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WO2012077932A2 - Nouveau dérivé de pyrazole pyridine ou sels de qualité pharmaceutique de celui-ci, leur procédé de production, et composition pharmaceutique les contenant - Google Patents

Nouveau dérivé de pyrazole pyridine ou sels de qualité pharmaceutique de celui-ci, leur procédé de production, et composition pharmaceutique les contenant Download PDF

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Publication number
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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Prior art keywords
pyrazolo
compound represented
formula
pyridine
amino
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Korean (ko)
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WO2012077932A3 (fr
Inventor
김명화
구일회
천광우
류동규
최정훈
김영하
조보영
박지선
이한창
김강전
김승현
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Jeil Pharmaceutical Co Ltd
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Jeil Pharmaceutical Co Ltd
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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

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Abstract

Cette invention concerne un nouveau dérivé de pyrazole pyridine ou des sels de qualité pharmaceutique de celui-ci, leur procédé de production, et une composition pharmaceutique les contenant. Le nouveau dérivé de pyrazole pyridine selon la présente invention inhibe la GSK-3ß, et peut être efficacement utilisé pour prévenir ou traiter les troubles liés à la démence, à la maladie d'Alzheimer, à la maladie de Parkinson, au parkinsonisme variante démence frontotemporale, au complexe Parkinson-démence de Guam, à la démence due au VIH, ou aux pathologies liées à des enchevêtrements neurofibrillaires.
PCT/KR2011/009224 2010-12-07 2011-11-30 Nouveau dérivé de pyrazole pyridine ou sels de qualité pharmaceutique de celui-ci, leur procédé de production, et composition pharmaceutique les contenant Ceased WO2012077932A2 (fr)

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US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
US10689369B2 (en) 2015-10-27 2020-06-23 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
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