5 is hydrogen, d-4 straight chain alkyl, or high; And R7 is hydrogen or Cw straight or branched alkyl, respectively, R8 is hydrogen, N¾, unsubstituted or d-4 straight or branched chain alkyl substituted with NR6R7; 5-8 membered heteroaryl d-4 alkyl or C5-10 aryl R2 is hydrogen, NR¾7 or unsubstituted or at least one OR5 C5-10 aryl; R3 is hydrogen or-(C) n-NRbR7; and n is 0-15, wherein R10 is NR6R7;-(CH2) n-C00R5;-(CH2) n-NR6R7 C5-12 aryl; 5-12 membered heteroaryl; 5-L2 membered heterocycloalkyl,-(C¾) n-C5-12 aryl,-(CH2) n-5-L2 membered heteroaryl ᅳ-( CH2) n-5 to L2 membered heterocycloalkyl, wherein the aryl, heteroaryl or heterocycloalkyl is unsubstituted or straight or branched chain alkyl, OR5, NR6R7,-(CH2) n-NR6R7, C00R5, halogen, N02, Or one or more substituents selected from the group consisting of CN, PMB, f, or wherein said heteroaryl or heterocycloalkyl contains one or more N or 0 in the ring). 2. The method of claim 1, wherein R 1 is hydrogen; Phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of amines and OR5; Pyridine,-(CH2) n-NR6R7,-(CH2) n-0H (-C00R8 or -COR8; wherein R5 is H, CH3, R6 and R7 are each H or c; and R8 is H, NH 2 N N (CH 3) 2, methyl, ethyl phenyl or η is 1 or 2, and a pyrazolopyridine derivative and a pharmaceutically acceptable salt thereof [Claim 3] The method according to claim 1, wherein R 2 is hydrogen, NH 2, NH (CH 3), N (CH 3) 2 or a pyrazolopyridine derivative and pharmaceutically acceptable salt thereof, which is unsubstituted or substituted with OH, 0C¾. The pyrazolopyridine according to claim 1, wherein R3 is hydrogen or _ (CH2) m-NR6R7, and when 0, m is 1 to 7; and wherein «is 0 to 5. Derivatives and pharmaceutically acceptable salts thereof [Claim 5] The compound of claim 1, wherein R4 is NH2, -NH- (CH2) nR or wherein n is 0 to 4; R10 is unsubstituted or methyl, ethyl, propyl, -OH, -OMe, -NH2l -N02-N (CH3) 2> -CH2N (C¾) 2,-(CH2) 2N (CH3) 2, -0 (C¾) ) 2N (CH3) 2, -COOH, -COOMe,-(CH3) 2C00H, -C0NH2) -CN, -F, -CI, -PMB, —SOOOH -S000CH2CH3> -S000 (CH2) 2CH3, -S000 (CH2 5CH3, or substituted with one or more substituents selected from the group consisting of; Pyrazole pyridine derivatives and pharmaceutically acceptable salts thereof, which are phenyl, pyridine, piperazine, piperidine, isoindolin, benz0 naphthalene i. [Claim 6] ο ο 入 / HO— / The compound according to claim 1, wherein R1 is one selected from the group consisting of hydrogen and 又 / ᅳ; ^ ΖΖ600 / ΐΐΟΖΗΜ / Χ3 <Ι ZC6..0 / ZT0Z OAV ^ ΖΖ600 / ΐΐΟΟΗΜ / Χ3 <Ι ZC6..0 / ZT0Z OAV A pyrazolopyridine derivative characterized by one member selected from the group consisting of OAV and pharmaceuticals thereof Acceptable salts by use. [Claim 7] The method of claim 1, wherein the derivative of Formula 1 is
( 1 ) 3-히드록시 -yV— [ 5- ( 2-히드록시페닐) - 피라졸로 [ 3， 4 피라진 -3-일 ]벤즈 아미드；  (1) 3-hydroxy-yV— [5- (2-hydroxyphenyl) -pyrazolo [3,4 pyrazin-3-yl] benzamide;
(2) 4-니트로 -vV-(5-페닐 -1그피라졸로 [4,3-b]피라진 -3-일)벤즈아미드;  (2) 4-nitro-vV- (5-phenyl-1gpyrazolo [4,3-b] pyrazin-3-yl) benzamide;
(3) V-[5-(4-메특시페닐) 피라졸로 [3,4-b]피라진 -3-일]니코틴아미드 하이 드로클로라이드;  (3) V- [5- (4-methoxyphenyl) pyrazolo [3,4-b] pyrazin-3-yl] nicotinamide hydrochloride;
(4) Λ 5-(4-메톡시페닐) -1^피라졸로 [3,4-b]피라진 -3-일] -4-니트로벤즈아미  (4) Λ 5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] -4-nitrobenzami
( 5 ) 4-플루오로 -Ν- 5- ( 4-메록시페닐 ) 피라졸로 [ 3 , 4 -b]피라진—3-일]벤즈아 미드； (5) 4-fluoro-Ν- 5- (4-methoxyphenyl) pyrazolo [3, 4 -b] pyrazin-3-yl] benzamide;
(6) -[5-(4-메톡시페닐) -1 -피라졸로 [3,4— ]피라진 -3—일]벤즈아미드;  (6)-[5- (4-methoxyphenyl) -1 -pyrazolo [3,4—] pyrazine-3] yl] benzamide;
(7) 4-메록시 -Λ 5-(4-메특시페닐) -1 ^피라졸로 [3 ,4-b]피라진 -3-일]벤즈아미  (7) 4-methoxy-Λ 5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] benzami
(8) ^[5— (4-메록시페닐) -1^피라졸로 [4,3-b]피라진 -3—일]이소니코틴아미드;(8) ^ [5— (4-methoxyphenyl) -1 ^ pyrazolo [4,3-b] pyrazin-3-yl] isonicotinamide;
(9) 3- (디메틸아미노) - [5-(4-메톡시페닐) -1^피라졸로 [3,4— 피라진— 3-일] 프로판아미드 하이드로클로라이드; (9) 3- (dimethylamino)-[5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4—pyrazine- 3-yl] propanamide hydrochloride;
(10) V-[5-(4-메톡시페닐) 피라졸로 [3,4-Ζ?]피라진 -3-일] -4-메틸벤즈아미  (10) V- [5- (4-methoxyphenyl) pyrazolo [3,4-VII?] Pyrazin-3-yl] -4-methylbenzami
(11) 4-시아노 -V-[5-(4 -메록시페닐) -1 -피라졸로 [3，4-/?]피라진 3ᅳ일]벤즈아 미드; (11) 4-cyano-V- [5- (4-methoxyphenyl) -1-pyrazolo [3,4-/?] Pyrazin 3-hexyl] benzamide;
(12) 5- (4-메톡시페닐 ) -1 -피라졸로 [3 , 4 피라진 3-일]테레프탈아미드; (12) 5- (4-methoxyphenyl) -1 -pyrazolo [3,4 pyrazin 3-yl] terephthalamide;
(13) 3-메록시 -ΛΗ 5— (4-메록시페닐) -1^피라졸로 [3, 4-Z?]피라진 -3-일]벤즈아 미드; (13) 3-methoxy-ΛΗ 5— (4-methoxyphenyl) -1 ^ pyrazolo [3,4-Z?] Pyrazin-3-yl] benzamide;
(14) 4- (디메틸아미노) -N-[ 5- ( 4-메톡시페닐 ) 피라졸로 [ 3， 4 - ]피라진 -3- 일]벤즈아미드; (14) 4- (dimethylamino) -N- [5- (4-methoxyphenyl) pyrazolo [3,4--pyrazin-3-yl] benzamide;
(15) Λ 5-페닐 피라졸로 [3,4-?]피라진 -3-일)니코틴아미드 하이드로클로 라이드; (15) Λ 5-phenyl pyrazolo [3,4-?] Pyrazin-3-yl) nicotinamide hydrochloride;
( 16) 7Η:5— (3-히드록시페닐 )-1^피라졸로 [3 피라진 -3-일 ]니코틴아미드 하이드로클로라이드;  (16) 7Η: 5— (3-hydroxyphenyl) -1 ^ pyrazolo [3 pyrazin-3-yl] nicotinamide hydrochloride;
(17) —[5— (4-메톡시페닐) -1^피라졸로 [3,4-Ζ?]피라진 -3-일]벤젠술폰아미드; (17) — [5— (4-methoxyphenyl) -1 ^ pyrazolo [3,4-VII?] Pyrazin-3-yl] benzenesulfonamide;
( 18) Λ45-(4-메톡시페닐 )— 1^피라졸로 [3 , 4-b]피라진 -3-일 ]피페라진 -1-카복 사아미드 하이드로클로라이드; (18) Λ45- (4-methoxyphenyl) —1 ^ pyrazolo [3,4-b] pyrazin-3-yl] piperazin-1-carboxamide hydrochloride;
(19) (4-메톡시페닐 )-L 피라졸로 [3 , 4-Z?]피라진 -3-일] -4-메틸피페라진 -1-카복사아미드 하이드로클로라이드;  (19) (4-methoxyphenyl) -L pyrazolo [3,4-Z?] Pyrazin-3-yl] -4-methylpiperazin-1-carboxamide hydrochloride;
(20) yi 5-{3-[2- (디메틸아미노)에톡시]페닐 }-L 피라졸로 [3,4- ]피라진 -3- 일)니코틴아미드;  (20) yi 5- {3- [2- (dimethylamino) ethoxy] phenyl} -L pyrazolo [3,4-] pyrazin-3-yl) nicotinamide;
(21) 3-시아노 -Λ 5-(4-메록시페닐 )-1^피라졸로 [3，4 ]피라진 -3-일 ]벤즈아 미드;  (21) 3-cyano-Λ 5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4] pyrazin-3-yl] benzamide;
(22) Λ45- ( 4-메톡시페닐) - 1^피라졸로 [ 3， 4 -b]피라진 -3-일] -2-페닐아세트아 미드;  (22) Λ45- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-b] pyrazin-3-yl] -2-phenylacetamide;
(23) 4-히드록시 -V-[5— (4-메특시페닐 )-L7-피라졸로 [3，4- ]피라진— 3ᅳ일 ]벤즈 아미드；  (23) 4-hydroxy-V- [5— (4-methoxyphenyl) -L7-pyrazolo [3,4-] pyrazine- 3xyl] benzamide;
(24) 3-히드록시 - -[5-(4-메록시페닐 )-L7-피라졸로 [3 ,4-A]피라진 -3-일 ]벤즈 아미드;  (24) 3-hydroxy-[5- (4-methoxyphenyl) -L7-pyrazolo [3,4-A] pyrazin-3-yl] benzamide;
(25) 4-히드록시 -Λ45-(4-히드록시페닐) 피라졸로 [3，4- ]피라진 -3-일]벤 즈아미드；  (25) 4-hydroxy-Λ45- (4-hydroxyphenyl) pyrazolo [3,4-] pyrazin-3-yl] benzamide;
(26) 3-히드록시 -V-[5-(4-히드록시페닐 )-1 -피라졸로 [3 , 4- 피라진 -3-일 ]벤 즈아미드；  (26) 3-hydroxy-V- [5- (4-hydroxyphenyl) -1-pyrazolo [3,4-pyrazin-3-yl] benzamide;
(27) -[5- (2-히드록시페닐 )-1 -피라졸로 [3， 4- 피라진 -3-일]니코틴아미드 하이드로클로라이드;  (27)-[5- (2-hydroxyphenyl) -1 -pyrazolo [3,4-pyrazin-3-yl] nicotinamide hydrochloride;
(28) V-[5- (피리딘 -3-일) -1 -피라졸로 [3,4-?]피라진 -3-일]니코틴아미드 디하 이드로클로라이드;  (28) V- [5- (pyridin-3-yl) -1 -pyrazolo [3,4-?] Pyrazin-3-yl] nicotinamide dihydrochloride;
(29) 4—아미노 -Λ 5-(2-히드록시페닐 )-L¾L피라졸로 [3 , 4-b]피라진 -3ᅳ일 ]벤즈 아미드 하이드로클로라이드; (29) 4—amino-Λ 5- (2-hydroxyphenyl) -L¾ L pyrazolo [3,4-b] pyrazin-3xyl] benzamide hydrochloride;
(30) 4-[5-(2-히드록시페닐 )-1^피라졸로 [3 피라진 -3-일카바모일]벤조익 엑시드;  (30) 4- [5- (2-hydroxyphenyl) -1 ^ pyrazolo [3 pyrazin-3-ylcarbamoyl] benzoic acid;
(31) 4-히드록시 -\H5-(2-히드톡시페닐 )-1^피라졸로 [3 ,4-6]피라진 -3-일]벤 즈아미드;  (31) 4-hydroxy- \ H5- (2-hydroxyphenyl) -1 ^ pyrazolo [3,4-6] pyrazin-3-yl] benzamide;
(32) 3-[5-(2-히드록시페닐 )-L 피라졸로 [3 , 4-A]피라진 -3-일카바모일 ]벤조익 엑시드;  (32) 3- [5- (2-hydroxyphenyl) -L pyrazolo [3, 4-A] pyrazine-3-ylcarbamoyl] benzoic acid;
(33) 메틸 3-[5-(2—히드록시페닐) -I 피라졸로 [3，4- 피라진 -3-일카바모일] 벤조에이트;  (33) methyl 3- [5- (2—hydroxyphenyl) -I pyrazolo [3,4-pyrazine-3-ylcarbamoyl] benzoate;
(34) 3-아미노 -7\Η5-(2—히드록시페닐 )-1^피라졸로 [3， 피라진 -3ᅳ일 ]벤즈 아미드 하이드로클로라이드;  (34) 3-amino-7 \ Η5- (2—hydroxyphenyl) -1 ^ pyrazolo [3, pyrazin-3xyl] benzamide hydrochloride;
(35) 소듐 2-[3-(3_옥시도벤즈아미도) -1 -피라졸로 [3，4- 피라진 -5-일]페놀 레이트;  (35) sodium 2- [3- (3_oxydobenzamido) -1-pyrazolo [3,4-pyrazin-5-yl] phenolate;
(36) 7lK5-(2-메특시페닐) -1 -피라졸로 [3，4- ]피라진 3ᅳ일]니코틴아미드 하 이드로클로라이드; (36) 7LK5- (2-Methoxyphenyl) -1-pyrazolo [3,4-] pyrazin 3-hexyl] nicotinamide hydrochloride;
(37) 에틸 6-아미노 -3- (니코틴아미도) 피라졸로 [3, 4-Ζ?]피리딘 -5-카복실레 이트 하이드로클로라이드; (37) ethyl 6-amino-3- (nicotinamido) pyrazolo [3, 4-VII?] Pyridine-5-carboxylate hydrochloride;
(38) 6-아미노 -3- (니코틴아미도) -1 -피라졸로 [3 , 4-Δ]피리진— 5—카복사아미드 하이드로클로라이드;  (38) 6-amino-3- (nicotinamido) -1-pyrazolo [3,4-Δ] pyrazine— 5—carboxamide hydrochloride;
(39) Λ 6-아미노 -5-페닐 피라졸로 [3，4- ]피라진 -3-일)니코틴아미드 하이 드로클로라이드;  (39) Λ 6-amino-5-phenyl pyrazolo [3,4-] pyrazin-3-yl) nicotinamide hydrochloride;
(40) 에틸 6-아미노 _3- (이소니코틴아미도) 피라졸로 [3,4- ]피리딘 -5-카복 실레이트 하이드로클로라이드;  (40) ethyl 6-amino_3- (isonicotinamido) pyrazolo [3,4-] pyridine-5-carboxylate hydrochloride;
(41) '에틸 6-아미노 -3-(3-시아노벤즈아미도) 피라졸로 [3,4-Ζ?]피리딘 -5-카 복실레이트; (41) ' ethyl 6-amino-3- (3-cyanobenzamido) pyrazolo [3,4-VII?] Pyridine-5-carboxylate;
(42) 에틸 6-아미노 -3-(3-카바모일벤즈아미도 피라졸로 [3,4-/?]피리딘-5- 카복실레이트;  (42) ethyl 6-amino-3- (3-carbamoylbenzamido pyrazolo [3,4-/?] Pyridine-5-carboxylate;
(43) 에틸 6-아미노-3-(3-니트로벤즈아미도)-1 -피라졸로[3,4-/?]피리딘-5-카 복실레이트;  (43) ethyl 6-amino-3- (3-nitrobenzamido) -1 -pyrazolo [3,4-/?] Pyridine-5-carboxylate;
(44) 에틸 6-아미노 -3-(3-아미노벤즈아미도) 피라졸로 [3,4-6]피리딘 -5-카 복실레이트 하이드로클로라이드;  (44) ethyl 6-amino-3- (3-aminobenzamido) pyrazolo [3,4-6] pyridine-5-carboxylate hydrochloride;
(45) 에틸 6-아미노 -3_(3-히드록시벤즈아미도 )-1 -피라졸로 [3， 4ᅳ ]피리딘 -5— 카복실레이트;  (45) ethyl 6-amino-3_ (3-hydroxybenzamido) -1-pyrazolo [3,4 ′] pyridine-5—carboxylate;
(46) 에틸 6-아미노 -3- (벤조 [0][1，3]디옥솔 5—카복사아미도)— L7-피라졸로 [3， 4- 피리딘 -5-카복실레이트；  (46) ethyl 6-amino-3- (benzo [0] [1,3] dioxol 5—carboxamido) —L7-pyrazolo [3,4-pyridine-5-carboxylate;
(47) Λ46-아미노 -5- (히드록시메틸 )-1# -피라졸로 [3 , 4-?]피리딘 -3-일]니코틴 아미드 하이드로클로라이드;  (47) Λ46-amino-5- (hydroxymethyl) -1 # -pyrazolo [3,4-?] Pyridin-3-yl] nicotin amide hydrochloride;
(48) 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-b]피리딘 -5-카복실릭 엑시 드 하이드로클로라이드;  (48) 6-amino-3- (nicotinamido) pyrazolo [3,4-b] pyridine-5-carboxylic acid hydrochloride;
(49) 에틸 6-아미노 -3-(1 ^벤조 /]이미다졸 -5-카복사아미도 )-1^피라졸로 [3， 4-ZJ]피리딘 -5-카복실레이트 하이드로클로라이드；  (49) ethyl 6-amino-3- (1 ^ benzo /] imidazole-5-carboxamido) -1 ^ pyrazolo [3,4-ZJ] pyridine-5-carboxylate hydrochloride;
(50) 에틸 6-아미노 -3-(4-메특시벤즈아미도) -ly 피라졸로 [3,4-?]피리딘ᅳ 5-카 복실레이트;  (50) ethyl 6-amino-3- (4-mesoxybenzamido) -ly pyrazolo [3,4-?] Pyridine ᅳ 5-carboxylate;
(51) 에틸 6-아미노 -3— (1 -인돌 -5-카복사아미도 )-1 -피라졸로 [3ᅳ 4-?]피리딘 -5-카복실레이트 하이드로클로라이드;  (51) ethyl 6-amino-3— (l-indole-5-carboxamido) -l-pyrazolo [3′4-?] Pyridine-5-carboxylate hydrochloride;
(52) 에틸 6-아미노 3-(6-클로로니코틴아미도) 피라졸로 [3,4- ]피리딘 -5- 카복실레이트 하이드로클로라이드;  (52) ethyl 6-amino 3- (6-chloronicotinamido) pyrazolo [3,4-] pyridine-5-carboxylate hydrochloride;
(53) 에틸 6-아미노 -3-(3-아미노 -4-메록시벤즈아미도) -1 -피라졸로 [3,4-b]피 리딘 -5-카복실레이트 하이드로클로라이드;  (53) ethyl 6-amino-3- (3-amino-4-methoxybenzamido) -1-pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(54) 에틸 6-아미노 -3-(6-히드록시니코틴아미도) 피라졸로 [3,4- 피리딘 -5-카복실레이트 하이드로클로라이드;  (54) ethyl 6-amino-3- (6-hydroxynicotinamido) pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(55) 에틸 6-아미노 -3-(4-메틸 -3， 4-디히드로 -2가벤조 [b] [1,4]옥사진 -7-카복 사아미도) 피라졸로 [3， 4-?]피리딘 -5-카복실레이트 하이드로클로라이드；  (55) Ethyl 6-amino-3- (4-methyl-3, 4-dihydro-divalent benzo [b] [1,4] oxazine-7-carbox saamido) pyrazolo [3, 4- ?] Pyridine-5-carboxylate hydrochloride;
(56) 에틸 6-아미노 -3-(6-아미노니코틴아미도) -1그피라졸로 [3，4-/?]피리딘 -5- 카복실레이트 하이드로클로라이드;  (56) ethyl 6-amino-3- (6-aminonicotinamido) -1gpyrazolo [3,4-/?] Pyridine-5-carboxylate hydrochloride;
(57) 에틸 6-아미노-3-(4-니트로벤즈아미도)-1 -피라졸로[3,4—6]피리딘-5-카 복실레이트;  (57) ethyl 6-amino-3- (4-nitrobenzamido) -1 -pyrazolo [3,4-6] pyridine-5-carboxylate;
(58) 에틸 6-아미노 -3-(4-아미노벤즈아미도) -1 -피라졸로 [3,4— /?]피리딘 -5-카 복실레이트 하이드로클로라이드; (58) ethyl 6-amino-3- (4-aminobenzamido) -1-pyrazolo [3,4 — /?] Pyridine-5-car Carboxylate hydrochloride;
(59) 에틸 6-아미노 -3-(1-메틸 인돌— 3-카복사아미도 )-1 피라졸로 [3，4- ] 피리딘 -5—카복실레이트;  (59) ethyl 6-amino-3- (1-methyl indole—3-carboxamido) -1 pyrazolo [3,4-] pyridine-5-carboxylate;
(60) 에틸 6-아미노 -3-(4-히드록시벤즈아미도 )-1^피라졸로 [3,4- ]피리딘 -5- 카복실레이트;  (60) ethyl 6-amino-3- (4-hydroxybenzamido) -1 ^ pyrazolo [3,4-] pyridine-5-carboxylate;
(61) 에틸 6- (메틸아미노 )-3- (니코틴아미도) -1 -피라졸로 [3，4- 피리딘—5-카 복실레이트 하이드로클로라이드;  (61) ethyl 6- (methylamino) -3- (nicotinamido) -1-pyrazolo [3,4-pyridine—5-carboxylate hydrochloride;
(62) 에틸 6-아미노 -3-(1，3-디옥소이소인돌린 -2-일) -1 -피라졸로 [3，4- 피리 딘 -5-카복실레이트;  (62) ethyl 6-amino-3- (1,3-dioxoisoindolin-2-yl) -1-pyrazolo [3,4-pyridine-5-carboxylate;
(63) 1-{4- [(디메틸아미노)메틸]페닐 }— 3-[5-(4-메톡시페닐) -1^피라졸로 [4,3-b]피라진 -3-일]우레아 하이드로클로라이드;  (63) 1- {4- [(dimethylamino) methyl] phenyl} — 3- [5- (4-methoxyphenyl) -1 ^ pyrazolo [4,3-b] pyrazin-3-yl] urea hydro Chloride;
(64) 1-(4-메톡시페닐 )-3-[5-(4-메톡시페닐 )-L ~피라졸로 [3 , 4- 피라진 -3- 일]우레아; (64) 1- (4-methoxyphenyl) -3- [5- (4-methoxyphenyl) -L to pyrazolo [3,4-pyrazin-3-yl] urea;
65) 1-(4-플루오로페닐 )-3- [5- (4-메톡시페닐 )-L 피라졸로 [3， 4-b]피라진 -3- 일]우레아;  65) 1- (4-fluorophenyl) -3- [5- (4-methoxyphenyl) -L pyrazolo [3,4-b] pyrazin-3-yl] urea;
(66) 1-[5-(4-메톡시페닐) -L 피라졸로 [3， 4-Z?]피라진 -3-일 ]ᅳ 3— (피리딘 -4-일 ) 우레아;  (66) 1- [5- (4-methoxyphenyl) -L pyrazolo [3,4-Z?] Pyrazin-3-yl] ᅳ 3— (pyridin-4-yl) urea;
(67) 1-(4-시아노페닐 )-3-[5-(4-메톡시페닐 )-1^피라졸로 [4， 3— 피라진 -3- 일]우레아;  (67) 1- (4-cyanophenyl) -3- [5- (4-methoxyphenyl) -1 ^ pyrazolo [4, 3—pyrazin-3- yl] urea;
(68) 1-[5— (4-메특시페닐) 피라졸로 [3ᅳ 4-b]피라진ᅳ 3-일] -3- (피리딘 -3-일) 우레아 하이드로클로라이드;  (68) 1- [5— (4-methoxyphenyl) pyrazolo [3 ′ 4-b] pyrazin-3- 3-yl] -3- (pyridin-3-yl) urea hydrochloride;
(69) 1-(4-메록시페닐) -3-(5-페닐 -1 -피라졸로 [3， 4-b]피라진 -3-일)우레아； (69) 1- (4-methoxyphenyl) -3- (5-phenyl-1 -pyrazolo [3,4-b] pyrazin-3-yl) urea;
(70) 1-(4-시아노페닐) -3- (5-페닐 -L 피라졸로 [3 피라진 -3-일 )우레아；(70) 1- (4-cyanophenyl) -3- (5-phenyl-L pyrazolo [3 pyrazin-3-yl) urea;
. .
(71) 1-(3-시아노페닐) -3-[5-(4—메록시페닐 )-L 피라졸로 [4,3-b]피라진 -3- 일]우레아; (71) 1- (3-cyanophenyl) -3- [5- (4—methoxyphenyl) -L pyrazolo [4,3-b] pyrazin-3-yl] urea;
(72) 1-(4-시아노페닐 )-3-[5-(3-히드록시페닐 )-L 피라졸로 [3， 4- 피라진 -3- 일]우레아;  (72) 1- (4-cyanophenyl) -3- [5- (3-hydroxyphenyl) -L pyrazolo [3,4-pyrazin-3-yl] urea;
(73) 1-[5-(4-메록시페닐) -1 -피라졸로 [3,4-b]피라진 -3-일] -3- (나프탈렌 -1- 일)우레아;  (73) 1- [5- (4-methoxyphenyl) -1-pyrazolo [3,4-b] pyrazin-3-yl] -3- (naphthalen-1-yl) urea;
(74) 1-(4—플루오로페닐 )-3-[5-페닐 피라졸로 [3,4-?]피라진 -3-일]우레아; (74) 1- (4—fluorophenyl) -3- [5-phenyl pyrazolo [3,4-?] Pyrazin-3-yl] urea;
(75) 1-(3-메록시페닐 )ᅳ3-[5-(4-메록시페닐 )-1 -피라졸로 [3， 4ᅳ 6]피라진 -3一 일]우레아; (75) 1- (3-methoxyphenyl) ᅳ 3- [5- (4-methoxyphenyl) -1 -pyrazolo [3, 4 ′ 6] pyrazine-3 one day] urea;
(76) 1-(6-시아노피리딘 -3-일 )-3ᅳ[5-(4-메록시페닐 )-L 피라졸로 [3， 4-/?]피라 진 -3-일]우레아 하이드로클로라이드;  (76) 1- (6-cyanopyridin-3-yl) -3 ᅳ [5- (4-methoxyphenyl) -L pyrazolo [3,4-/?] Pyrazin-3-yl] urea hydro Chloride;
(77) 1-[5-(4-메톡시페닐) -1 -피라졸로 [3，4- 피라진— 3-일] -3— (3-니트로페 닐)우레아;  (77) 1- [5- (4-methoxyphenyl) -1-pyrazolo [3,4-pyrazin— 3-yl] -3— (3-nitrophenyl) urea;
(78) 1-[5-(4-메톡시페닐)-1^피라졸로[3,4-6]피라진-3-일]—3-(피리딘-2-일 메틸)우레아 하이드로클로라이드;  (78) 1- [5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4-6] pyrazin-3-yl] —3- (pyridin-2-yl methyl) urea hydrochloride;
(79) 메틸 3-(3-{3-[3-(4-시아노페닐)우레이도] -1^피라졸로 [3,4- ]피라진 -5-일 }페녹시 )프로파노에이트；  (79) methyl 3- (3- {3- [3- (4-cyanophenyl) ureido] -1 ^ pyrazolo [3,4-] pyrazin-5-yl} phenoxy) propanoate;
(80) 1-(6-시아노피리딘 -3-일 )-3-[5-(3-히드록시페닐 )-1^피라졸로 [4 ,3-b]피 라진 -3-일]우레아;  (80) 1- (6-cyanopyridin-3-yl) -3- [5- (3-hydroxyphenyl) -1 ^ pyrazolo [4,3-b] pyrazin-3-yl] urea;
(81) 1-(4-히드록시페닐 )-3-[5-(4-메록시페닐 )-L 피라졸로 [3， 4-/?]피라진 -3- 일]우레아; (81) 1- (4-hydroxyphenyl) -3- [5- (4-hydroxyphenyl) -L pyrazolo [3, 4-/?] Pyrazine-3- Urea;
(82) 1-[5-(4-메톡시페닐 )-L 피라졸로 [4,3— ]피라진 -3-일] -3- (피페리딘 -4- 일)우레아 하이드로클로라이드;  (82) 1- [5- (4-methoxyphenyl) -L pyrazolo [4,3—] pyrazin-3-yl] -3- (piperidin-4-yl) urea hydrochloride;
(83) 1-(6-시아노피리딘 -3-일 )-3-[5-(4-히드록시페닐 피라졸로 [3 , 4-Ζ)]피 라진 -3-일]우레아 하이드로클로라이드;  (83) 1- (6-cyanopyridin-3-yl) -3- [5- (4-hydroxyphenyl pyrazolo [3,4-VII)] pyrazin-3-yl] urea hydrochloride;
(84) 1-[5-(4-메록시페닐 )-1 -피라졸로 [3ᅳ 4-/?]피라진 -3-일] _3_(2—메틸이소인 돌린 -4-일)우레아 하이드로클로라이드;  (84) 1- [5- (4-Methoxyphenyl) -1 -pyrazolo [3 ′ 4-/?] Pyrazin-3-yl] _3_ (2—methylisoin doolin-4-yl) urea hydrochloride ;
(85) 1-[2-(4—메록시벤질)이소인돌린 -4-일] -3_[5-(4-메특시페닐) -1 -피라졸 로 [3, 4-b]피라진 -3-일]우레아 하이드로클로라이드;  (85) 1- [2- (4—Methoxybenzyl) isoindolin-4-yl] -3_ [5- (4-methoxyphenyl) -1-pyrazolo [3,4-b] pyrazine 3-yl] urea hydrochloride;
(86) 1-[5-(4-메록시페닐) -1^피라졸로 [3,4— 피라진 -3-일] -3-(1-메틸피페리 딘 -4-일)우레아 하이드로클로라이드;  (86) 1- [5- (4-methoxyphenyl) -1 ^ pyrazolo [3,4—pyrazin-3-yl] -3- (1-methylpiperidin-4-yl) urea hydrochloride;
(87) 1-[5-(4-아미노페닐 )-1 -피라졸로 [3 ,4-b]피라진 -3-일] -3-(4-플루오로페 닐)우레아;  (87) 1- [5- (4-aminophenyl) -1 -pyrazolo [3,4-b] pyrazin-3-yl] -3- (4-fluorophenyl) urea;
(88) 소듐 4-{3_[5-(4-메록시페닐; 피라졸로 [3,4-b]피라진 -3-일]우레이 도}벤조에이트;  (88) sodium 4- {3_ [5- (4-methoxyphenyl) pyrazolo [3,4-b] pyrazin-3-yl] ureido dobenzoate;
(89) 1-[5-(4-아미노페닐 )-L7-피라졸로 [3 , 4-Z>]피라진— 3-일 ] -3_(4-메록시페 닐 )우레아;  (89) 1- [5- (4-aminophenyl) -L7-pyrazolo [3, 4-Z>] pyrazin— 3-yl] -3_ (4-methoxyphenyl) urea;
(90) 1-(4-히드록시페닐 )-3- [5-(4-히드록시페닐 )-1^피라졸로 [3， 4 - ^피라진 -3-일]우레아;  (90) 1- (4-hydroxyphenyl) -3- [5- (4-hydroxyphenyl) -1 ^ pyrazolo [3, 4- ^ pyrazin-3-yl] urea;
(91) 1-(4-히드톡시페닐)-3-[5-(2-히드록시페닐)-1 -피라졸로[3，4- 피라진 -3-일]우레아;  (91) 1- (4-hydroxymethoxyphenyl) -3- [5- (2-hydroxyphenyl) -1 -pyrazolo [3,4-pyrazin-3-yl] urea;
(92) 1-(4-히드록시페닐 )_3-[5- (피리딘 -3—일 )-1 -피라졸로 [3， 4— /]피라진 -3- 일]우레아 하이드로클로라이드;  (92) 1- (4-hydroxyphenyl) _3- [5- (pyridin-3-yl) -1 -pyrazolo [3, 4 — /] pyrazin-3- yl] urea hydrochloride;
(93) 에틸 6-아미노 -3— [3-(4-메특시페닐)우레이도]ᅳ 1^피라졸로 [3，4- 피리 딘 -5-카복실레이트;  (93) ethyl 6-amino-3— [3- (4-methoxyphenyl) ureido] # 1 ^ pyrazolo [3,4-pyridine-5-carboxylate;
(94) 에틸 6-아미노 -3-[3-(4-히드록시페닐)우레이도)] -1^피라졸로 [3ᅳ4- 피 리딘 -5-카복실레이트;  (94) ethyl 6-amino-3- [3- (4-hydroxyphenyl) ureido)]-1 ^ pyrazolo [3′4-pyridine-5-carboxylate;
(95) 4-[3-(5-{3-[2— (디메틸아미노)에특시]페닐 }-L 피라졸로 [3,4- 피라진 -3-일)우레이도]벤즈아미드 하이드로클로라이드；  (95) 4- [3- (5- {3- [2— (dimethylamino) -specific] phenyl} -L pyrazolo [3,4-pyrazin-3-yl) ureido] benzamide hydrochloride;
(96) 2-{3- [4- (피리딘 -4-일)부틸아미노] 피라졸로 [3 , 4 -b]피라진 -5-일 }페 놀 하이드로클로라이드;  (96) 2- {3- [4- (pyridin-4-yl) butylamino] pyrazolo [3,4-b] pyrazin-5-yl} phenol hydrochloride;
(97) ^벤질 -5-(4-메톡시페닐) -L 피라졸로 [3，4- 피라진 -3-아민;  (97) ^ benzyl-5 (4-methoxyphenyl) -L pyrazolo [3,4-pyrazine-3-amine;
(98) 5-(4-메록시페닐 )-Λ 피리딘 -3-일메틸 )-L 피라졸로 [3 ,4-b]피라진 -3-아 민 하이드로클로라이드;  (98) 5- (4-methoxyphenyl) -Λ pyridin-3-ylmethyl) -L pyrazolo [3,4-b] pyrazine-3-aminemine chloride;
(99) 5-(4-메록시페닐 ) -yV- (피리딘 -4-일메틸 )-1 -피라졸로 [3， 4- 피라진 -3-아 민 하이드로클로라이드;  (99) 5- (4-methoxyphenyl) -yV- (pyridin-4-ylmethyl) -1 -pyrazolo [3, 4-pyrazine-3-aminemine chloride;
(100) 에틸 6-아미노 -3- (피리딘 -3-일메틸아미노 )-1 ―피라졸로 [3, 4-6]피리딘 -5-카복실레이트 하이드로클로라이드;  (100) ethyl 6-amino-3- (pyridin-3-ylmethylamino) -1 -pyrazolo [3, 4-6] pyridine-5-carboxylate hydrochloride;
(101) 2-{3-[3_ (피리딘 -4-일)프로필아미노 ]-1 -피라졸로 [3,4-b]피라진 -5_일} 페놀 하이드로클로라이드;  (101) 2- {3- [3_ (pyridin-4-yl) propylamino] -1 -pyrazolo [3,4-b] pyrazin-5_yl} phenol hydrochloride;
(102) 2-[3- (피리딘 -3-일메틸아미노 )-L¾L피라졸로 [3,4-A]피라진 -5-일]페놀 하이드로클로라이드;  (102) 2- [3- (pyridin-3-ylmethylamino) -L¾Lpyrazolo [3,4-A] pyrazin-5-yl] phenol hydrochloride;
(103) 2- [3- (벤질아미노) -L 피라졸로 [3 , 4-b]피라진 -5-일 ]페놀; (103) 2- [3- (benzylamino) -L pyrazolo [3, 4-b] pyrazin-5-yl] phenol;
(104) 2— [3- (시클로펜틸아미노)—I 피라졸로 [3,4-b]피라진 -5-일]페놀; (104) 2— [3- (cyclopentylamino) —I pyrazolo [3,4-b] pyrazin-5-yl] phenol;
( 105) ~{6-아미노— 5- [(디메틸아미노)메틸] 피라졸로 [3 , 4-/?]피리딘 -3-일 } 니코틴아미드 디하이드로클로라이드; (105) - {6-amino- 5- [(dimethylamino) methyl] pyrazolo [3, 4-/?] Pyridin-3-yl} nicotinamide dihydrochloride;
(106) 피리딘 -3-일메틸 6-아미노 -3-(4-메록시벤즈아미도) -1^피라졸로 [3 , 4- 피리딘 -5-카복실레이트 하이드로클로라이드；  (106) pyridin-3-ylmethyl 6-amino-3- (4-methoxybenzamido) -1 ^ pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(107) 페닐 6-아미노 -3- (니코틴아미도) 피라졸로 [3,4-b]피리딘 -5—카복실 레이트 하이드로클로라이드;  (107) phenyl 6-amino-3- (nicotinamido) pyrazolo [3,4-b] pyridine-5—carboxylate hydrochloride;
(108) 3- (디메틸아미노)프로필 6-아미노 -3-(4-메록시벤즈아미도) -L 피라졸 로 [3 , 4-Z?]피리딘 -5-카복실레이트 하이드로클로라이드；  (108) 3- (dimethylamino) propyl 6-amino-3- (4-methoxybenzamido) -L pyrazole low [3,4-Z?] Pyridine-5-carboxylate hydrochloride;
(109) 메틸 6-아미노 -3- (니코틴아미도) -1 ―피라졸로 [3， 4- 피리딘 -5-카복실 레이트 하이드로클로라이드;  (109) methyl 6-amino-3- (nicotinamido) -1 -pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(110) 피리딘 -3-일메틸 6-아미노 -3- (니코틴아미도) -1^피라졸로 [3,4— />]피리 딘 -5-카복실레이트 디하이드로클로라이드;  (110) pyridin-3-ylmethyl 6-amino-3- (nicotinamido) -1 ^ pyrazolo [3,4 — />] pyridine-5-carboxylate dihydrochloride;
(111) 피리딘 -3-일메틸 6-아미노 -3— (4-니트로벤즈아미도)—1 ―피라졸로 [3， 4-b]피리딘 -5-카복실레이트 하이드로클로라이드；  (111) pyridin-3-ylmethyl 6-amino-3— (4-nitrobenzamido) -1-pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
( 112) 6-아미노-씨디메틸 -3- (니코틴아미도) 피라졸로 [3 , 4 -b]피리딘ᅳ 5- 카복사아미드 하이드로클로라이드;  (112) 6-amino-cidimethyl-3- (nicotinamido) pyrazolo [3, 4-b] pyridine® 5-carboxamide hydrochloride;
(113) 에틸 6-아미노 -3-{4-[2- (디메틸아미노)에틸]벤즈아미도 }— 1 -피라졸로 [3， 4-b]피리딘 -5-카복실레이트 하이드로클로라이드；  (113) ethyl 6-amino-3- {4- [2- (dimethylamino) ethyl] benzamido} —1-pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(114) 에틸 6-아미노 -3-[3- (디메틸아미노)프로판아미도 ]-1 -피라졸로 [3，4- ] 피리딘 -5-카복실레이트 하이드로클로라이드;  (114) ethyl 6-amino-3- [3- (dimethylamino) propaneamido] -1 -pyrazolo [3,4-] pyridine-5-carboxylate hydrochloride;
(115) 에틸 6-아미노-3-(3-모폴리노프로판아미도)-1그피라졸로[3，4- ]피리딘 -5-카복실레이트 하이드로클로라이드;  (115) ethyl 6-amino-3- (3-morpholinopropaneamido) -1gpyrazolo [3,4-] pyridine-5-carboxylate hydrochloride;
(116) 에틸 6-아미노 -3-{4- [(디메틸아미노)메틸]벤즈아미도 }— 피라졸로 [3,4-6]피리딘 -5-카복실레이트 하이드로클로라이드；  (116) ethyl 6-amino-3- {4-[(dimethylamino) methyl] benzamido} —pyrazolo [3,4-6] pyridine-5-carboxylate hydrochloride;
(117) 에틸 6-아미노 -3ᅳ {4- (모폴리노메틸)벤즈아미도] -1가피라졸로 [3,4-6]피 리딘 -5-카복실레이트 하이드로클로라이드;  (117) ethyl 6-amino-3 ′ {4- (morpholinomethyl) benzamido] -1gapyrazolo [3,4-6] pyridine-5-carboxylate hydrochloride;
(118) 에틸 6-아미노 -3-[4-(2-모폴리노에틸)벤즈아미도] 피라졸로 [3，4- 피리딘 -5-카복실레이트 하이드로클로라이드;  (118) ethyl 6-amino-3- [4- (2-morpholinoethyl) benzamido] pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
(119) 에틸 6-아미노 -3-{3-[3- (디메틸아미노)프로판아미도]벤즈아미도 }_1 ᅳ 피라졸로 [3， 4-b]피리딘— 5-카복실레이트 하이드로클로라이드；  (119) ethyl 6-amino-3- {3- [3- (dimethylamino) propaneamido] benzamido} _1 ′ pyrazolo [3, 4-b] pyridine—5-carboxylate hydrochloride;
(120) 에틸 6-아미노 -3-[3-(3-모폴리노프로판아미도)벤즈아미도] -1 -피라졸 로 [3， 4- ]피리딘 -5-카복실레이트 하이드로클로라이드；  (120) ethyl 6-amino-3- [3- (3-morpholinopropaneamido) benzamido] -1 -pyrazolo [3,4-] pyridine-5-carboxylate hydrochloride;
(121) 피리딘 -3-일메틸 6-아미노 -3— [4- (피리딘 -3-일메록시)벤즈아미도] -L 피라졸로 [3 , -b]피리딘 -5-카복실레이트 디하이드로클로라이드；  (121) pyridin-3-ylmethyl 6-amino-3— [4- (pyridin-3-ylmethoxy) benzamido] -L pyrazolo [3, -b] pyridine-5-carboxylate dihydrochloride;
(122) 에틸 6-아미노 -3-{4-[2- (디메틸아미노)에특시]벤즈아미도 피라졸 로 [3， 4- 피리딘 -5—카복실레이트 하이드로클로라이드；  (122) ethyl 6-amino-3- {4- [2- (dimethylamino) special]] benzamido pyrazole lo [3,4-pyridine-5—carboxylate hydrochloride;
(123) 에틸 6-아미노 -3-[4- (피리딘 -3-일메록시)벤즈아미도] L¥-피라졸로 [3 ,4-?]피리딘 -5-카복실레이트 하이드로클로라이드;  (123) ethyl 6-amino-3- [4- (pyridin-3-ylmethoxy) benzamido] L-pyrazolo [3,4-?] Pyridine-5-carboxylate hydrochloride;
(124) 에틸 6-아미노 -3— {6-[2— (디메틸아미노)에톡시]니코틴아미도 피라 졸로 [3,4-b]피리딘ᅳ 5-카복실레이트 디하이드로클로라이드;  (124) ethyl 6-amino-3— {6- [2— (dimethylamino) ethoxy] nicotinamido pyrazolo [3,4-b] pyridine ᅳ 5-carboxylate dihydrochloride;
(125) 에틸 6-아미노 -3-[6- (피리딘 -3-일메톡시)니코틴아미도 ]-1 ^피라졸로 [3， 4-Z>]피리딘 -5-카복실레이트 디하이드로클로라이드； (125) ethyl 6-amino-3- [6- (pyridin-3-ylmethoxy) nicotinamido] -1 ^ pyrazolo [3,4-Z>] pyridine-5-carboxylate dihydrochloride;
(126) 에틸 6-아미노 -3- [4-(2-모폴리노에록시)벤즈아미도] -1 -피라졸로 [3,4-b]피리딘 -5-카복실레이트 하이드로클로라이드； (126) ethyl 6-amino-3- [4- (2-morpholinoethoxy) benzamido] -1-pyrazolo [3,4-b] pyridine-5-carboxylate hydrochloride;
(127) 에틸 6-아미노 -3-[4- (니코티노일옥시)벤즈아미도 ]-1 -피라졸로 [3,4-?] 피리딘 -5-카복실레이트 하이드로클로라이드;  (127) ethyl 6-amino-3- [4- (nicotinoyloxy) benzamido] -1 -pyrazolo [3,4-?] Pyridine-5-carboxylate hydrochloride;
(128) 에틸 6-아미노 -3-{4-[2- (피리딘 -4-일)에톡시]벤즈아미도 }— 1 -피라졸로 [3，4- 피리딘 -5-카복실레이트 하이드로클로라이드;  (128) ethyl 6-amino-3- {4- [2- (pyridin-4-yl) ethoxy] benzamido} — 1-pyrazolo [3,4-pyridine-5-carboxylate hydrochloride;
( 129) Λ46-아미노 -5- (4-메톡시페닐 피라졸로 [3 ,4 -b]피라진 -3-일] -2- (4- 메록시페닐) - 2-옥소아세트아미드;  (129) Λ46-amino-5- (4-methoxyphenyl pyrazolo [3,4-b] pyrazin-3-yl] -2- (4-methoxyphenyl) -2-oxoacetamide;
(130) 2-(4-아미노페닐 ) -ΛΗ5-(4-메특시페닐 )-1 -피라졸로 [3,4 -Α]피라진 -3- 일] -2-옥소아세트아미드 하이드로클로라이드;  (130) 2- (4-aminophenyl) -ΛΗ5- (4-methoxyphenyl) -1 -pyrazolo [3,4-Α] pyrazin-3-yl] -2-oxoacetamide hydrochloride;
(131) 에틸 6-아미노 -3-[2-(4-메톡시페닐) -2-옥소아세트아미도] -1 -피라졸로 [3 , 4— /?]피리딘 -5-카복실레이트；  (131) ethyl 6-amino-3- [2- (4-methoxyphenyl) -2-oxoacetamido] -1 -pyrazolo [3, 4 — /?] Pyridine-5-carboxylate;
(132) 에틸 6-아미노 -3-[3- (핵실옥시술포닐)벤즈아미도]— 1 -피라졸로 [3,4-Z?] 피리딘 -5-카복실레이트;  (132) ethyl 6-amino-3- [3- (nuxyloxysulfonyl) benzamido] — 1-pyrazolo [3,4-Z?] Pyridine-5-carboxylate;
( 133) 3- [6-아미노 -5— (에톡시카보닐 피라졸로 [3， 4-b]피리딘 -3-일카바모 일]벤젠술포닉 엑시드;  (133) 3- [6-amino-5— (ethoxycarbonyl pyrazolo [3, 4-b] pyridin-3-ylcarbamo yl] benzenesulfonic acid;
(134) 에틸 6-아미노 -3-[3- (에톡시술포닐)벤즈아미도 꾀라졸로 [3,4— b]피 리딘 -5-카복실레이트;  (134) ethyl 6-amino-3- [3- (ethoxysulfonyl) benzamido zarazolo [3,4—b] pyridine-5-carboxylate;
(135) 에틸 6-아미노 -3-[3- (프로폭시술포닐)벤즈아미도] 피라졸로 [3,4-Δ] 피리딘 -5-카복실레이트;  (135) ethyl 6-amino-3- [3- (propoxysulfonyl) benzamido] pyrazolo [3,4-Δ] pyridine-5-carboxylate;
(136) 소듐 3-{3-[5-(4-메록시페닐) 피라졸로 [3,4-Ζ>]피라진 -3-일]우레이 도}프로파노에이트;  (136) sodium 3- {3- [5- (4-methoxyphenyl) pyrazolo [3,4-VII>] pyrazin-3-yl] urei do} propanoate;
(137) 에틸 6-아미노 -1-(2-아미노아세틸 )-3- (니코틴아미도) -1 -피라졸로 [3， 4-?]피리딘 -5-카복실레이트 디하이드로클로라이드；  (137) ethyl 6-amino-1- (2-aminoacetyl) -3- (nicotinamido) -1-pyrazolo [3,4-?] Pyridine-5-carboxylate dihydrochloride;
(138) 에틸 6-아미노 -1-(2-아미노 -3-메틸부타노일 )-3- (니코틴아미도) -1 -피 라졸로 [3， 4-b]피리딘 -5-카복실레이트 디하이드로클로라이드；  (138) ethyl 6-amino-1- (2-amino-3-methylbutanoyl) -3- (nicotinamido) -1-pyrazolo [3,4-b] pyridine-5-carboxylate dihydro Chloride;
(139) 에틸 6-아미노 -1-[2- (메틸아미노)아세틸 ]-3- (니코틴아미도 피라졸 로 [3， 피리딘 -5-카복실레이트 디하이드로클로라이드；  (139) ethyl 6-amino-1- [2- (methylamino) acetyl] -3- (nicotinamido pyrazole [3, pyridine-5-carboxylate dihydrochloride;
(140) 에틸 6-아미노 -1ᅳ (2-모폴리노아세틸)— 3- (니코틴아미도) 피라졸로 [3， 4 -Z?]피리딘 -5-카복실레이트 디하이드로클로라이드;  (140) ethyl 6-amino-1 ′ (2-morpholinoacetyl) —3- (nicotinamido) pyrazolo [3,4-Z?] Pyridine-5-carboxylate dihydrochloride;
(141) 에틸 6-아미노 -l-[2-( 특시카보닐아미노)아세틸 ]-3- (니코틴아미 도) 피라졸로 [3， 4- 피리딘 -5-카복실레이트；  (141) ethyl 6-amino-1-[2- (specialcarbonylamino) acetyl] -3- (nicotinamido) pyrazolo [3,4-pyridine-5-carboxylate;
(142) 에틸 6-아미노 -1-[2-(2-아미노아세트아미도)아세틸 ]-3- (니코틴아미 도) 피라졸로 [3 , 4-/?]피리딘— 5-카복실레이트 디하이드로클로라이드；  (142) ethyl 6-amino-1- [2- (2-aminoacetamido) acetyl] -3- (nicotinamido) pyrazolo [3, 4-/?] Pyridine— 5-carboxylate dihydrochloride ;
(143) 에틸 1-(2-아세트아미도아세틸 )-6-아미노 -3- (니코틴아미도) 피라졸 로 [3， 4-Z?]피리딘 -5-카복실레이트 하이드로클로라이드;  (143) ethyl 1- (2-acetamidoacetyl) -6-amino-3- (nicotinamido) pyrazolo [3, 4-Z?] Pyridine-5-carboxylate hydrochloride;
(144) 에틸 6-아미노 -3- (니코틴아미도) -1-{2-[(2,2,2-트리클로로에록시)카보 닐아미노]아세틸 피라졸로 [3 ,4-b]피리딘 -5—카복실레이트；  (144) ethyl 6-amino-3- (nicotinamido) -1- {2-[(2,2,2-trichloroethoxy) carbonylamino] acetyl pyrazolo [3,4-b] pyridine 5—carboxylate;
(145) 에틸 6-아미노 -1-(2, 6-디아미노핵사노일) -3- (니코틴아미도) -1 -피라졸 로 [3， 4-b]피리딘 -5-카복실레이트 트리하이드로클로라이드；  (145) ethyl 6-amino-1- (2, 6-diaminonucleoanoyl) -3- (nicotinamido) -1-pyrazolo [3,4-b] pyridine-5-carboxylate trihydrochloride ;
(146) 에틸 6-아미노 -1-(3-아미노프로파노일) -3- (니코틴아미도) 피라졸로 [3 , 4- 피리딘 -5-카복실레이트 디하이드로클로라이드；  (146) ethyl 6-amino-1- (3-aminopropanoyl) -3- (nicotinamido) pyrazolo [3,4-pyridine-5-carboxylate dihydrochloride;
(147) 5—에틸 1-페닐 6-아미노 -3- (니코틴아미도)— 1 ^피라졸로 [3，4ᅳ 피리딘 -1,5-디카복실레이트 하이드로클로라이드; (147) 5—Ethyl 1-phenyl 6-amino-3- (nicotinamido) — 1 ^ pyrazolo [3，4′pyridine -1,5-dicarboxylate hydrochloride;
148) 디에틸 6-아미노 -3- (니코틴아미도) -L7-피라졸로 [3,4-b]피리딘 -1,5-디카 복실레이트 하이드로클로라이드;  148) diethyl 6-amino-3- (nicotinamido) -L7-pyrazolo [3,4-b] pyridine-1,5-dicarboxylate hydrochloride;
(149) 에틸 5-(2-히드록시페닐 )-3- (니코틴아미도) -1 -피라졸로 [3，4- 피라진 -1-카복실레이트;  (149) ethyl 5- (2-hydroxyphenyl) -3- (nicotinamido) -1-pyrazolo [3,4-pyrazine-1-carboxylate;
(150) 에틸 6-아미노 -1-[3- (디메틸아미노)프로필 ]-3- (니코틴아미도) 피라 졸로 [3， 4-Z?]피리딘 -5-카복실레이트 디하이드로클로라이드；  (150) ethyl 6-amino-1- [3- (dimethylamino) propyl] -3- (nicotinamido) pyrazolo [3, 4-Z?] Pyridine-5-carboxylate dihydrochloride;
( 151) 6-(4-히드톡시페닐 )-L 피라졸로 [3 ,4-b]피리딘 -3-아민；  (151) 6- (4-hydroxythoxyphenyl) -L pyrazolo [3,4-b] pyridin-3-amine;
(152) 6-(4-메록시페닐) -3- (피를리딘 -1-일) -1^피라졸로 [3ᅳ 4->]피리딘; 및 (152) 6- (4-methoxyphenyl) -3- (pyridin-1-yl) -1 ^ pyrazolo [3 ′ 4->] pyridine; And
(153) 6-(4-히드록시페닐) -3- (피를리딘 -1-일 )-L 피라졸로 [3， 4-ώ]피리딘으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 피라졸로 피리딘 유도체 및 이의 약학적으로 허용 가능한 염 . (153) Pyrazolo pyridine derivatives, characterized in that it is selected from the group consisting of 6- (4-hydroxyphenyl) -3- (pyridin-1-yl) -L pyrazolo [3,4-ώ] pyridine And pharmaceutically acceptable salts thereof.
【청구항 8】 [Claim 8]
하기 반웅식 1에 나타낸 바와 같이, 화학식 2로 표시되는 케톤 화합물을 산 화시켜 화학식 3으로 표시되는 화합물을 얻는 단계 (단계 1);  As shown in the following reaction formula 1, the step of oxidizing the ketone compound represented by the formula (2) to obtain a compound represented by the formula (3) (step 1);
상기 단계 1에서 제조된 화학식 3으로 표시되는 화합물을 탈수반응을 수행하 여 화학식 4로 표시되는 화합물을 얻는 단계 (단계 2);  Dehydrating the compound represented by Chemical Formula 3 prepared in Step 1 to obtain a compound represented by Chemical Formula 4 (step 2);
상기 단계 2에서 제조된 화학식 4로 표시되는 화합물을 2-아미노말로노니트 릴과 축합반응을 수행하여 화학식 5로 표시되는 화합물을 얻는 단계 (단계 3); 상기 단계 3에서 제조된 화학식 5로 표시되는 화합물을 삼염화인과 환원반응 시켜 화학식 6으로 표시되는 화합물을 얻는 단계 (단계 4);  Performing a condensation reaction of the compound represented by Chemical Formula 4 prepared in Step 2 with 2-aminomalononitrile to obtain a compound represented by Chemical Formula 5 (step 3); Reducing the compound represented by Chemical Formula 5 prepared in Step 3 with phosphorus trichloride to obtain a compound represented by Chemical Formula 6 (step 4);
상기 단계 4에서 제조된 화학식 6으로 표시되는 화합물을 샌드마이어 (sandmeyer)반응을 수행하여 화학식 7로 표시되는 화합물을 얻는 단계 (단계 5); 상기 단계 5에서 제조된 화학식 7로 표시되는 화합물을 보호기로 보호된 히 드라진 수화물과 고리화반웅을 수행하여 화학식 8로 표시되는 화합물을 얻는 단계 (단계 6);  Performing a sandmeyer reaction on the compound represented by Chemical Formula 6 prepared in Step 4 to obtain a compound represented by Chemical Formula 7 (step 5); Performing a cyclization reaction with a hydrazine hydrate protected with a protecting group, the compound represented by Chemical Formula 7 prepared in Step 5 to obtain a compound represented by Chemical Formula 8 (step 6);
화학식 8로 표시되는 화합물을 화학식 9로 표시되는 각각의 화합물과 반응을 수행하여 화학식 10으로 표시되는 화합물을 얻는 단계 (단계 7); 및  Reacting the compound represented by Formula 8 with each compound represented by Formula 9 to obtain a compound represented by Formula 10 (step 7); And
상기 화학식 10으로 표시되는 화합물의 보호기를 제거하는 반웅을 수행하여 화학식 la로 표시되는 화합물을 얻는 단계 (단계 8)를 포함하는 것을 특징으로 하는 피라졸로 피리딘 유도체의 제조방법:  Method of preparing a pyrazolo pyridine derivative comprising the step (step 8) of performing a reaction to remove the protecting group of the compound represented by the formula (10) to obtain a compound represented by the formula la:
[반웅식 1]
Figure imgf000135_0001
[Banungsik 1]
Figure imgf000135_0001
단계 4  Step 4
O O
ci 1 c ci 1 c
Figure imgf000135_0002
Figure imgf000135_0002
단계 7  Step 7
Figure imgf000135_0003
Figure imgf000135_0003
10 1a  10 1a
(상기 반웅식 1에서 A, R5, R10은 제 1항의 화학식 1에서 정의한 바와 같고， P는 보호기로써 , 벤질옥시카보닐기 (Cbz), t—부록시카보닐기 (t-Boc), p—메록시벤질 기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). (In the reaction formula 1, A, R 5 , R 10 are the same as defined in Formula 1 of claim 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t—buoxycarbonyl group (t-Boc), p —Methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
【청구항 9】 [Claim 9]
하기 반웅식 2에 나타낸 바와 같이， 화학식 11로 표시되는 시아노아세테이트 화합물에 에틸클로로포르메이트를 첨가하여 화학식 12로 표시되는 화합물을 얻는 단계 (단계 1)；  As shown in the following reaction formula 2, adding ethylchloroformate to the cyanoacetate compound represented by the formula (11) to obtain a compound represented by the formula (12) (step 1);
상기 단계 1에서 제조된 화학식 12로 표시되는 화합물을 메틸화 반웅을 수행 하여 화학식 13으로 표시되는 화합물을 얻는 단계 (단계 2);  Performing a methylation reaction on the compound represented by Chemical Formula 12 prepared in Step 1 to obtain a compound represented by Chemical Formula 13 (step 2);
상기 단계 2에서 제조된 화학식 13으로 표시되는 화합물을 2-시아노아세트아 미드와 축합 반응시켜 화학식 14로 표시되는 화합물을 얻는 단계 (단계 3);  Condensing the compound represented by Chemical Formula 13 prepared in Step 2 with 2-cyanoacetamide to obtain a compound represented by Chemical Formula 14 (step 3);
상기 단계 3에서 제조된 화학식 14로 표시되는 화합물에 할로겐화반응을 수 행하여 화학식 15로 표시되는 화합물을 얻는 단계 (단계 4);  Performing a halogenation reaction on the compound represented by Chemical Formula 14 prepared in Step 3 to obtain a compound represented by Chemical Formula 15 (step 4);
상기 단계 4에서 제조된 화학식 15로 표시되는 화합물을 보호기로 보호된 히 드라진 수화물과 고리화반웅을 수행하여 화학식 16으로 표시되는 화합물을 얻는 단 계 (단계 5);  Performing a cyclization reaction with the hydrazine hydrate protected with a protecting group with the compound represented by Chemical Formula 15 prepared in Step 4 to obtain a compound represented by Chemical Formula 16 (step 5);
상기 단계 5에서 제조된 화학식 16으로 표시되는 화합물과 화학식 9로 표시 되는 화합물을 반응시켜 화학식 17로 표시되는 화합물을 얻는 단계 (단계 6); 및  Reacting the compound represented by Formula 16 prepared in Step 5 with the compound represented by Formula 9 to obtain a compound represented by Formula 17 (step 6); And
상기 단계 6에서 제조된 화학식 17로 표시되는 화합물의 보호기를 제거하는 반웅을 수행하여 화학식 lb로 표시되는 화합물을 얻는 단계 (단계 7)을 포함하는 것 을 특징으로 하는 피라졸로 피리딘 유도체의 제조방법: Comprising the step of removing the protecting group of the compound represented by the formula (17) prepared in step 6 to obtain a compound represented by the formula (lb) (step 7) Method for producing a pyrazolo pyridine derivative characterized in that:
[반응식 2]  Scheme 2
Figure imgf000136_0001
Figure imgf000136_0001
1b  1b
(상기 반웅식 2에서 A, R1, R5는 제 1항의 화학식 1에서 정의한 바와 같고， P 는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (tᅳ Boc), p—메톡시벤질기 (PMB) 또는 9—플루오렌일메특시카보닐기 (Fmoc)이다). (In the reaction formula 2, A, R 1 , R 5 are as defined in Formula 1 of claim 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (tc Boc), p —Methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc).
【청구항 10】 [Claim 10]
하기 반웅식 3에 나타낸 바와 같이， 화학식 a로 표시되는 화합물은 트리포스 젠올 이용하여 화학식 a'로 표시되는 화합물을 얻는 단계 (단계 A);  As shown in the following reaction formula 3, the compound represented by the formula (a) is obtained by obtaining a compound represented by the formula (a ') using Trifoss genol (step A);
화학식 8 또는 16으로 표시되는 화합물을 상기 반응식 A에서 제조된 화학식 a'로 표시되는 화합물과 반웅을 수행하여 화학식 18로 표시되는 화합물을 얻는 단 계 (단계 1)； 및  Reacting the compound represented by Chemical Formula 8 or 16 with the compound represented by Chemical Formula a ′ prepared in Scheme A to obtain a compound represented by Chemical Formula 18 (step 1); and
상기 화학식 18로 표시되는 화합물의 보호기를 제거하는 반응을 수행하여 화 학식 lc로 표시되는 화합물을 얻는 단계 (단계 2)를 포함하는 것을 특징으로 하는 피라졸로 피리딘 유도체의 제조방법:  A method for preparing a pyrazolo pyridine derivative, comprising the step (step 2) of obtaining a compound represented by Chemical Formula lc by performing a reaction of removing the protecting group of the compound represented by Chemical Formula 18:
[반웅식 3] H2N-R10 [Banungsik 3] H 2 NR 10
Figure imgf000137_0001
Figure imgf000137_0001
(상기 반웅식 3에서 A, R1, R2 및 R10은 제 1항의 화학식 1에서 정의한 바와 같고， P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), p-메톡 시벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). (A, R 1 , R 2 and R 10 in the above formula 3 are as defined in Formula 1 of claim 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc ), p-methoxy cibenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
【청구항 111 [Claim 111]
하기 반웅식 4에 나타낸 바와 같이 , 상기 반응식 2에서 제조된 화학식 15로 표시되는 화합물에 보호기를 도입하여 화학식 19로 표시되는 화합물을 얻는 단계 (단계 1);  As shown in the following reaction formula 4, a step of obtaining a compound represented by the formula (19) by introducing a protecting group to the compound represented by the formula (15) prepared in Scheme 2 (step 1);
상기 단계 1에서 제조된 화학식 19로 표시되는 화합물을 보호기로 보호된 히 드라진 수화물과 고리화반웅을 수행하여 화학식 20으로 표시되는 화합물을 얻는 단 계 (단계 2);  Performing a cyclization reaction with the hydrazine hydrate protected with a protecting group, the compound represented by Chemical Formula 19 prepared in Step 1 to obtain a compound represented by Chemical Formula 20 (step 2);
상기 단계 2에서 제조된 화학식 20으로 표시되는 화합물을 화학식 21로 표시 되는 알데하이드 화합물과 환원성 아미노 반웅을 수행하여 화학식 22로 표시되는 화합물을 얻는 단계 (단계 3); 및  Obtaining a compound represented by Chemical Formula 22 by performing a reducing amino reaction with the aldehyde compound represented by Chemical Formula 21 and the compound represented by Chemical Formula 20 prepared in Step 2 (Step 3); And
상기 단계 3에서 제조된 화학식 22로 표시되는 화합물의 보호기를 제거하는 반웅을 수행하여 화학식 Id로 표시되는 화합물을 얻는 단계 (단계 4)를 포함하는 것 을 특징으로 하는 피라졸로 피리딘 유도체의 제조방법:  Method of preparing a pyrazolo pyridine derivative comprising the step (step 4) of performing a reaction to remove the protecting group of the compound represented by formula 22 prepared in step 3 to obtain a compound represented by formula (Id):
[반응식 4]  Scheme 4
Figure imgf000137_0002
Figure imgf000137_0002
(상기 반응식 4에서 A 및 R1은 제 1항의 화학식 1에서 정의한 바와 같고， R10'은 피리딘， 벤질 및 시클로펜탄으로 이루어지는 군으로부터 선택되고， P는 보호 기로써， 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), p-메록시벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다). (A and R 1 in Scheme 4 are as defined in Formula 1 of claim 1, R 10 ' is selected from the group consisting of pyridine, benzyl and cyclopentane, P is protection Group is benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
【청구항 12】 [Claim 12]
하기 반웅식 5에 나타낸 바와 같이， 화학식 17로 표시되는 화합물을 환원 반 응을 수행하여 화학식 23으로 표시되는 화합물올 얻는 단계 (단계 1);  As shown in the following reaction formula 5, a step of obtaining a compound represented by the formula (23) by performing a reduction reaction on the compound represented by the formula (17) (step 1);
상기 단계 1에서 제조된 화학식 23으로 표시되는 화합물을 산화 반웅을 수행 하여 화학식 24로 표시되는 화합물을 얻는 단계 (단계 2);  Performing a reaction reaction on the compound represented by Chemical Formula 23 prepared in Step 1 to obtain a compound represented by Chemical Formula 24 (step 2);
상기 단계 2에서 제조된 화학식 24로 표시되는 화합물을 환원성 아미노화 반 웅을 수행하여 화학식 25로 표시되는 화합물을 얻는 단계 (단계 3); 및  Performing a reductive amination reaction on the compound represented by Chemical Formula 24 prepared in Step 2 to obtain a compound represented by Chemical Formula 25 (step 3); And
상기 단계 3에서 제조된 화학식 25로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 le로 표시되는 화합물을 얻는 단계 (단계 4)를 포함하는 것을 특징으 로 하는 피라졸로 피리딘 유도체의 제조방법: Method of preparing a pyrazolo pyridine derivative, comprising the step (step 4) of performing a deprotection reaction of the compound represented by Formula 25 prepared in step 3 to obtain a compound represented by Formula l e :
[반웅식 5]  [Bungungsik 5]
Figure imgf000138_0001
Figure imgf000138_0001
1e 25  1e 25
(상기 반응식 5에서 R6ᅳ R7 및 R10은 제 1항의 화학식 1에서 정의한 바와 같 고， R5'는 H, 에틸 (CH2)3N(CH3)2, 를루엔 및 벤젠으로 이루어진 군으로부터 선택되 고, P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), p-메록시 벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다). (In Reaction Scheme 5, R 6 ᅳ R 7 and R 10 are as defined in Formula 1 of claim 1, R 5 ' is composed of H, ethyl (CH 2 ) 3 N (CH 3 ) 2 , toluene and benzene P is selected from the group, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p- methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group ( Fmoc).
【청구항 13】 [Claim 13]
하기 반웅식 6에 나타낸 바와 같이ᅳ 화학식 15로 표시되는 화합물에 보호기 를 도입하여 화학식 26으로 표시되는 화합물을 얻는 단계 (단계 1);  As shown in the following reaction formula 6 to obtain a compound represented by the formula (26) by introducing a protecting group to the compound represented by the formula (15) (step 1);
상기 단계 1에서 제조된 화학식 26으로 표시되는 화합물을 보호기로 보호된 히드라진 수화물과 고리화반웅을 수행하여 화학식 27로 표시되는 화합물을 얻는 단 계 (단계 2);  Performing a cyclization reaction with the hydrazine hydrate protected with a protecting group by the compound represented by Chemical Formula 26 prepared in Step 1 to obtain a compound represented by Chemical Formula 27 (step 2);
상기 단계 2에서 제조된 화학식 27로 표시되는 화합물과 화학식 9로 표시되 는 화합물을 반웅시켜 화학식 28로 표시되는 화합물을 얻는 단계 (단계 3);  Reacting the compound represented by Chemical Formula 27 and the compound represented by Chemical Formula 9 prepared in Step 2 to obtain a compound represented by Chemical Formula 28 (step 3);
상기 단계 3에서 제조된 화학식 28로 표시되는 화합물을 가수분해하여 화학 식 29로 표시되는 화합물을 얻는 단계 (단계 4); Hydrolysis of the compound represented by Formula 28 prepared in step 3 Obtaining the compound represented by formula 29 (step 4);
상기 단계 4에서 제조된 화학식 29로 표시되는 화합물을 알코올과 커플링 반 웅 (coupling reaction)을 수행하여 화학식 30으로 표시되는 화합물을 얻는 단계 (단 계 5); 및  Performing a coupling reaction with the compound represented by Chemical Formula 29 prepared in Step 4 with alcohol to obtain a compound represented by Chemical Formula 30 (step 5); And
상기 단계 5에서 제조된 화학식 30으로 표시되는 화합물을 탈보호화 반응을 수행하여 화학식 if로 표시되는 화합물을 얻는 단계 (단계 6)를 포함하는 것을 특징 으로 하는 피라졸로 피리딘 유도체의 제조방법:  Method for preparing a pyrazolo pyridine derivative, comprising the step (step 6) of performing a deprotection reaction of the compound represented by formula 30 prepared in step 5 to obtain a compound represented by formula if:
[반응식 6]  Scheme 6
Figure imgf000139_0001
Figure imgf000139_0001
Figure imgf000139_0002
Figure imgf000139_0002
1f  1f
(상기 반응식 6에서 A 및 R10은 제 1항의 화학식 1에서 정의한 바와 같고， R5'는 H, 에틸， (CH2)3N(C¾)2, 를루엔 및 벤젠으로 이루어진 군으로부터 선택되고, P 는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), p—메톡시벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다) . - (A and R 10 in Scheme 6 are as defined in Formula 1 of claim 1, R 5 ' is selected from the group consisting of H, ethyl, (CH 2 ) 3 N (C¾) 2 , toluene and benzene, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc). -
【청구항 14】 [Claim 14]
하기 반응식 7에 나타낸 바와 같이， 화학식 29로 표시되는 화합물과 아민 화 합물을 커플링 반웅을 수행하여 화학식 31로 표시되는 화합물을 얻는 단계 (단계 1)； 및  As shown in Scheme 7 below, the step of performing a coupling reaction between the compound represented by the formula (29) and the amine compound to obtain the compound represented by the formula (31); and
상기 단계 1에서 제조된 화학식 31로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lg로 표시되는 화합물을 얻는 단계 (단계 2)를 포함하는 것을 특징으 로 하는 피라졸로 피리딘 유도체의 제조방법:  A method for preparing a pyrazolo pyridine derivative, comprising the step (step 2) of performing a deprotection reaction of the compound represented by Chemical Formula 31 prepared in step 1 to obtain a compound represented by Chemical Formula lg:
[반웅식 7]
Figure imgf000140_0001
[Bungungsik 7]
Figure imgf000140_0001
29 31 ig 29 31 ig
(상기 반웅식 7에서 R6, R7 및 R10은 제 1항의 화학식 1에서 정의한 바와 같 고, P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), p—메록시 벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다). (In the above formula 7, R 6 , R 7 and R 10 are as defined in Formula 1 of claim 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc) , p—methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
【청구항 15】 [Claim 15]
하기 반웅식 8에 나타낸 바와 같이 , 화학식 16으로 표시되는 화합물과 화학 식 32로 표시되는 화합물을 반웅시켜 화학식 33으로 표시되는 화합물을 얻는 단계 (단계 1);  As shown in Reaction Formula 8 below, reacting the compound represented by Chemical Formula 16 and the compound represented by Chemical Formula 32 to obtain a compound represented by Chemical Formula 33 (step 1);
상기 단계 1에서 제조된 화학식 33으로 표시되는 화합물과 아민 화합물을 N- 알킬화 반웅을 수행하여 화학식 34로 표시되는 화합물을 얻는 단계 (단계 2); 및 상기 단계 2에서 제조된 화학식 34로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lh로 표시되는 화합물을 얻는 단계 (단계 3)를 포함하는 것을.특징으 로 하는 피라졸로 피리딘 유도체의 제조방법:  Performing a N-alkylation reaction of the compound represented by Formula 33 and the amine compound prepared in Step 1 to obtain a compound represented by Formula 34 (step 2); And deprotecting the compound represented by Chemical Formula 34 prepared in Step 2 to obtain a compound represented by Chemical Formula lh (Step 3). A method of preparing a pyrazolo pyridine derivative, characterized in that:
[반웅식 8]  [Banungsik 8]
Figure imgf000140_0002
Figure imgf000140_0002
(상기 반응식 8에서 A, R6, 및 R7은 제 1항의 화학식 1에서 정의한 바와 같 고， R5'는 H, 에틸， (CH2)3N(CH3)2, 를루엔 및 벤젠으로 이루어진 군으로부터 선택되 고, P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), P-메록시 벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). (In Scheme 8, A, R 6 , and R 7 are as defined in Formula 1 of claim 1, R 5 ′ is H, ethyl, (CH 2 ) 3 N (CH 3 ) 2 , toluene and benzene. P is a protecting group, and benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), P-methoxy benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
【청구항 16] [Claim 16]
하기 반응식 9에 나타낸 바와 같이， 화학식 27로 표시되는 화합물과 화학식 35로 표시되는 화합물을 반웅시켜 화학식 36으로 표시되는 화합물올 얻는 단계 (단 계 1); As shown in Scheme 9, the compound represented by Formula 27 and Formula Reacting the compound represented by 35 to obtain a compound represented by Chemical Formula 36 (step 1);
상기 단계 1에서 제조된 화학식 36으로 표시되는 화합물과 화학식 37로 표시 되는 화합물을 반웅시켜 화학식 38로 표시되는 화합물을 얻는 단계 (단계 2);  Reacting the compound represented by Chemical Formula 36 and the compound represented by Chemical Formula 37 prepared in Step 1 to obtain a compound represented by Chemical Formula 38 (step 2);
상기 단계 2에서 제조된 화학식 38로 표시되는 화합물과 아민 화합물을 반웅 시켜 화학식 39로 표시되는 화합물을 얻는 단계 (단계 3); 및  Reacting the compound represented by Formula 38 and the amine compound prepared in Step 2 to obtain a compound represented by Formula 39 (step 3); And
상기 단계 3에서 제조된 화학식 39로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 li로 표시되는 화합물을 얻는 단계 (단계 4)를 포함하는 것을 특징으 로 하는 피라졸로 피리딘 유도체의 제조방법:  Method of preparing a pyrazolo pyridine derivative comprising the step (step 4) of performing a deprotection reaction of the compound represented by formula 39 prepared in step 3 to obtain a compound represented by formula li:
[반웅식 9]  [Banungsik 9]
Figure imgf000141_0001
Figure imgf000141_0001
1i  1i
(상기 반응식 9에서 A, R6 ， R7 및 n은 제 1항의 화학식 1에서 정의한 바와 같고， R5'는 H, 에틸ᅳ (CH2)3N(CH3)2, 틀루엔 및 벤젠으로 이루어진 군으로부터 선택 되고， P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), p-메톡 시벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)아다). (In Scheme 9, A, R 6 , R 7 and n are as defined in Formula 1 of claim 1, and R 5 ′ is H, ethyl ᅳ (CH 2 ) 3 N (CH 3 ) 2 , toluene and benzene. P is a protecting group, and benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxy thibenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group ( Fmoc)
【청구항 17] [Claim 17]
하기 반응식 10에 나타낸 바와 같이 , 화학식 40으로 표시되는 화합물에 산을 첨가하여 화학식 41로 표시되는 화합물을 얻는 단계 (단계 1);  As shown in Scheme 10, adding an acid to the compound represented by the formula (40) to obtain a compound represented by the formula (41) (step 1);
상기 단계 1에서 제조된 화학식 41로 표시되는 화합물과 화학식 42로 표시되 는 화합물을 0-알킬화 반응을 수행하여 화학식 43으로 표시되는 화합물을 얻는 단 계 (단계 2); Compound represented by Formula 41 prepared in Step 1 and represented by Formula 42 Performing a 0-alkylation reaction of the compound to obtain a compound represented by the formula (43) (step 2);
상기 단계 2에서 제조된 화학식 43으로 표시되는 화합물을 가수분해하여 화. 학식 44로 표시되는 화합물을 얻는 단계 (단계 3);  Hydrolysis of the compound represented by the formula (43) prepared in step 2 above. Obtaining a compound represented by Formula 44 (step 3);
상기 단계 3에서 제조된 화학식 44로 표시되는 화합물과 화학식 20으로 표시 되는 화합물을 반응시켜 화학식 45로 표시되는 화합물을 얻는 단계 (단계 4); 및  Reacting the compound represented by Chemical Formula 44 prepared in Step 3 with the compound represented by Chemical Formula 20 to obtain a compound represented by Chemical Formula 45 (step 4); And
상기 단계 4에서 제조된 화학식 45로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lj로 표시되는 화합물을 얻는 단계 (단계 5)를 포함하는 것올 특징으 로 하는 피라졸로 피리딘 유도체의 제조방법:  Method for preparing a pyrazolo pyridine derivative, characterized in that it comprises a step (step 5) to obtain a compound represented by the formula (lj) by performing a deprotection reaction of the compound represented by formula 45 prepared in step 4:
[반응식 10]  Scheme 10
Figure imgf000142_0001
Figure imgf000142_0001
1j  1j
(상기 반웅식 10에서 R1, R10 및 n은 제 1항의 화학식 1에서 정의한 바와 같 고， R5'는 메틸기이고， R10'은 피리딘 또는 몰폴린이고， P는 보호기로써， 벤질옥시카 보닐기 (Cbz), t-부록시카보닐기 (t-Boc), p-메록시벤질기 (PMB) 또는 9—플루오렌일메 톡시카보닐기 (Fmoc)이다). (In the reaction formula 10, R 1 , R 10 and n are as defined in Formula 1 of claim 1, R 5 ' is a methyl group, R 10' is pyridine or morpholine, P is a protecting group, benzyloxyka Carbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
【청구항 18】 [Claim 18]
하기 반응식 11에 나타낸 바와 같이， 화학식 46으로 표시되는 화합물을 셀레 늄옥사이드와 반웅을 수행하여 화학식 47로 표시되는 화합물을 얻는 단계 (단계 1); 상기 단계 1에서 제조된 화학식 47로 표시되는 화합물과 화학식 20으로 표시 되는 화합물을 반웅시켜 화학식 48로표시되는 화합물을 얻는 단계 (단계 2); 및  As shown in Scheme 11, the compound represented by the formula (46) is subjected to reaction with selenium oxide to obtain a compound represented by the formula (47) (step 1); Reacting the compound represented by Chemical Formula 47 and the compound represented by Chemical Formula 20 prepared in Step 1 to obtain a compound represented by Chemical Formula 48 (step 2); And
상기 단계 2에서 제조된 화학식 48로 표시되는 화합물을 탈보호화 반응을 수 행하여 화학식 lk로 표시되는 화합물을 얻는 단계 (단계 3)를 포함하는 것을 특징으 로 하는 피라졸로 피리딘 유도체의 제조방법: Deprotection reaction of the compound represented by Formula 48 prepared in step 2 A process for preparing a pyrazolo pyridine derivative, comprising the step (step 3) of obtaining a compound represented by the formula lk:
[반응식 11]  Scheme 11
Figure imgf000143_0001
Figure imgf000143_0001
(상기 반웅식 11에서 A, R1 및 R10은 제 1항의 화학식 1에서 정의한 바와 같 고， P는 보호기로써, 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-Boc), p-메톡시 벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다). (In the reaction formula 11, A, R 1 and R 10 are as defined in Formula 1 of claim 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxy benzyl group (PMB) or 9-fluorenyl methoxycarbonyl group (Fmoc)).
【청구항 19] [Claim 19]
하기 반웅식 12에 나타낸 바와 같이， 화학식 49로 표시되는 화합물과 화학식 20으로 표시되는 화합물을 반웅시켜 화학식 50으로 표시되는 화합물을 얻는 단계 (단계 1)；  As shown in Reaction 12 below, reacting the compound represented by the formula (49) with the compound represented by the formula (20) to obtain a compound represented by the formula (50) (step 1);
상기 단계 1에서 제조된 화학식 50으로 표시되는 화합물과 알코을을 커플링 반응을 수행하여 화학식 51로 표시되는 화합물을 얻는 단계 (단계 2); 및  Performing a coupling reaction between the compound represented by Formula 50 prepared in step 1 and an alcohol to obtain a compound represented by Formula 51 (step 2); And
상기 단계 2에서 제조된 화학식 51로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 11로 표시되는 화합물을 얻는 단계 (단계 3)을 포함하는 것을 특징으 로 하는 피라졸로 피리딘 유도체의 제조방법：  A method for preparing a pyrazolo pyridine derivative, comprising the step (step 3) of performing a deprotection reaction of the compound represented by Chemical Formula 51 prepared in step 2 to obtain a compound represented by Chemical Formula 11:
[반응식 12] Scheme 12
Figure imgf000144_0001
Figure imgf000144_0001
(상기 반웅식 12에서 A 및 R1은 제 1항의 화학식 1에서 정 의 한 바와 같고， R10'은 H 및 d-6 직 쇄알킬로 이루어진 군으로부터 선택되고， P는 보호기로써 , 벤질옥 시카보닐기 (Cbz) , t-부록시 카보닐기 (t-Boc)ᅳ P-메록시 벤질기 (PMB) 또는 9-플루오렌 일메록시카보닐기 (Fmoc)이 다) . (In Formula 12, A and R 1 are as defined in Formula 1 of claim 1, R 10 ' is selected from the group consisting of H and d- 6 linear alkyl, P is a protecting group, benzyloxyca Carbonyl group (Cbz), t-butoxy carbonyl group (t-Boc) ᅳ P-methoxy benzyl group (PMB) or 9-fluorene ylmethoxycarbonyl group (Fmoc)).
【청구항 20] [Claim 20]
하기 반응식 13에 나타낸 바와 같이， 화학식 16으로 표시되는 화합물과 아민 화합물을 우레아 반응을 수행하여 화학식 52로 표시되는 화합물을 얻는 단계 (단계 1)；  As shown in Scheme 13 below, a step (step 1) of obtaining a compound represented by Chemical Formula 52 by performing a urea reaction between the compound represented by Chemical Formula 16 and an amine compound;
상기 단계 1에서 제조된 화학식 53으로 표시되는 화합물을 가수분해하여 화 학식 54로 표시되는 화합물을 얻는 단계 (단계 2) ; 및  Hydrolyzing the compound represented by Chemical Formula 53 prepared in Step 1 to obtain a compound represented by Chemical Formula 54 (step 2); And
상기 단계 2에서 제조된 화학식 54로 표시되는 화합물을 탈보호화 반웅을 수 행하여 화학식 lm으로 표시되는 화합물을 얻는 단계 (단계 3)를 포함하는 것을 특징 으로 하는 피라졸로 피 리딘 유도체의 제조방법 :  Method of preparing a pyrazolo pyridine derivative, comprising the step (step 3) of performing a deprotection reaction of the compound represented by formula 54 prepared in step 2 to obtain a compound represented by formula lm:
[반웅식 13] [Banungsik 13]
Figure imgf000145_0001
Figure imgf000145_0001
1m 53  1 m 53
(상기 반응식 13에서 A, R1, 및 n은 제 1항의 화학식 1에서 정의한 바와 같 고， R10'은 다이메틸아민 또는 몰폴린이고， P는 보호기로써， 벤질옥시카보닐기 (Cbz), t-부톡시카보닐기 (t-B0C), P-메록시벤질기 (PMB) 또는 9-플루오렌일메록시카보닐기 (Fmoc)이다；). (In Scheme 13, A, R 1 , and n are as defined in Formula 1 of claim 1, R 10 ' is dimethylamine or morpholine, P is a protecting group, benzyloxycarbonyl group (Cbz), t -butoxy a carbonyl group (t -B 0C), P- methoxy hydroxy benzyl (PMB) or 9-hydroxy-fluorene-ylmethoxy carbonyl group (Fmoc);).
【청구항 21】 [Claim 21]
하기 반응식 14에 나타낸 바와 같이， 화학식 lb로 표시되는 화합물과 화학식 54로 표시되는 화합물을 커플링 반응올 수행하여 화학식 55로 표시되는 화합물을 얻는 단계 (단계 1); 및  As shown in Scheme 14, a step of performing a coupling reaction between the compound represented by the formula lb and the compound represented by the formula 54 to obtain a compound represented by the formula 55 (step 1); And
상기 단계 1에서 제조된 화학식 55로 표시되는 화합물을 탈보호화 반응을 수 행하여 화학식 In으로 표시되는 화합물을 얻는 단계 (단계 2)를 더 포함하는 것을 특징으로 하는 피라졸로 피리딘 유도체의. 제조방법 :  Depyrolyzing the compound represented by Chemical Formula 55 prepared in Step 1 to obtain a compound represented by the chemical formula In (Step 2) of the pyrazolo pyridine derivative. Method of manufacture:
[반웅식 14] [Banungsik 14]
Figure imgf000146_0001
Figure imgf000146_0001
(상기 반웅식 14에서 R1, R9 및 R10은 제 1항의 화학식 1에서 정의한 바와 같 고, P는 보호기로써, 벤질옥시카보닐기 (Cbz), t-부록시카보닐기 (t-Boc), P-메록시 벤질기 (PMB) 또는 9-플루오렌일메톡시카보닐기 (Fmoc)이다). (In the reaction formula 14, R 1 , R 9 and R 10 are as defined in Formula 1 of claim 1, P is a protecting group, benzyloxycarbonyl group (Cbz), t-buoxycarbonyl group (t-Boc) , P-methoxy benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
【청구항 22】 [Claim 22]
하기 반웅식 15에 나타낸 바와 같이， 화학식 lb로 표시되는 화합물과 화학식 56으로 표시되는 화합물을 반웅시켜 화학식 lo로 표시되는 화합물을 얻는 단계 (단 계 1)를 더 포함하는 것을 특징으로 하는 피라졸로 피리딘 유도체의 제조방법:  As shown in the following reaction formula 15, pyrazolo pyridine, further comprising the step of reacting the compound represented by the formula lb and the compound represented by the formula 56 to obtain a compound represented by the formula lo (step 1). Preparation of Derivatives:
[반웅식 15]  [Banungsik 15]
Figure imgf000146_0002
Figure imgf000146_0002
1b 56 1o  1b 56 1o
(상기 반웅식 15에서 R1 및 R10은 제 1항의 화학식 1에서 정의한 바와 같고， R9'은 벤젠 또는 에틸이다). (In Formula 15, R 1 and R 10 are as defined in Formula 1 of claim 1, and R 9 ' is benzene or ethyl).
【청구항 23] [Claim 23]
제 1항의 화학식 1로 표시되는 피라졸로 피리딘 유도체 또는 이의 약학적으 로 허용 가능한 염을 유효성분으로 함유하는 GSK-3P (글리코겐 합성 효소 카이네이 즈 -3β) 관련 질환의 예방 또는 치료용 약학적 조성물.  A pharmaceutical composition for preventing or treating a disease related to GSK-3P (glycogen synthase kinase -3β) containing a pyrazolo pyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 24] [Claim 24]
제 23항에 있어서， 상기 GSK-33 관련 질환은 치매, 알츠하이머 병， 파킨슨 병， 전두측두 (Frontotemporal) 치매 파킨슨 유형, 괌 (Guam) 파킨슨 치매 복합증, HIV 치매 또는 신경섬유 얽힘 병리학과 관련된 질환인 것을 특징으로 하는 GSK-3P 관련 질환의 예방 또는 치료용 약학적 조성물. 24. The method of claim 23, wherein the GSK-33 related disease is dementia, Alzheimer's disease, Parkinson's A pharmaceutical composition for the prophylaxis or treatment of GSK-3P-related diseases, characterized in that the disease, a frontal temporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology.
【청구항 25] [Claim 25]
제 23항에 있어서， 상기 약학적 조성물은 경구용 또는 비경구용으로 투여되 는 것을 특징으로 하는 GSK-3I3 관련 질환의 예방 또는 치료용 약학적 조성물.  The pharmaceutical composition for preventing or treating GSK-3I3-related diseases according to claim 23, wherein the pharmaceutical composition is administered orally or parenterally.
【청구항 26】 [Claim 26]
제 23항에 있어서, 상기 약학적 조성물의 투여용량은 0.01 내지 200 mg/kg/ 일인 것을 특징으로 하는 GSK-3P 관련 질환의 예방 또는 치료용 약학적 조성물.  The pharmaceutical composition for preventing or treating GSK-3P-related diseases according to claim 23, wherein the dosage of the pharmaceutical composition is 0.01 to 200 mg / kg / day.
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