JP2005534713A - Dihydropyrazolopyridine compounds - Google Patents

Abstract

（式中、各記号は明細書中に定義した通りである。）
により表されるジヒドロピラゾロピリジン化合物、その光学活性体、およびそれらの医薬上許容される塩およびそれらの水和物を提供する。本発明化合物は、グリコーゲンシンターゼキナーゼ−３ベータ（ＧＳＫ−３β）への選択的かつ強力な阻害活性を示し、糖尿病、糖尿病合併症および神経変性疾患の予防および／または治療薬として、または免疫賦活薬として有用である。The present invention
Formula (I):
[Chemical 1]

(In the formula, each symbol is as defined in the specification.)
The dihydropyrazolopyridine compound represented by these, the optically active form thereof, and pharmaceutically acceptable salts and hydrates thereof are provided. The compound of the present invention exhibits selective and potent inhibitory activity on glycogen synthase kinase-3 beta (GSK-3β), and is used as a prophylactic and / or therapeutic agent for diabetes, diabetic complications and neurodegenerative diseases, or as an immunostimulant Useful as.

Description

(Technical field of the invention)
The present invention relates to a novel pharmaceutical compound having glycogen synthase kinase-3 beta (GSK-3β) inhibitory activity and use thereof.

(Background technology)
It has been reported that glycogen synthase kinase-3 beta (GSK-3β), which is a protein kinase, is involved in the causes of various diseases as described below.

  Type 2 diabetes is a disease in which the insulin responsiveness of β-cells in the pancreas is lowered and glucose in the blood is increased. As a result, complications such as diabetic nephropathy, retinopathy, and heart disease are induced. GSK-3β phosphorylates glycogen synthase to inhibit glycogen accumulation in peripheral tissues, thereby reducing insulin reactivity and increasing blood glucose. In fact, lithium having GSK-3β inhibitory activity lowers blood glucose by GSK-3β inhibitory activity (Proceeding of National Academy of Science of the United States of America). (Proc. Nat. Acad. Sci.), 93, 8455 (1996)). Therefore, it is considered that a drug having GSK-3β inhibitory activity is an effective drug for improving type 2 diabetes and its complications.

  The mechanism of Alzheimer-type dementia has yet to be clarified. However, amyloid aggregation and neurofibrillary tangles are thought to be closely related to the cause of development. GSK-3β is involved in both amyloid aggregation and neurofibrillary tangles as follows. (1) GSK-3β binds to mutant presenilin and increases the production of insoluble amyloid (Procedure of National Academy of Science of the United States of America (Proc. Nat. Acad. Sci.), 95, 9637 (1998)). (2) GSK-3β induces phosphorylation of tau protein that causes neurofibrillary tangles, weakens the skeleton of nerve cells and induces nerve cell death (Neuroscience Letters (Neurosci. Lett.), 128, 195 (1991)). In addition to the above, (3) Involvement of GSK-3β in direct neuronal cell death in which pyruvate dehydrogenase is inactivated by phosphorylation to reduce the amount of acetylcholine production necessary for maintaining cell activity ( Proceding of the National Academy of Science of the United States of America (Proc. Nat. Acad. Sci., Vol. 93, p. 2719 (1996)) ing.

  In addition, effectiveness against AIDS encephalopathy has been suggested as a neurodegenerative disease other than Alzheimer-type dementia. Tat, an HIV virus-producing protein that causes AIDS, increases neuronal GSK-3β activity and causes neuronal cell death (J. Neurochem., 73, 578) (1999)). From the above, GSK-3β inhibitors are considered to be effective drugs for improving neurodegenerative diseases including Alzheimer-type dementia.

  Lithium and valproic acid having antidepressant activity have GSK-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The relationship between antidepressant activity and GSK-3β inhibitory activity is not clear, but it is an inhibitory activity against glutamate toxicity (Proceeding of National Academy of Science of the United States of America (Proc Nat. Acad. Sci.), 95, 2642 (1998)) is thought to be partly involved in maintaining the activity of nerve cells. From the above, GSK-3β inhibitor is considered to be an effective drug for the improvement of manic depression.

  The transcription factor NF-AT is dephosphorylated by calcineurin and enhances the immune response (Science, 275, 1930 (1997)). On the contrary, GSK-3β acts to suppress immune function by phosphorylating NF-AT. Therefore, GSK-3β inhibitors are considered to be effective drugs for immune stimulation.

  By the way, JP-A-3-272189 (invention of an improved method for synthesizing mevalolactone intermediate), JP-A-2-275878 (therapeutic agent for hyperlipoproteinemia / atherosclerosis), JP-A-1-272484. The publication (therapeutic agent for hyperlipoproteinemia) discloses pyrazolo [3,4-b] pyridine compounds, which are either methyl, isopropyl or cyclopropyl at the 6-position. These publications do not disclose or suggest any action of these compounds on GSK-3β or on the central nervous system.

  JP-A-59-65089, JP-A-59-118786, JP-A-60-55979, JP-A-60-197685, etc. describe 6-, which is used for the treatment of cardiovascular diseases. Methyl-4-substituted phenyl-4,7-dihydropyrazolo [3,4-b] pyridine-5-carboxylate compounds are disclosed and are prepared in a similar manner. When the inventors conducted a follow-up test of the following reaction A based on the method described in JP-A-59-65089, the compound of Example 14 described below (the following formula (IV)) was not obtained. It was. The present inventors have confirmed that only a pyrazolo [1,5-a] pyrimidine derivative represented by the formula (V) can be produced. The inventors measured IR, NMR, and melting point of the compound of the formula (V) and found that they were consistent with IR, NMR, and melting point described in the specification of the publication. Accordingly, it is recognized that these structural publications disclose an incorrect structural formula. That is, 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo [3,4-b] pyridine-5-carboxylate cannot be synthesized by the methods described in these publications.

  The compound of the above formula (IV) is synthesized by the method described in J. Chem. Soc., Perkin Trans. 1 page 947 (1996). This publication discloses methyl 4- (2-chlorophenyl) -6-methyl-4,7-dihydro-1H-pyrazolo [3,4-b] pyridine-5-carboxylate and the like.

(Disclosure of the present invention)
It is an object of the present invention to provide novel compounds having selective and potent inhibitory activity against glycogen synthase kinase-3 beta (GSK-3β), and medicaments containing these compounds and these compounds It is providing the pharmaceutical composition containing this.

  As a result of intensive research aimed at achieving the above-mentioned problems, the present inventors have found that 4,7-dihydropyrazolo [3,4-b] pyridine derivatives have selective and potent inhibitory activity against GSK-3β. As a result, the present invention has been completed. That is, the present invention has a GSK-3β inhibitory activity and can be used as a pharmaceutical, which is a dihydropyrazolopyridine compound represented by the following formula (I), an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydration thereof. The present invention relates to a medicine containing a product as an active ingredient.

The present invention provides the following.
[1]
Formula (I):

[Where,
R ⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenyl Sulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, optionally substituted phenyl, optionally substituted aromatic heterocyclic group, substituted May be phenylalkyl, or —COOR ⁸ (wherein R ⁸ is hydrogen, alkyl, aryl optionally having substituent (s), or aralkyl optionally having substituent (s)). A group of
R ¹ is hydrogen;
R ² is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, amino Alkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, substituted Optionally phenyl, aromatic heterocyclic group or phenylalkyl;
R ³ is (1) alkyl or haloalkyl,
(2) cycloalkyl,
(3) phenyl optionally having substituent (s),
(4) an aromatic heterocyclic group,
(5) a group derived from a benzene ring fused with a saturated or unsaturated 5- or 6-membered carbocyclic ring,
(6) a group derived from a benzene ring fused with a saturated or unsaturated 5- to 7-membered carbon ring containing 1 to 3 heteroatoms, or (7) 1 to 3 fused with a benzene ring A group derived from a saturated or unsaturated 5- to 7-membered carbocyclic ring containing
The groups (2) to (7) may have one or more substituents, or
R ³ represents the following formulas (II) and (III):

(Wherein R ⁶ and R ⁷ are each an optionally substituted phenyl or aromatic heterocyclic group)
Or a group selected from the group represented by
R ² and R ³ are bonded to form a ring that may contain a hetero atom, and the ring may be condensed with an optionally substituted benzene ring;
R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, optionally substituted phenyl, optionally substituted. An aromatic heterocyclic group, cyano or nitro; and R ⁵ is alkyl,
Phenylaminoalkyl,
Acyl,
Acylalkyl,
Aminocarbonyl,
Arylaminocarbonyl,
A saturated or unsaturated 4- to 7-membered heterocyclic ring which may have a substituent,
A saturated 3- to 7-membered carbocyclic ring having a substituent,
Alkyl optionally substituted with a saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms, or
Formula: — (CR ^a R ^b ) _n NR ¹¹ R ¹² (wherein n is an integer of 1 to 4, R ^a is hydrogen or alkyl, R ^b is hydrogen or alkyl, and R ¹¹ is hydrogen) , Alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, R ¹² is hydrogen or Group which is alkyl).
Provided that when R ⁰ , R ¹ and R ² are each hydrogen, R ⁴ is methoxycarbonyl and R ⁵ is methyl, R ³ is phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxy When neither phenyl nor 4-methoxycarbonylphenyl and R ⁵ is alkyl, R ⁴ is alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano, nitro is not. ]
A dihydropyrazolopyridine compound, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

[2]
R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, optionally substituted phenyl, substituted aromatic heterocyclic group , Cyano or nitro; and R ⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, an optionally substituted saturated or unsaturated 4- to 7-membered heterocyclic ring A saturated 3- to 7-membered carbocyclic ring having a substituent, an alkyl substituted with a saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms which may have a substituent Or the formula: — (CH ₂ ) _n NR ¹¹ R ¹² (where n is an integer of 1 to 4) R ¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl. And R ¹² is hydrogen or alkyl), the dihydropyrazolopyridine compound of the above [1], its optically active isomer, or a pharmaceutically acceptable salt thereof.

[3]
The dihydropyrazolopyridine compound of the above [1] or [2], wherein R ² is hydrogen or alkyl, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

[4]
R ³ may optionally have 1 to 3 substituents phenyl, naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl A certain dihydropyrazolopyridine compound of the above [1] or [2], an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

[5]
R ⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms The dihydropyrazolopyridine compound of the above [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[6]
R ⁵ is represented by the formula: — (CH ₂ ) _n NR ¹¹ R ¹² (wherein n is an integer of 1 to 4, R ¹¹ is hydrogen, alkyl or alkoxycarbonyl, and R ¹² is hydrogen or alkyl) The dihydropyrazolopyridine compound of the above-mentioned [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[7]
Wherein R ⁰ is hydrogen or a group of the formula: —COOR ⁸ , wherein R ⁸ is alkyl, aryl optionally having substituent (s) or aralkyl optionally having substituent (s); Or a dihydropyrazolopyridine compound of [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[8]
(2) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4 b] pyridine,
(3) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(11) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(14) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridine- 4-yl) -2H-pyrazolo [3,4-b] pyridine,
(23) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4- (N, N-dimethylamino) cyclohexyl)- 2H-pyrazolo [3,4-b] pyridine,
(27) 6- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -4- (2,1,3-benzooxadiazol-4-yl) -5-cyano-4 , 7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(33) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-ethylpiperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(37) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine,
(38) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine ,
(41) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2H-pyrazolo [3,4-b] pyridine ,
(46) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2H-pyrazolo [3,4-b] pyridine ,
(48) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -2H -Pyrazolo [3,4-b] pyridine,
(51) 6- (1-Acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine ,
(52) 6- (1-Benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine ,
(53) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-4-yl) -2H-pyrazolo [3,4-b] Pyridine,
(59) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-oxocyclohexane-1-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(62) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexane-1-yl) -2H-pyrazolo [3,4-b] pyridine ,
(63) 6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(73) 5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine,
(75) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine-6-carboxylic acid phenylamide ,
(78) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (4-phenylpiperazin-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine,
(81) 6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(82) 6-acetyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(84) 4- (2-Bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine,
(86) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (pyrrolidin-3-yl) -2H-pyrazolo [3,4-b] pyridine, and (87) 4- ( 2,1,3-Benzoxadiazol-4-yl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine The dihydropyrazolopyridine compound of the above-mentioned [1] or [2] selected from: tautomers thereof, optically active isomers thereof, or pharmaceutically acceptable salts thereof.

[9]
A medicament comprising the dihydropyrazolopyridine compound of the above [1] or [2], an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

[10]
A pharmaceutical composition comprising the dihydropyrazolopyridine compound of the above [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[11]
A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of the dihydropyrazolopyridine compound of the above [1], an optically active isomer thereof, and a pharmaceutically acceptable salt thereof.

[12]
The medicament of the above-mentioned [9], which is used for prevention and / or treatment of a disease caused by glycogen synthase kinase-3 beta hyperfunction.

[13]
The medicament of the above-mentioned [9] used for prevention and / or treatment of neurodegenerative diseases.

[14]
Diseases include Alzheimer's disease, ischemic cerebrovascular disorder, Down syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalic parkinsonism, post encephalitis parkinsonism, fighter encephalopathy, guam -The medicine of the above-mentioned [13], which is selected from the group consisting of Parkinson dementia complex, Lewy body disease, Pick's disease, cortical base degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic depression.

[15]
The medicament of the above-mentioned [9], which is used for prevention and / or treatment of diabetes and diabetic complications.

[16]
The pharmaceutical of [9] above, which is used as an immunostimulant.

[17]
[9] The medicament of the above-mentioned [9], which is used for the prevention and / or treatment of alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia or virus-induced tumor.

(Detailed description of the invention)
Formula (I) represents that tautomers represented by the following formulas (Ia) and (Ib) exist depending on the position of the hydrogen atom of the pyrazole ring. The invention also encompasses the individual isomers of formula (Ia) and formula (Ib) and mixtures of these isomers.

  In the present specification, the compound represented by the formula (I) is described in detail below.

“Alkyl” means a straight or branched hydrocarbon chain having from 1 to 8 carbon atoms, methyl, ethyl, propyl, butyl, pentyl (ie, amyl), hexyl, or structures thereof Examples include isomers (isopropyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, neopentyl, tertiary pentyl, etc.), and alkyl having 1 to 4 carbon atoms is preferable. Alkyl R ² is preferably alkyl having 1 to 4 carbon atoms. The alkyl of R ⁵ is preferably an alkyl having 2 to 8 carbon atoms. Specific examples of the “alkyl having 2 to 8 carbon atoms” include ethyl, propyl, butyl, pentyl (ie, amyl), hexyl, heptyl, octyl, and structural isomers thereof (isopropyl, isobutyl). Secondary butyl, tertiary butyl, isopentyl, neopentyl, tertiary pentyl, etc.). Alkyl having 2 to 4 carbon atoms is more preferred, and propyl is particularly preferred.

“Acyl” means C ₂ -C ₁₄ acyl and is an “alkylcarbonyl” having 2 to 8 carbon atoms, preferably 2 to 5 carbon atoms in R ⁴ (eg, acetyl, propionyl, Butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl, etc.), “C ₇ -C ₁₂ arylcarbonyl” (eg, benzoyl, naphthoyl, etc.), and “C ₇ -C ₁₂ aralkylcarbonyl” (eg, benzylcarbonyl, 2- Phenylethylcarbonyl, 3-phenylpropylcarbonyl, etc.). The benzene ring and naphthalene ring may have 1 to 5 substituents, and the substitution position is not particularly limited.

“Acylalkyl” is an acylalkyl composed of the C ₁ -C ₈ alkyl and the C ₂ -C ₁₄ acyl, and includes, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyrylmethyl, valerylmethyl, pivaloylmethyl, Examples include 2-acetylethyl, 2-propionylethyl, 3-acetylpropyl, and the like.

  “Cycloalkyl” means a cyclic hydrocarbon chain having 3 to 8 carbon atoms. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, and cycloalkyl having 3 to 6 carbon atoms is preferable. Cycloalkyl may have 1 to 5 substituents, and the substitution position is not particularly limited.

  “Halogen” refers to fluorine, chlorine, bromine or iodine.

“Amino” is a primary or secondary amino or secondary amino having C ₁ -C ₈ alkyl, such as amino, mono- or di-C ₁ -C ₈ alkyl substituted amino (methylamino, dimethyl) Amino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino, etc.).

  “Alkylthio” is a straight or branched alkylthio having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, butylthio, pentylthio (ie, amylthio), hexylthio, and structures thereof Isomers (isopropylthio, isobutylthio, secondary butylthio, tertiary butylthio, isopentylthio, neopentylthio, tertiary pentylthio, etc.) and the like, and alkylthio having 1 to 3 carbon atoms is preferred. .

  “Phenylthio” means phenylthio optionally having 1 to 5 substituents on the phenyl, and the substitution position is not particularly limited.

“Haloalkyl” means the C ₁ -C ₈ alkyl substituted with 1 to 5 halogens, such as fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like are shown.

“Aminoalkyl” is C ₁ -C ₈ alkyl having _primary amino, and examples thereof include aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl and the like. Preferred are aminoalkyls, including alkyls having 5 carbon atoms.

“Acylamino” is an acylamino having the above C ₂ -C ₁₄ acyl, such as acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino, etc. Indicates.

“Alkoxy” is alkoxy having the aforementioned C ₁ -C ₈ alkyl, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy (ie, amyloxy), hexyloxy, and structural isomers thereof (isopropoxy) , Isobutoxy, secondary butoxy, tertiary butoxy, isopentyloxy, neopentyloxy, tertiary pentyloxy and the like, and alkoxy having 1 to 4 carbon atoms is preferable.

“Cycloalkoxy” is a cycloalkoxy having the above C ₃ -C ₈ cycloalkyl, and examples thereof include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc., having 3 to 6 carbon atoms. Cycloalkoxy having cycloalkyl is preferred.

  “Phenoxy” means phenyloxy optionally having 1 to 5 substituents on the phenyl, and the substitution position is not particularly limited.

“Phenylalkoxy” is phenylalkoxy having the above C ₁ -C ₈ alkoxy, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-methyl -1-phenylethoxy, 1-methyl-2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 1-methyl-1-phenylpropoxy, 1-methyl-2-phenylpropoxy, 1-methyl-3-phenyl Propoxy and the like are mentioned, and phenylalkoxy including alkoxy having 1 to 4 carbon atoms is preferable. The phenylalkoxy may have 1 to 5 substituents on the phenyl, and the substitution position is not particularly limited.

“Aminoalkoxy” is an aminoalkoxy composed of the amino and the C ₁ -C ₈ alkoxy, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2- (dimethylamino) ethoxy, 3- (dimethyl Amino) propoxy, 4- (dimethylamino) butoxy and the like, and aminoalkoxy composed of tertiary amino containing alkyl having 1 to 4 carbon atoms and alkoxy having 1 to 4 carbon atoms is preferable. .

The “alkoxyalkyl” is an alkoxyalkyl composed of the C ₁ -C ₈ alkoxy and the C ₁ -C ₈ alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl An alkoxyalkyl composed of an alkoxy having 1 to 4 carbon atoms and an alkyl having 1 to 4 carbon atoms is preferable.

The “phenoxyalkyl” is phenoxyalkyl composed of the phenoxy and the C ₁ -C ₈ alkyl, and examples thereof include phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, and the like. Phenoxyalkyl, including alkyl having carbon atoms, is preferred. The phenoxyalkyl may have 1 to 5 substituents on its phenyl, and the substitution position is not particularly limited.

“Hydroxyalkyl” is a hydroxyalkyl having the aforementioned C ₁ -C ₈ alkyl, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc., having 1 to 4 carbon atoms. Hydroxyalkyl containing alkyl is preferred.

“Alkoxycarbonyl” is an alkoxycarbonyl having the above C ₁ -C ₈ alkoxy, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and structural isomers thereof. (Such as isopropoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tertiary pentyloxycarbonyl, etc.) Alkoxycarbonyl having 4 carbon atoms is preferred. The alkoxycarbonyl of R ⁴ is preferably alkoxycarbonyl having 2 to 5 carbon atoms.

  “Phenoxycarbonyl” is phenoxycarbonyl optionally having 1 to 5 substituents on the phenyl, and the substitution position is not particularly limited.

“Aminocarbonyl” means an aminocarbonyl having said amino, including mono- or di-C ₁ -C ₈ alkyl substituted amino, such as aminocarbonyl (ie, carbamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethyl Examples include aminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl and the like.

“Alkylthiocarbonyl” is an alkylthiocarbonyl having the above C ₁ -C ₆ alkylthio, such as methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl, and structural isomers thereof (isopropylthiocarbonyl, Isobutylthiocarbonyl, secondary butylthiocarbonyl, tertiary butylthiocarbonyl, etc.) and the like, and alkylthiocarbonyl having an alkyl portion of 1 to 3 carbon atoms is preferred.

“Carboxyalkyl” is a carboxyalkyl having the above C ₁ -C ₈ alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl, etc. Alkyl is preferred.

“Cycloalkoxyalkyl” is a cycloalkoxyalkyl composed of the C ₃ -C ₈ cycloalkoxy and the C ₁ -C ₈ alkyl, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclopentyloxy Examples thereof include methyl, cyclohexyloxymethyl and the like, and cycloalkoxyalkyl composed of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atoms is preferable. Cycloalkoxyalkyl may have 1 to 3 substituents on the cycloalkyl, and the substitution position is not particularly limited.

“Alkylsulfinyl” is an alkylsulfinyl having the above C ₁ -C ₈ alkyl, and examples thereof include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, etc., and alkyl having 1 to 5 carbon atoms. Alkylsulfinyl containing is preferred. R ⁴ alkylsulfinyl is preferably alkylsulfinyl having 1 to 4 carbon atoms.

  “Phenylsulfinyl” means phenylsulfinyl optionally having 1 to 5 substituents on the phenyl, and the substitution position is not particularly limited.

The “alkylsulfonyl” is an alkylsulfonyl having the above C ₁ -C ₈ alkyl, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, etc., and alkyl having 1 to 5 carbon atoms. Alkylsulfonyl containing is preferred. The alkylsulfonyl of R ⁴ is preferably an alkylsulfonyl having 1 to 4 carbon atoms.

  “Phenylsulfonyl” means phenylsulfonyl optionally having 1 to 5 substituents on the phenyl, and the substitution position is not particularly limited.

“Mercaptoalkyl” is a mercaptoalkyl having the above C ₁ -C ₈ alkyl, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl, etc., and a mercapto containing an alkyl having 1 to 4 carbon atoms. Alkyl is preferred.

“Alkylthioalkyl” is an alkylthioalkyl composed of the C ₁ -C ₆ alkylthio and the C ₁ -C ₈ alkyl, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, Examples include ethylthiopropyl and the like, and alkylthioalkyl composed of alkylthio having 1 to 3 carbon atoms and alkyl having 1 to 4 carbon atoms is preferable.

  “Aryl” is aryl having 6 to 14 carbon atoms, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and the like. These may have 1 to 5 substituents, and the substitution position is not particularly limited.

“Aralkyl” refers to an aralkyl in which the C ₁ -C ₈ alkyl is substituted with the C ₆ -C ₁₄ aryl, and includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl. Etc. These may have 1 to 5 substituents in the aryl part, and the substitution position is not particularly limited.

“Acyloxyacetyl” is acyloxyacetyl having the C ₂ -C ₁₄ acyl, and examples thereof include acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.

The “acyloxyalkyl” is an acyloxyalkyl having the C ₂ -C ₁₄ acyl and the C ₁ -C ₈ alkyl, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, Examples include 2-acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-benzoyloxyethyl and the like.

  Examples of the substituent of “optionally substituted phenyl” include those mentioned in the following “substituent”, and the number of substituents is usually 1 to 5, preferably 1 to 1. Three. Phenyl having 1 or 2 substituents is particularly preferred, and the substitution position is not particularly limited.

  The “aromatic heterocyclic group” is, for example, a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxadiazolyl (for example, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, etc.) It is done. The aromatic heterocyclic group may have 1 to 6 substituents, and the substitution position is not particularly limited.

  Examples of the “saturated or unsaturated 4- to 7-membered heterocyclic ring optionally having substituent (s)” include the following groups.

In the formula, each R ⁹ independently represents hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, Carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, optionally substituted aryl, optionally substituted It is phenylalkyl which may have an aromatic heterocyclic group or a substituent.

  Examples of the “saturated 3- to 7-membered carbocycle having a substituent” include the following groups.

Wherein R ¹⁰ is alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkyl Sulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent, aromatic heterocyclic group optionally having substituent or substituent R ¹⁰ ′ is hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, Phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, optionally substituted aryl, substituted An aromatic heterocyclic group which may have a group or phenylalkyl which may have a substituent.

  Examples of the substituent of the “optionally substituted aromatic heterocyclic group” include those mentioned in the following “substituent”, and the number of the substituent is usually 1 to 6 The substitution position is not particularly limited.

“Phenylalkyl” is phenylalkyl composed of phenyl and the aforementioned C ₁ -C ₈ alkyl. For example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, Methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl, etc. And phenylalkyl consisting of alkyl having 1 to 4 carbon atoms.

  The kind and number of the substituents of “optionally substituted phenylalkyl” are the same as those of the above-mentioned “aromatic heterocyclic group”, and the substitution position is not particularly limited.

The “dialkylphosphinyl” is a dialkylphosphinyl having the C ₁ -C ₈ alkyl, and examples thereof include dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl, etc. Preferred are dialkylphosphinyl containing alkyl having 4 carbon atoms.

The “dialkylphosphonyl” is a dialkylphosphonyl having the above C ₁ -C ₈ alkyl, and examples thereof include dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, having 1 to 4 carbon atoms. Preferred are dialkylphosphonyl containing alkyls having

  In the present specification, as the “substituent”, alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic group, phenylalkyl, hydroxy, carboxy, thiol, halogen, amino, formyl, carbamoyl, cyano, nitro, alkylthio, Examples include haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl and the like.

The “ring optionally containing a heteroatom” is a 5- or 6-membered carbocyclic ring optionally containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A ring containing a sulfur atom is particularly preferred. The ring may be substituted with one or more substituents or oxo groups. The substitution position is not particularly limited. The ring is formed with the carbon atom to which it is attached from R ² and R ³ of formula (I). By forming the ring, a spiro ring is formed in the compound of formula (I). The ring which may contain the hetero atom may be condensed with a benzene ring which may have a substituent, and the substitution position is not particularly limited. Examples of such a ring include 2,3-dihydrobenzo [b] thiophene and 2,3-dihydrobenzo [b] thiophene-1-oxide.

  “Group derived from a benzene ring condensed with a saturated or unsaturated 5- or 6-membered carbocycle” means naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indane, etc. Indicates the group to be derived. Among these, naphthyl (for example, naphthalen-1-yl and the like) and indanyl (for example, indan-4-yl and the like) are preferable. The group may have 1 to 4 substituents, and the substitution position is not particularly limited.

  Examples of the “group derived from a benzene ring condensed with a saturated or unsaturated 5- to 7-membered carbocyclic ring containing 1 to 3 heteroatoms” include the following groups.

  Of these, 2,1,3-benzoxadiazole, dihydrobenzo [b] furan, methylenedioxyphenyl and 3,4-dihydro-2H-benzopyran are preferable, and 2,1,3-benzoxadiazole- 4-yl, 2,3-dihydrobenzo [b] furan-7-yl, 2,3- (methylenedioxy) phenyl and 3,4-dihydro-2H-benzopyran-8-yl are particularly preferred. The group may have 1 to 3 substituents, and the substitution position is not particularly limited.

  Examples of the “group derived from a saturated or unsaturated 5- to 7-membered carbocyclic ring containing 1 to 3 heteroatoms that are condensed with a benzene ring” include the following groups.

  The group may have 1 to 5 substituents, and the substitution position is not particularly limited.

“Alkylcarbonylalkyl” is, for example, C ₁ -C ₄ alkyl-carbonyl-C ₁ -C ₄ alkyl, and examples thereof include methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butylcarbonylmethyl and the like. .

“Aruleaminocarbonyl” is C ₆ -C ₁₀ aryl-aminocarbonyl, and examples thereof include phenylaminocarbonyl, naphthylaminocarbonyl, and the like. The arylaminocarbonyl may have 1 to 3 substituents on the aryl, and the substitution position is not particularly limited.

“Aralkylaminocarbonyl” refers to C ₇ -C ₁₄ aralkyl-aminocarbonyl, and examples thereof include benzylaminocarbonyl and the like. Aralkylaminocarbonyl may have 1 to 3 substituents on its aryl, and the substitution position is not particularly limited.

“Optionally substituted alkyl substituted with a saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms” means C ₁ -C ₄ alkyl, C _6- “Saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms” which may have a substituent such as C ₁₀ aryl (eg phenyl, naphthyl etc.) (eg pyrrole, pyrrolidine) , pyrazole, pyridine, piperidine, piperazine, homopiperazine, mean _C 1 -C ₈ alkyl substituted with morpholine), for example, (4-phenyl-piperazin-1-yl) methyl, 2- (4-phenyl piperazine -1-yl) ethyl, 3- (4-phenylpiperazin-1-yl) propyl, (4-naphthalen-1-yl) piperazin-1-yl) methyl, 2- (4- (na The array type 1-yl) piperazin-1-yl) ethyl, and (4-methyl homopiperazine-1-yl) methyl and the like.

“Phenylaminoalkyl” is phenylamino-C ₁ -C ₄ alkyl, and examples thereof include phenylaminomethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl, and the like. The phenylaminoalkyl may have 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

“Phenylalkylcarbonyl” is phenyl-C ₁ -C ₄ alkyl-carbonyl, and examples thereof include benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl and the like. The phenylalkylcarbonyl may have 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

The “alkyl” in R ¹¹ is C ₁ -C ₄ alkyl, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like.

The “alkylsulfonyl” in R ¹¹ is C ₁ -C ₄ alkyl-sulfonyl, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.

“Phenylsulfonyl” in R ¹¹ is phenylsulfonyl optionally having 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

The “phenylalkylsulfonyl” in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-sulfonyl, and examples thereof include benzylsulfonyl, 2-phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl and the like. It is done. The phenylalkylsulfonyl may have 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

“Alkylsulfinyl” in R ¹¹ is C ₁ -C ₄ alkyl-sulfinyl, and examples thereof include methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.

“Phenylsulfinyl” in R ¹¹ is phenylsulfinyl optionally having 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

“Phenylalkylsulfinyl” in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-sulfinyl, and examples thereof include benzylsulfinyl, 2-phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4-phenylbutylsulfinyl and the like. It is done. The phenylalkylsulfinyl may have 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

The “alkoxycarbonyl” in R ¹¹ is C ₁ -C ₄ alkoxy-carbonyl, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertiary butoxycarbonyl and the like.

“Phenylalkoxycarbonyl” in R ¹¹ is phenyl-C ₁ -C ₄ alkoxy-carbonyl, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl and the like. Can be mentioned. The phenylalkoxycarbonyl may have 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

The “alkylcarbonyl” in R ¹¹ is C ₁ -C ₄ alkyl-carbonyl, and examples thereof include acetyl, propionyl, butylcarbonyl and the like.

“Phenylcarbonyl” in R ¹¹ is phenylcarbonyl optionally having 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

“Phenylalkylcarbonyl” in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-carbonyl, and examples thereof include benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl and the like. It is done. The phenylalkylcarbonyl may have 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

“Phenoxycarbonyl” in R ¹¹ means phenoxycarbonyl optionally having 1 to 3 substituents on the phenyl, and the substitution position is not particularly limited.

The “alkyl” in R ¹² is C ₁ -C ₄ alkyl, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like.

  The compound represented by the formula (I) of the present invention can be converted into an acid addition salt using a pharmaceutically acceptable acid, and such an acid addition salt is also included in the present invention. Examples of such acid addition salts include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (eg, formic acid, acetic acid, Trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid, etc.) Of these salts. When an asymmetric carbon atom is present, optical isomers and racemates thereof may exist, but the present invention includes all of them.

Among the compounds of the present invention (I), a compound in which R ⁰ is hydrogen is J. Chem. Soc., Perkin Trans. 1 (page 947) (1996). ) Can be synthesized as shown below.
(First manufacturing method)

(Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.)

  The amide derivative of formula (IX) is obtained by reacting the meldrum acid of formula (VI) and the carbonyl derivative of formula (VII) with the carbonyl derivative of formula (VIII) in the presence of ammonium acetate. The reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction. As the solvent, formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are usually used. The reaction is performed at an arbitrary temperature, for example, 0 ° C to 200 ° C, preferably 60 ° C to 100 ° C.

(Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.)

  The resulting amide derivative of formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of formula (X). The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide and the like are usually used. The reaction is performed at an arbitrary temperature, for example, 0 ° C to 200 ° C, preferably 0 ° C to 60 ° C.

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)

  The compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine. This reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, alcohol and the like are usually used. The reaction is performed at an arbitrary temperature, for example, 0 ° C to 200 ° C, preferably 60 ° C to 100 ° C.

The starting carbonyl derivative of formula (VII) is described in Journal of Organic Chemistry (J. Org. Chem.), 46, 783 (1981), European Journal of Medicinal. According to the method described in Chemistry (Eur. J. Med. Chem.), Vol. 31, page 3 (1996) and Tetrahedron Lett., Vol. 24, page 5023 (1983). Can be synthesized. The carbonyl derivative of formula (VIII) can be synthesized by the method described in Synthesis, page 290 (1993).
(Second manufacturing method)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)

  The compound (I) of the present invention can be produced by reacting an aminopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII). This reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are usually used. The reaction is performed at an arbitrary temperature, for example, 0 ° C to 200 ° C, preferably 60 ° C to 100 ° C.

Among the compounds (I) of the present invention, compounds in which R ⁰ is a substituent other than hydrogen can be synthesized as follows.
(Third manufacturing method)

(Wherein R ⁰ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, X represents a halogen, provided that R ⁰ is not hydrogen.)

The compound (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with a halide of the formula (XII) in the presence of a base. Suitable bases include, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like. This reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, for example, a solvent not containing a hydroxyl group such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone is usually used. The reaction is performed at an arbitrary temperature, for example, -10 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
(Fourth manufacturing method)

(Wherein R ⁰ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, provided that R ⁰ is not hydrogen.)

  The compound (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with an anhydride of the formula (XIII) such as acetic anhydride in the presence of a base. Suitable bases include, for example, triethylamine, pyridine, 4-dimethylaminopyridine and the like. This reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, for example, a solvent not containing a hydroxyl group such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like is usually used. The reaction is performed at an arbitrary temperature, for example, -10 ° C to 200 ° C, preferably 0 ° C to 100 ° C.

  One skilled in the art should appreciate that the above process can be modified depending on the desired compound.

  The compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation / purification is performed by ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography. When the purified product obtained is a racemate, it can be separated into the desired optically active compound by, for example, fractional recrystallization with an optically active acid or by passing through a column packed with an optically active carrier. The present invention further includes optically active compounds.

The compound of the present invention obtained by the above method has weak inhibitory activity against kinases other than GSK-3β (CaM kinase II, MAP kinase, casein kinase, PKA, PKC, ROCK, etc.), but is potent against GSK-3β. Has inhibitory activity. Therefore, the compound of the present invention has a GSK-3β selective inhibitory activity, and diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progression Supranuclear palsy, subacute sclerosing panencephalic Parkinson syndrome, post-encephalitic Parkinson syndrome, fist encephalopathy, Guam-Parkinson dementia complex, Lewy body disease, Pick disease, cortical base degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic depression, etc.), alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia, and can be a drug with few side effects on some virus-induced tumors. The compound of the present invention is also useful as an immunostimulant.

  A preparation containing the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients and other additives usually used for formulation. The carrier or excipient for the preparation may be solid or liquid, for example, lactose, magnesium stearate, corn starch and other starches, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, Examples include ethylene glycol and other conventional ones. Administration may be oral administration such as tablets, pills, capsules, granules, powders, liquids, or parenteral administration such as injections (intravenous injection, intramuscular injection, etc.), suppositories, transdermal agents, and the like. The dose is appropriately determined depending on the individual case in consideration of symptoms, age and gender of the administration subject, and is usually 1 to 1,000 mg per adult, preferably 50 to 200 mg (once daily). 1 to 500 mg per day per adult (when administered orally several times), or once or several times a day, or intravenously administered 1 to 24 hours per day If).

(Example)
The present invention will be described in detail below based on Examples, Formulation Examples and Test Examples. The scope of the present invention is not limited to these examples.

Example 1
4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine Ethyl isonipecotate (10.0 g) in THF (200 mL) at 0 ° C. with triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di-tert-butyl dicarbonate. (15.3 g) was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give ethyl N-Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. To a solution of acetonitrile (3.2 g) in THF (300 mL) was added n-BuLi (44 mmol) at −78 ° C. and stirred for 3 hours. Further ethyl N-Boc-piperidine-4-carboxylate (16.3 g) was added and the mixture was stirred for 1 hour. After acidifying with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5: 1)) to give 1- (N-Boc-piperidin-4-yl) -2 as a colorless oil. -Cyanoethane-1-one (11.6 g) was obtained. 2,1,3-Benzoxadiazole-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2- (N-Boc-piperidin-4-yl)-in acetonitrile (10 mL) A solution of 1-cyanoethane-2-one (1.7 g) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.
MP: 226 ^o C.
Calculated _{C 23 H 25 N 7 O 3} : C, 61.73; H, 5.63; N, 21.97.
Found: C, 61.45; H, 5.82; N, 21.61.
MS (EI): 447 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42 (9H, m), 1.59-1.62 (2H, m), 1.89-1.92 (2H, m), 2.62-2.86 (3H, m) , 4.05-4.08 (2H, m), 5.40 (1H, s), 7.26 (1H, s), 7.41 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.92 (1H, d, J = 9.0Hz), 9.81 (1H, brs), 12.24 (1H, brs).

Example 2
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine 4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine (1.7 g) was added to trifluoroacetic acid (20 mL) at 0 ° C. and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure. After alkalizing with sodium hydrogen carbonate, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.83 g) as yellow crystals.
MP: 216 ^o C.
MS (EI): 348 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.78-1.81 (2H, m), 2.07-2.11 (2H, m), 2.80-2.86 (3H, m), 3.27-3.30 (3H, m), 5.39 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.86 (1H, brs), 12.24 (1H, brs).

Example 3
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4 b] 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H- in pyridine MeOH (200 mL) To a solution of pyrazolo [3,4-b] pyridine (0.7 g) at room temperature was added 37% formaldehyde (0.18 g), sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) and the mixture was Stir overnight. After alkalizing with sodium hydrogen carbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals.
MP:> 270 ^o C.
MS (EI): 361 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.57-1.60 (2H, m), 1.82-1.88 (2H, m), 2.01-2.06 (2H, m), 2.15 (3H, s) , 2.58-2.61 (1H, m), 2.85-2.88 (2H, m), 5.40 (1H, s), 7.26 (1H, s), 7.40 (1H, d, J = 6.6Hz), 7.58 (1H, dd , J = 9.0Hz and 6.6Hz), 7.91 (1H, d, J = 9.0Hz), 9.76 (1H, brs), 12.17 (1H, brs).

Example 4
4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpiperidin-3-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl nipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 229 ^o C.
Calculated _{C 23 H 25 N 7 O 3} : C, 61.73; H, 5.63; N, 21.97.
Found: C, 61.56; H, 5.66; N, 21.67.
MS (EI): 447 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.32-1.40 (2H, m), 1.39 (9H, s), 1.69-1.78 (2H, m), 2.69-2.76 (2H, m) , 3.16-3.19 (1H, m), 3.92-3.95 (2H, m), 5.42 (1H, s), 7.28 (1H, s), 7.42 (1H, d, J = 6.6Hz), 7.58 (1H, dd , J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.87 (1H, brs), 12.21 (1H, brs).

Example 5
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-3-yl) -2H-pyrazolo [3,4-b] pyridine The title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpiperidin-3-yl) -5-cyano-4,7-dihydro-2H- Prepared from pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MP: 202 ^o C.
Calculated for C ₁₈ H ₁₇ N ₇ O: C, 62.24; H, 4.93; N, 28.23.
Found: C, 61.97; H, 5.13; N, 27.89.
MS (EI): 347 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42-1.45 (1H, m), 1.72-1.88 (3H, m), 2.66-2.84 (5H, m), 2.94-3.02 (1H, m), 5.38 (1H, s), 7.26 (1H, s), 7.39 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.91 (1H, d, J = 9.0Hz), 10.39 (1H, brs), 12.17 (1H, brs).

Example 6
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2H-pyrazolo [3,4 b] Pyridine The title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-3-yl) -2H-pyrazolo [3 , 4-b] pyridine was prepared in the same manner as in Example 3.
MP: 228 ^o C.
MS (EI): 361 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.76 (4H, m), 2.21 (3H, s), 2.47-2.55 (4H, m), 2.93-2.96 (1H, m) , 5.38 (1H, s), 7.27 (1H, s), 7.40 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 10.16 (1H, brs), 12.20 (1H, brs).

Example 7
4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpiperidin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl pipecolate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (EI): 447 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27 and 1.32 (9H, s), 1.42-1.97 (6H, m), 3.30-3.33 (1H, m), 3.53-3.61 (1H, m), 4.47-4.50 (1H, m), 5.37 and 5.39 (1H, s), 7.26 and 7.29 (1H, s), 7.38-7.44 (1H, m), 7.54-7.60 (1H, m), 7.90- 7.93 (1H, m), 9.63 and 9.73 (1H, brs), 12.16 (1H, brs).

Example 8
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-2-yl) -2H-pyrazolo [3,4-b] pyridine The title compound was converted to 4- (2,1,3-benzooxadiazol-4-yl) -6- (1-t-butoxycarbonylpiperidin-2-yl) -5-cyano-4,7-dihydro-2H- Prepared from pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MS (EI): 347 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27-1.88 (6H, m), 3.12-3.16 (1H, m), 4.12-4.15 (1H, m), 4.48-4.58 (1H, m), 5.64 and 5.66 (1H, s), 7.22-7.28 (1H, m), 7.45-7.52 (2H, m), 7.87-7.90 (1H, m), 8.26 (1H, br), 10.92 and 10.94 ( 1H, brs), 12.35 (1H, brs).

Example 9
4- (2,1,3-Benzoxadiazol-4-yl) -6- (4-tert-butoxycarbonylmorpholin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl morpholine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (EI): 449 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.36 and 1.40 (9H, s), 2.95-3.06 (2H, m), 3.50-3.52 (1H, m), 3.75-3.95 (3H, m), 4.34-4.40 (1H, m), 5.44 and 5.48 (1H, s), 7.26 and 7.30 (1H, s), 7.42-7.45 (1H, m), 7.57-7.62 (1H, m), 7.93- 7.96 (1H, m), 9.84 and 9.92 (1H, brs), 12.23 (1H, brs).

Example 10
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (morpholin-2-yl) -2H-pyrazolo [3,4-b] pyridine The title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -6- (4-tert-butoxycarbonylmorpholin-2-yl) -5-cyano-4,7-dihydro-2H- Prepared from pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MS (EI): 349 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.64-2.95 (4H, m), 3.53 (1H, br), 3.55-3.57 (1H, m), 3.82-3.85 (1H, m) , 4.41-4.45 (1H, m), 5.43 and 5.44 (1H, s), 7.24 and 7.28 (1H, s), 7.38-7.41 (1H, m), 7.56-7.61 (1H, m), 7.91-7.94 ( 1H, m), 9.74 and 9.76 (1H, brs), 12.19 (1H, brs).

Example 11
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2H-pyrazolo [3,4 b] Pyridine title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (morpholin-2-yl) -2H-pyrazolo [3 , 4-b] pyridine was prepared in the same manner as in Example 3.
MP: 143 ^o C.
MS (EI): 363 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.21 (3H, s), 2.19-2.30 (2H, m), 2.60-2.69 (2H, m), 3.60-3.62 (1H, m) , 3.88-3.92 (1H, m), 4.48-4.50 (1H, m), 5.44 (1H, s), 7.28 (1H, s), 7.39 (1H, d, J = 6.6Hz), 7.58 (1H, dd , J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.80 (1H, brs), 12.20 (1H, brs).

Example 12
4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) -5-cyano-4 , 7-Dihydro-2H-pyrazolo [3,4-b] pyridine The title compound is converted to ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde. And 3-aminopyrazole in the same manner as in Example 1.
MP: 222 ^o C.
MS (EI): 445 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 2.35-2.39 (2H, m), 3.46-3.48 (2H, m), 3.90-3.92 (2H, m) , 5.43 (1H, s), 6.06-6.09 (1H, m), 7.28 (1H, s), 7.45 (1H, d, J = 6.6Hz), 7.60 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.93 (1H, d, J = 9.0Hz), 9.94 (1H, brs), 12.19 (1H, brs).

Example 13
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1,2,3,6-tetrahydropyridin-4-yl) -2H- The title compound of pyrazolo [3,4-b] pyridine is converted to 4- (2,1,3-benzoxadiazol-4-yl) -6- (1-t-butoxycarbonyl-1,2,3,4-tetrahydro Prepared in the same manner as in Example 2 from pyridin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine.
MP: 180 ^o C.
MS (EI): 345 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.26-2.32 (2H, m), 2.87-2.90 (2H, m), 3.30-3.36 (3H, m), 5.42 (1H, s) , 6.09-6.10 (1H, m), 7.30 (1H, s), 7.43 (1H, d, J = 6.6Hz), 7.60 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.87 (1H, brs), 12.18 (1H, brs).

Example 14
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl ) -2H -pyrazolo [3,4-b] pyridine The title compound is converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1, 2,3,6-Tetrahydropyridin-4-yl) -2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as Example 3.
MP: 218 ^o C.
MS (EI): 359 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.24 (3H, s), 2.35-2.42 (2H, m), 2.91-2.93 (2H, m), 3.31-3.33 (2H, m) , 5.42 (1H, s), 6.04-6.05 (1H, m), 7.27 (1H, s), 7.43 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.92 (1H, d, J = 9.0Hz), 9.87 (1H, brs), 12.17 (1H, brs).

Example 15
4- (2,1,3-Benzoxadiazol-4-yl) -6- (2- (Nt-butoxycarbonyl-N-methylamino) ethyl) -5-cyano-4,7-dihydro- To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in 2H-pyrazolo [3,4-b] pyridine THF (600 mL) at 0 ° C. triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di- -Tert-Butyl dicarbonate (30 g) was added and the mixture was stirred at 40 ° C. for 4 h. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give ethyl N-Boc-3-aminopropionate (16.7 g) as a colorless oil. To a solution of ethyl N-Boc-3-aminopropionate (5.0 g) in THF (50 mL) at 0 ° C. was added t-BuOK (2.8 g) and methyl iodide (4.9 g) and the mixture was Stir at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give ethyl 3- (N-Boc-N-methylamino) propionate (4.3 g) as a colorless oil. The title compound was then prepared in the same manner as Example 1 from ethyl 3- (N-Boc-N-methylamino) propionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 240 ^o C.
Calculated _{C 21 H 23 N 7 O 3} : C, 59.85; H, 5.50; N, 23.26.
Found: C, 59.69; H, 5.45; N, 23.22.
MS (EI): 421 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.26 and 2.32 (9H, s), 2.62-2.63 (2H, m), 2.81 (3H, s), 3.48-3.55 (2H, m) , 5.40 (1H, s), 7.27 (1H, s), 7.40 (1H, d, J = 6.6Hz), 7.57 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 10.07 (1H, brs), 12.15 (1H, brs).

Example 16
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2- (N-methylamino) ethyl) -2H-pyrazolo [3,4 -B ] pyridine The title compound is 4- (2,1,3-benzoxadiazol-4-yl) -6- (2- (Nt-butoxycarbonyl-N-methylamino) ethyl) -5-cyano. Prepared from -4,7-dihydro-2H-pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MP: 174 ^o C.
MS (EI): 321 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.29 (3H, s), 2.50-2.78 (4H, m), 3.31 (3H, br), 5.39 (1H, s), 7.24 (1H , s), 7.43 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.91 (1H, d, J = 9.0Hz).

Example 17
4- (2,1,3-Benzoxadiazol-4-yl) -6- (2- (Nt-butoxycarbonylamino) ethyl) -5-cyano-4,7-dihydro-2H-pyrazolo [ The 3,4-b] pyridine title compound was prepared in the same manner as Example 1 from ethyl 3-aminopropionate hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 231 ^o C.
Calculated for C ₂₀ H ₂₁ N ₇ O ₃ : C, 58.96; H, 5.20; N, 24.06.
Found: C, 58.81; H, 5.19; N, 23.82.
MS (EI): 407 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.33 (9H, s), 2.55-2.60 (2H, m), 3.23-3.33 (2H, m), 5.41 (1H, s), 6.81 (1H, brs), 7.25 (1H, s), 7.44 (1H, d, J = 6.6Hz), 7.57 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz ), 9.94 (1H, brs), 12.14 (1H, brs).

Example 18
6- (2-Aminoethyl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -6- (2- (Nt-butoxycarbonylamino) ethyl) -5-cyano-4,7-dihydro-2H- Prepared from pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MS (EI): 307 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.50-2.54 (2H, m), 2.88 (2H, t, J = 7.3 Hz), 3.35 (4H, br), 5.40 (1H, s ), 7.25 (1H, s), 7.44 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz).

Example 19
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2-N, N-dimethylamino) ethyl) -2H-pyrazolo [3 4-b] pyridine The title compound is 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2- (N-methylamino) ethyl). Prepared in the same manner as Example 3 from -2H-pyrazolo [3,4-b] pyridine.
MP: 215 ^o C.
MS (EI): 335 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.19 (6H, s), 2.45-2.62 (4H, m), 5.41 (1H, s), 7.27 (1H, s), 7.43 (1H , d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 10.04 (1H, brs), 12.16 (1H, brs).

Example 20
4- (2,1,3-Benzoxadiazol-4-yl) -6-((Nt-butoxycarbonyl-N-methylamino) methyl) -5-cyano-4,7-dihydro-2H- The pyrazolo [3,4-b] pyridine title compound was prepared in the same manner as Example 15 from glycine ethyl ester hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 207 ^o C.
Calculated for C ₂₀ H ₂₁ N ₇ O ₃ : C, 58.96; H, 5.20; N, 24.06.
Found: C, 58.80; H, 5.12; N, 24.38.
MS (EI): 407 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.33 and 1.39 (9H, s), 2.81 (3H, s), 4.13-4.20 (2H, m), 5.42 (1H, s), 7.29 (1H, s), 7.43 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.94 (1H, d, J = 9.0Hz), 9.33 (1H, brs ), 12.15 (1H, brs).

Example 21
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6-((N-methylamino) methyl) -2H-pyrazolo [3,4-b ] Pyridine trifluoroacetate 4- (2,1,3-Benzoxadiazol-4-yl) -6-((Nt-butoxycarbonyl-N-methylamino) methyl) -5-cyano-4, 7-Dihydro-2H-pyrazolo [3,4-b] pyridine (0.6 g) was added to trifluoroacetic acid (10 mL) at 0 ° C. and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, the residue was crystallized with ethanol, and the precipitated crystals were collected by filtration to give the title compound (0.1 g) as yellow crystals.
MP: 174 ^o C.
MS (EI): 307 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 3.10 (3H, s), 4.51-4.68 (2H, m), 7.24 (1H, d, J = 6.6Hz), 7.45 (1H, s ), 7.52 (1H, dd, J = 9.0Hz and 6.6Hz), 7.89 (1H, d, J = 9.0Hz), 8.08-8.20 (2H, br), 10.81 (1H, brs), 12.41 (1H, brs ).

Example 22
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4- (N-methylamino) cyclohexyl) -2H-pyrazolo [3,4 -B ] Pyridine The title compound was prepared from ethyl 4-aminocyclohexanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole as in Example 15 followed by Example 2.
MS (EI): 375 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.32-1.35 (2H, m), 1.81-2.12 (6H, m), 2.57 (3H, s), 2.65-2.69 (1H, m) , 2.81-2.85 (1H, m), 5.39 (1H, s), 7.28 (1H, s), 7.41 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.92 (1H, d, J = 9.0Hz), 8.54 (1H, br), 9.79 (1H, brs), 12.22 (1H, brs).

Example 23
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4- (N, N-dimethylamino) cyclohexyl) -2H-pyrazolo [3 , 4-b] pyridine The title compound is converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4- (N-methylamino) cyclohexyl. ) -2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as in Example 3.
MP: 241 ^o C.
MS (EI): 389 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.15-2.02 (9H, m), 2.15 and 2.21 (6H, s), 2.62-2.76 (1H, m), 5.38 and 5.43 (1H, s), 7.26 (1H, s), 7.38-7.44 (1H, m), 7.56-7.62 (1H, m), 7.90-7.96 (1H, m), 9.74 (1H, brs), 12.18 (1H, brs) .

Example 24
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-phenylpiperidin-4-yl) -2H-pyrazolo [3,4 b] To a solution of ethyl isonipecotate (8.9 g) in pyridine CH ₂ Cl ₂ (500 mL) at room temperature was added triphenylbismuth (25 g) and copper (II) acetate (10.3 g) and the mixture was stirred overnight. . After filtration, the mixture was extracted with _CH 2 Cl _2. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as colorless crystals. Obtained. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-BuLi (41 mmol) at -78 ° C. Further ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for 1 hour. After acidifying with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give 1- (1-phenylpiperidin-4-yl) -2-cyanoethane-1- On (2.0 g) was obtained as colorless crystals. 2,1,3-Benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1- (1-phenylpiperidin-4-yl) -2 in acetonitrile (10 mL) -A solution of cyanoethane-1-one (0.5 g) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.
MS (FAB): 424 (M ⁺ +1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.73-1.76 (2H, m), 2.14-2.18 (2H, m), 2.62-2.66 (2H, m), 2.81-2.84 (1H, m), 3.80-3.84 (2H, m), 5.41 (1H, s), 6.75 (1H, dd, J = 7.3Hz and 7.2Hz), 6.94-6.96 (2H, m), 7.18-7.27 (3H, m ), 7.42 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.81 (1H, brs), 12.17 ( 1H, brs).

Example 25
6- (1-Acetylpiperidin-4-yl) -4- (2,1,3-benzooxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4 b] To a solution of ethyl isonipecotate (8.0 g) in pyridine THF (100 mL) at 0 ° C., triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) were added and the mixture was Stir for 1 hour. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. N-BuLi (57 mmol) was added to a solution of acetonitrile (2.5 g) in THF (300 mL) at -78 ° C. Further ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for 1 hour. After acidifying with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give 1- (1-acetylpiperidin-4-yl) -2-cyanoethane-1- On (7.5 g) was obtained as a colorless oil. 2,1,3-Benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1- (1-acetylpiperidin-4-yl) -2 in acetonitrile (10 mL) -A solution of cyanoethane-1-one (0.4 g) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
MP: 248 ^o C.
MS (FAB): 340 (M ⁺⁺ 1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.62-1.64 (2H, m), 1.82-1.84 (1H, m), 2.00-2.02 (4H, m), 2.49-2.50 (1H, m), 2.94-3.07 (2H, m), 3.89-3.92 (1H, m), 4.48-4.51 (1H, m), 5.40 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.81 (1H, brs), 12.18 (1H, brs).

Example 26
4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-benzoylpiperidin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4 b] Pyridine The title compound was prepared in the same manner as Example 25 from benzoyl chloride, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 228 ^o C.
MS (FAB): 452 (M ⁺ +1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.59-1.76 (2H, m), 2.04-2.08 (2H, m), 2.76-2.80 (1H, m), 3.01-3.09 (2H, m), 3.58-3.60 (1H, m), 4.60-4.63 (1H, m), 5.41 (1H, s), 7.28 (1H, s), 7.43-7.46 (6H, m), 7.56-7.59 (1H, m), 7.92 (1H, d, J = 9.0Hz), 9.90 (1H, brs), 12.21 (1H, brs).

Example 27
6- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7- Dihydro-2H-pyrazolo [3,4-b] pyridine The title compound was converted to acetyl chloride, ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde. And 3-aminopyrazole were prepared in the same manner as Example 25.
MP: 237 ^o C.
MS (EI): 387 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.00 and 2.04 (3H, s), 2.46-2.49 (2H, m), 3.55-3.58 (2H, m), 4.00-4.06 (2H, m), 5.44 (1H, s), 6.10 (1H, s), 7.29 (1H, s), 7.45 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.93 (1H, d, J = 9.0Hz), 9.94 (1H, brs), 12.17 (1H, brs).

Example 28
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1- (ethoxycarbonyl) piperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine The title compound was prepared in the same manner as Example 25 from ethyl chloroformate, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (EI): 419 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.19 (3H, t, J = 7.3 Hz), 1.61-1.63 (2H, m), 1.90-1.94 (2H, m), 2.84-2.88 (3H, m), 4.02-4.07 (4H, m), 5.40 (1H, s), 7.26 (1H, s), 7.41 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.80 (1H, brs), 12.17 (1H, brs).

Example 29
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-4-yl) -2H-pyrazolo [3,4 -B ] pyridine The title compound was prepared in the same manner as Example 25 from methanesulfonyl chloride, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 243 ^o C.
MS (EI): 425 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.73-1.76 (2H, m), 2.04-2.08 (2H, m), 2.74-2.78 (3H, m), 2.88 (3H, s) , 3.66-3.69 (2H, m), 5.41 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.93 (1H, d, J = 9.0Hz), 9.84 (1H, brs), 12.20 (1H, brs).

Example 30
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1- (N, N-dimethylaminocarbonyl) piperidin-4-yl)- 2H-pyrazolo [3,4-b] pyridine The title compound was prepared from 1-chloro-N, N-dimethylformamide, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole. This was produced in the same manner as 25.
MS (EI): 418 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.61-1.63 (2H, m), 2.00-2.06 (2H, m), 2.65-2.67 (2H, m), 2.75 (6H, s) , 2.81-2.85 (1H, m), 3.64-3.67 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.41 (1H, d, J = 6.6Hz), 7.59 (1H, dd , J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.86 (1H, brs), 12.18 (1H, brs).

Example 31
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-guanylpiperidin-4-yl) -2H-pyrazolo [3,4 b] 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H- in pyridine MeOH (30 mL) To a solution of pyrazolo [3,4-b] pyridine (1.5 g) was added diisopropylethylamine (4.2 g) and 1H-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. . The precipitated crystals were collected by filtration to give the title compound (1.0 g) as yellow crystals.
MP:> 270 ^o C.
MS (EI): 389 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.56 (2H, m), 1.86-1.91 (2H, m), 2.47-2.50 (2H, m), 2.71-2.77 (1H, m), 3.00-3.03 (2H, m), 3.32-3.36 (3H, br), 5.39 (1H, s), 7.26 (1H, s), 7.39 (1H, d, J = 6.6Hz), 7.59 (1H , dd, J = 9.0Hz and 6.6Hz), 7.91 (1H, d, J = 9.0Hz), 9.79 (1H, brs), 12.21 (1H, brs).

Example 32
6- (1-acetylpiperidin-3-yl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4 b] Pyridine The title compound was prepared in the same manner as Example 25 from acetyl chloride, ethyl nipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 219 ^o C.
Calculated for C ₂₀ H ₁₉ N ₇ O ₂ : C, 61.69; H, 4.92; N, 25.18.
Found: C, 61.36; H, 4.90; N, 25.12.
MS (EI): 389 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.25-1.49 (1H, m), 1.74-1.78 (2H, m), 2.00 (3H, s), 2.01-2.04 (1H, m) , 2.49-2.98 (3H, m), 3.78-3.81 (1H, m), 4.37-4.40 (1H, m), 5.29 and 5.42 (1H, s), 7.28 (1H, s), 7.41-7.48 (1H, m), 7.58-7.62 (1H, m), 7.92-7.95 (1H, m), 9.90 (1H, brs), 12.21 (1H, brs).

Example 33
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-ethylpiperidin-4-yl) -2H-pyrazolo [3,4 b] Pyridine title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine and acetaldehyde were prepared in the same manner as in Example 3.
MP: 231 ^o C.
MS (EI): 375 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.99 (3H, t, J = 7.3 Hz), 1.60-1.63 (2H, m), 1.85-1.88 (2H, m), 2.00-2.04 (2H, m), 2.31-2.34 (2H, m), 2.64-2.66 (1H, m), 2.97-3.00 (2H, m), 5.39 (1H, s), 7.26 (1H, s), 7.40 (1H , d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.75 (1H, brs), 12.18 (1H, brs).

Example 34
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-propylpiperidin-4-yl) -2H-pyrazolo [3,4 b] Pyridine title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine and propionaldehyde were prepared in the same manner as in Example 3.
MP: 246 ^o C.
Calculated for C ₂₁ H ₂₃ N ₇ O: C, 64.76; H, 5.95; N, 25.18.
Found: C, 64.23; H, 5.87; N, 24.86.
MS (EI): 389 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 7.3 Hz), 1.40-1.45 (2H, m), 1.59-1.62 (2H, m), 1.82-1.86 (2H, m), 2.00-2.05 (2H, m), 2.21 (2H, t, J = 7.3Hz), 2.62-2.65 (1H, m), 2.94-2.97 (2H, m), 5.39 (1H, s ), 7.26 (1H, s), 7.40 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.91 (1H, d, J = 9.0Hz), 9.77 ( 1H, brs), 12.18 (1H, brs).

Example 35
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-isopropylpiperidin-4-yl) -2H-pyrazolo [3,4 b] Pyridine title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine and acetone in the same manner as in Example 3.
MP: 260 ^o C.
MS (EI): 389 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.22 (6H, d, J = 7.3 Hz), 1.82-3.42 (10H, m), 5.40 (1H, s), 7.27 (1H, s ), 7.42 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.66 (1H, brs), 12.22 ( 1H, brs).

Example 36
4- (2-Bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP:> 270 ^o C.
Calculated for C ₂₄ H ₂₅ BrN ₆ O ₂ : C, 56.59; H, 4.95; N, 16.50.
Found: C, 56.47; H, 4.87; N, 16.52.
MS (EI): 509 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.59-1.66 (2H, m), 1.85-1.90 (2H, m), 2.65-2.82 (3H, m) , 4.05-4.07 (2H, m), 5.47 (1H, s), 7.33 (1H, s), 7.56-7.60 (2H, m), 7.84 (1H, d, J = 7.3Hz), 9.81 (1H, brs ), 12.26 (1H, brs).

Example 37
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Example from 2-bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 was produced in the same manner.
MP:> 270 ^o C.
MS (EI): 409 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.56 (2H, m), 1.83-1.87 (2H, m), 2.46-2.50 (3H, m), 2.71-2.74 (1H, m), 3.00-3.04 (1H, m), 5.45 (1H, s), 7.32 (1H, s), 7.56-7.58 (2H, m), 7.81 (1H, d, J = 7.3Hz), 9.74 (1H , brs), 12.26 (1H, brs).

Example 38
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Same as Example 3 from 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Produced by the method.
MP:> 270 ^o C.
MS (EI): 423 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.65-1.71 (2H, m), 2.02-2.08 (3H, m), 2.29 (3H, s), 2.48-2.52 (1H, m) , 1.66-1.69 (1H, m), 2.95-2.98 (2H, m), 5.50 (1H, s), 7.34 (1H, s), 7.55-7.57 (2H, m), 7.83 (1H, d, J = 7.3Hz), 9.83 (1H, brs), 12.32 (1H, brs).

Example 39
4- (2-Bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-3-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl nipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP: 238 ^o C.
Calculated for C ₂₄ H ₂₅ BrN ₆ O ₂ : C, 56.56; H, 4.95; N, 16.50.
Found: C, 56.49; H, 4.85; N, 16.50.
MS (EI): 509 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.37 and 1.39 (9H, s), 1.68-2.06 (4H, m), 2.65-2.75 (2H, m), 3.30-3.32 (1H, m), 3.94-3.97 (2H, m), 5.47 and 5.49 (1H, s), 7.34 (1H, s), 7.58-7.61 (2H, m), 7.82-7.86 (1H, m), 9.89 (1H, brs), 12.31 (1H, brs).

Example 40
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-3-yl) -2H-pyrazolo [3,4-b] pyridine trifluoroacetate title compound 4- (2-Bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-3-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] Prepared from pyridine in the same manner as in Example 21.
MP: 225 ^o C.
Calculated for C ₁₉ H ₁₇ BrN ₆ CF ₃ COOH: C, 48.20; H, 3.47; N, 16.06.
Found: C, 47.98; H, 3.52; N, 15.97.
MS (EI): 409 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.68-1.98 (4H, m), 2.65-2.68 (1H, m), 3.21-3.33 (4H, m), 5.50 (1H, s) , 7.35 (1H, s), 7.55-7.66 (2H, m), 7.84-7.87 (1H, m), 8.54 (1H, br), 8.96 (1H, br), 9.96 (1H, brs), 12.36 (1H , br).

Example 41
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2H-pyrazolo [3,4-b] pyridine Performed from 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-3-yl) -2H-pyrazolo [3,4-b] pyridine trifluoroacetate Prepared in the same manner as Example 3.
MP: 174 ^o C.
MS (EI): 423 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.54-1.78 (4H, m), 2.18-2.20 (1H, m), 2.20 (3H, s), 2.55-2.58 (2H, m) , 2.94-2.96 (1H, m), 3.31-3.34 (1H, m), 5.47 (1H, s), 7.33 (1H, s), 7.57-7.58 (2H, m), 7.84 (1H, d, J = 7.3Hz), 10.06 (1H, brs), 12.29 (1H, brs).

Example 42
4- (2-Bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl pipecolate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MS (EI): 509 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.35 (9H, s), 1.34-1.90 (6H, m), 3.48-3.52 (2H, m), 4.42-4.48 (1H, m) , 5.43 and 5.46 (1H, s), 7.36-7.39 (1H, m), 7.53-7.57 (2H, m), 7.80-7.83 (1H, m), 9.68 and 9.82 (1H, brs), 12.26 (1H, brs).

Example 43
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-2-yl) -2H-pyrazolo [3,4-b] pyridine trifluoroacetate title compound 4- (2-bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] Prepared from pyridine in the same manner as in Example 21.
MP: 232 ^o C.
MS (EI): 409 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27-1.98 (5H, m), 2.47-2.51 (2H, m), 3.12-3.18 (1H, m), 4.7-4.10 (1H, m), 4.50-4.57 (1H, m), 7.40-7.63 (3H, m), 7.79-7.82 (2H, m), 8.06 (1H, br), 10.93 (1H, brs), 12.41 (1H, brs) .

Example 44
4- (2-Bromo-3-cyanophenyl) -6- (4-t-butoxycarbonylmorpholin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl morpholine-2-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP: 219 ^o C.
MS (EI): 511 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.40 (9H, s), 2.97-3.10 (2H, m), 3.47-3.53 (1H, m), 3.77-3.94 (3H, m) , 4.37-4.39 (1H, m), 5.52 and 5.54 (1H, s), 7.34-7.36 (1H, m), 7.58-7.65 (2H, m), 7.94-7.96 (1H, m), 9.87 and 9.92 ( 1H, brs), 12.33 (1H, brs).

Example 45
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (morpholin-2-yl) -2H-pyrazolo [3,4-b] pyridine trifluoroacetate title compound 4- (2-bromo-3-cyanophenyl) -6- (4-t-butoxycarbonylmorpholin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] Prepared from pyridine in the same manner as in Example 21.
MP: 236 ^o C.
MS (EI): 411 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.02-3.05 (1H, m), 3.24-3.33 (3H, m), 3.80-3.84 (1H, m), 4.08-4.11 (1H, m), 4.82-4.85 (1H, m), 5.55 (1H, s), 7.36 (1H, s), 7.55-7.62 (2H, m), 7.84-7.87 (1H, m), 9.14 (2H, br) , 10.04-10.09 (1H, brs), 12.40 (1H, brs).

Example 46
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2H-pyrazolo [3,4-b] pyridine Performed from 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (morpholin-2-yl) -2H-pyrazolo [3,4-b] pyridine trifluoroacetate Prepared in the same manner as Example 3.
MP: 180 ^o C.
MS (EI): 425 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.18-2.20 (1H, m), 2.20 and 2.21 (3H, s), 2.26-2.29 (1H, m), 2.58-2.62 (1H, m), 2.75-2.78 (1H, m), 3.58-3.62 (1H, m), 3.88-3.91 (1H, m), 4.48-4.50 (1H, m), 5.51 (1H, s), 7.35 (1H, s), 7.56-7.61 (2H, m), 7.84-7.86 (1H, m), 9.81 and 9.84 (1H, brs), 12.31 (1H, brs).

Example 47
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,2,3,6-tetrahydropyridin-4-yl) -2H-pyrazolo [3,4 b] Pyridine The title compound was prepared from ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole as in Example 1, followed by Example 2. did.
MP: 226 ^o C.
MS (EI): 407 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.36-2.40 (2H, m), 2.95-2.98 (2H, m), 3.56-3.60 (3H, m), 5.51 (1H, s) , 6.15 (1H, s), 7.34 (1H, s), 7.56-7.60 (2H, m), 7.84 (1H, d, J = 7.3Hz), 9.93 (1H, brs), 12.32 (1H, brs).

Example 48
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -2H-pyrazolo [ 3,4-b] pyridine The title compound is converted to 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,2,3,6-tetrahydropyridin-4-yl ) -2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as in Example 3.
MP: 233 ^o C.
MS (EI): 421 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.31 (3H, s), 2.56-2.67 (4H, m), 3.00-3.03 (2H, m), 5.50 (1H, s), 6.10 (1H, s), 7.34 (1H, s), 7.58-7.60 (2H, m), 7.83 (1H, d, J = 7.3Hz), 9.91 (1H, brs), 12.29 (1H, brs).

Example 49
4- (2-Bromo-3-cyanophenyl) -6-((Nt-butoxycarbonyl-N-methylamino) methyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4 b] Pyridine The title compound was prepared in the same manner as Example 15 from glycine ethyl ester hydrochloride, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MS (EI): 469 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39 (9H, s), 2.85 (3H, s), 4.15-4.18 (2H, m), 5.49 (1H, s), 7.37 (1H , s), 7.56-7.57 (2H, m), 7.83 (1H, d, J = 7.3Hz), 9.78-9.93 (1H, br), 12.31 (1H, brs).

Example 50
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6-((N-methylamino) methyl) -2H-pyrazolo [3,4-b] pyridine trifluoroacetate The title compound was converted to 4- (2-bromo-3-cyanophenyl) -6-((Nt-butoxycarbonyl-N-methylamino) methyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine was prepared in the same manner as in Example 21.
MP: 258 ^o C.
MS (EI): 369 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.10 (3H, s), 4.46-4.66 (2H, m), 5.50 (1H, s), 7.47-7.48 (2H, m), 7.65 (1H, s), 7.80-7.81 (2H, m), 8.09 (1H, br), 10.81 (1H, brs), 12.38 (1H, brs).

Example 51
6- (1-acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as in Example 25 from acetyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP:> 280 ^o C.
MS (EI): 451 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.63-1.82 (3H, m), 1.98-2.00 (1H, m), 2.00 (3H, s), 2.49-2.51 (1H, m) , 2.94-3.10 (2H, m), 3.89-3.91 (1H, m), 4.48-4.50 (1H, m), 5.47 (1H, s), 7.34 (1H, s), 7.56-7.58 (2H, m) , 7.84 (1H, d, J = 7.3Hz), 9.81 (1H, brs), 12.27 (1H, brs).

Example 52
6- (1-Benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as in Example 25 from benzoyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP:> 280 ^o C.
MS (FAB): 514 (M ⁺ +1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.64-2.04 (4H, m), 2.76-2.80 (1H, m), 3.05-3.10 (2H, m), 3.60-3.63 (1H, m), 4.62-4.65 (1H, m), 5.48 (1H, s), 7.34-7.58 (8H, m), 7.84 (1H, d, J = 7.3Hz), 9.90 (1H, brs), 12.31 (1H , brs).

Example 53
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine title compound Was prepared in the same manner as Example 25 from methanesulfonyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP:> 280 ^o C.
MS (EI): 487 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.75-2.07 (4H, m), 2.76-2.79 (2H, m), 2.89 (3H, s), 3.66-3.69 (2H, m) , 5.48 (1H, s), 7.34 (1H, s), 7.56-7.58 (2H, m), 7.84 (1H, d, J = 7.3Hz), 9.84 (1H, brs), 12.30 (1H, brs).

Example 54
6- (1-t-Butoxycarbonylpiperidin-4-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound is ethyl isonipecotate , 2-chlorobenzaldehyde and 3-aminopyrazole were prepared in the same manner as in Example 1.
MP:> 280 ^o C.
Calculated for C ₂₃ H ₂₆ ClN ₅ O ₂ : C, 62.79; H, 5.96; N, 15.92.
Found: C, 62.81; H, 5.87; N, 16.01.
MS (EI): 439 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.58-1.67 (2H, m), 1.86-1.91 (2H, m), 2.84-2.90 (3H, m) , 4.06-4.09 (2H, m), 5.35 (1H, s), 7.21-7.33 (4H, m), 7.42 (1H, d, J = 7.3Hz), 9.69 (1H, brs), 12.18 (1H, brs ).

Example 55
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine The title compound is converted to 6- (1-t-butoxy Prepared in the same manner as in Example 2 from carbonylpiperidin-4-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine.
MP: 221 ^o C.
MS (EI): 339 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.92 (2H, m), 2.10-2.16 (2H, m), 2.96-3.00 (3H, m), 3.30-3.40 (2H, m), 5.36 (1H, s), 7.22-7.33 (4H, m), 7.42 (1H, d, J = 7.2Hz), 8.56 (1H, br), 9.76 (1H, brs), 12.26 (1H, brs ).

Example 56
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared from trifluoroacetate salt in the same manner as Example 3.
MP:> 270 ^o C.
Calculated for C ₁₉ H ₂₀ ClN ₅ : C, 64.49; H, 5.70; N, 19.79.
Found: C, 64.71; H, 5.68; N, 19.59.
MS (EI): 353 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.56-1.65 (2H, m), 1.84-1.90 (2H, m), 2.02-2.06 (2H, m), 2.16 (3H, s) , 2.60-2.65 (1H, m), 2.85-2.88 (2H, m), 5.34 (1H, s), 7.21-7.33 (4H, m), 7.41 (1H, d, J = 7.3Hz), 9.63 (1H , brs), 12.17 (1H, brs).

Example 57
2-acetyl-6- (1-acetylpiperidin-4-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridinepyridine (1. Solution of 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine (1.0 g) in 2 mL) Was added acetic anhydride (0.42 mL) at room temperature and the mixture was stirred for 2 h. The mixture was evaporated under reduced pressure, the residue was washed with methanol, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.
MS (EI): 423 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.58-1.70 (2H, m), 1.91-1.96 (1H, m), 1.99-2.00 (1H, m), 2.02 (3H, s) , 2.51 (3H, s), 2.55-2.58 (1H, m), 3.11-3.18 (2H, m), 3.91-3.94 (1H, m), 4.49-4.52 (1H, m), 5.37 (1H, s) , 7.32-7.37 (3H, m), 7.48 (1H, d, J = 7.3Hz), 7.84 (1H, s), 10.24 (1H, brs).

Example 58
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexane-1-yl) -2H-pyrazolo [3,4 b] Ethylene glycol (10.1 g) and p-toluenesulfonic acid (2.8 g) were added at room temperature to a solution of ethyl 2-cyclohexanone carboxylate (25 g) in pyridine toluene (200 mL) and the mixture was added to a Dean-Stark apparatus. And heated at reflux for 5 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)), and ethyl 1,4-dioxa-spiro [4, 5] Decane-6-carboxylate (31 g) was obtained as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at -78 ° C. Further ethyl 1,4-dioxa-spiro [4,5] decane-6-carboxylate (31 g) was added and the mixture was stirred for 1 hour. After acidifying with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give 1-cyano-2- (1,4-dioxa-spiro [4,5]. Decan-6-yl) ethane-2-one (14.5 g) was obtained as a colorless oil. 2,1,3-Benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2- (1,4-dioxa-spiro in acetonitrile (10 mL) A solution of [4,5] decan-6-yl) ethane-2-one (1.2 g) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, and 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1 , 4-Dioxa-spiro [4,5] decan-6-yl) -2H-pyrazolo [3,4-b] pyridine (1.3 g) was obtained as colorless crystals.
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1,4-dioxa-spiro [4,5] in methanol (30 mL) To a solution of decan-6-yl) -2H-pyrazolo [3,4-b] pyridine (1.0 g) was added 4N HCl dioxane solution (6.0 mL) at room temperature and the mixture was heated at 60 ° C. for 2 h. After alkalizing with sodium bicarbonate, the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to obtain the title compound (20 mg) as colorless crystals.
MP:> 270 ^o C.
MS (EI): 360 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.74-1.80 (5H, m), 2.60-2.65 (3H, m), 3.31-3.35 (1H, m), 5.98 (1H, s) , 6.92 (1H, d, J = 6.6Hz), 7.39 (1H, s), 7.47 (1H, dd, J = 9.0Hz and 6.6Hz), 7.84 (1H, d, J = 9.0Hz), 9.33 (1H , brs), 12.15 (1H, brs).

Example 59
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-oxocyclohexane-1-yl) -2H-pyrazolo [3,4 b] Pyridine The title compound was prepared in the same manner as Example 58 from ethyl 4-cyclohexanone carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (FAB): 361 (M ⁺ +1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.96-2.12 (3H, m), 2.22-2.30 (3H, m), 2.48-2.51 (1H, m), 3.27-3.31 (2H, m), 5.42 (1H, s), 7.26 (1H, s), 7.38-7.46 (1H, m), 7.57-7.61 (1H, m), 7.88-7.95 (1H, m), 9.76 (1H, brs) , 12.16 (1H, br).

Example 60
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2-oxocyclopentan-1-yl) -2H-pyrazolo [3,4 -B ] pyridine The title compound was prepared in the same manner as Example 58 from ethyl 2-cyclopentanone carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (FAB): 347 (M ⁺ +1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.60-1.63 (2H, m), 1.86-2.05 (2H, m), 2.31-2.34 (2H, m), 3.43-3.46 (1H, m), 5.47 (1H, s), 7.25 and 7.30 (1H, s), 7.39-7.46 (1H, m), 7.56-7.60 (1H, m), 7.91-7.94 (1H, m), 9.90 (1H, brs), 12.20 (1H, brs).

Example 61
6-acetylmethyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 58 from acetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MP: 200 ^o C.
MS (FAB): 321 (M ⁺ +1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.22 (3H, s), 3.63-3.66 (2H, m), 5.48 (1H, s), 7.30 (1H, s), 7.47 (1H , d, J = 6.6Hz), 7.61 (1H, dd, J = 9.0Hz and 6.6Hz), 7.94 (1H, d, J = 9.0Hz), 10.00 (1H, brs), 12.21 (1H, brs).

Example 62
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexane-1-yl) -2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 58 from ethyl 2-cyclohexanone carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MP: 273 ^o C.
MS (EI): 422 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.72-1.81 (5H, m), 2.59-2.65 (3H, m), 3.30-3.32 (1H, m), 5.91 (1H, s) , 7.05 (1H, d, J = 7.3Hz), 7.40-7.43 (2H, m), 7.52 (1H, s), 7.74 (1H, d, J = 7.3Hz), 9.33 (1H, brs), 12.24 ( 1H, brs).

Example 63
6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound is ethyl acetoacetate, 2-bromo- Prepared in the same manner as in Example 58 from 3-cyanobenzaldehyde and 3-aminopyrazole.
MP: 230 ^o C.
MS (EI): 382 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.23 (3H, s), 3.60-3.67 (2H, m), 5.50 (1H, s), 7.39 (1H, s), 7.60 (1H , dd, J = 7.3Hz and 7.2Hz), 7.70 (1H, d, J = 7.3Hz), 7.83 (1H, d, J = 7.3Hz), 9.97 (1H, brs), 12.29 (1H, brs).

Example 64
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride 4- (2-Chlorophenyl) -5 -Cyano-4,7-dihydro-6- (1-t-butoxycarbonylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine (2.0 g) at 0 ° C. in 4N HCl dioxane solution (20 mL) and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, the residue was washed with ethanol, and the precipitated crystals were collected by filtration to give the title compound (1.2 g) as yellow crystals.
MS (EI): 339 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.83-1.90 (2H, m), 2.07-2.15 (2H, m), 2.94-2.97 (3H, m), 3.34-3.37 (2H, m), 5.36 (1H, s), 7.22-7.33 (4H, m), 7.42 (1H, d, J = 7.3Hz), 8.41 (1H, br), 9.17 (1H, br), 9.77 (1H, brs ), 12.27 (1H, brs).

Example 65
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine The hydrochloride title compound is converted to 4- (2,1,3-benzoxadiazol-4-yl) -6- (1-tert-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro- Prepared in the same manner as in Example 64 from 2H-pyrazolo [3,4-b] pyridine.
MP:> 270 ^o C.
Calculated for C ₁₈ H ₁₇ N ₇ OHCl: C, 56.09; H, 5.20; N, 24.10.
Found: C, 55.80; H, 5.00; N, 23.80.
MS (EI): 347 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.82-1.85 (2H, m), 2.14-2.20 (2H, m), 2.93-2.99 (3H, m), 3.34-3.36 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J = 6.6Hz), 7.58 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 8.44 (1H, br), 9.21 (1H, br), 9.87 (1H, brs), 12.25 (1H, brs).

Example 66
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride 4 From-(2-bromo-3-cyanophenyl) -6- (1-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as in Example 64.
MP:> 270 ^o C.
MS (EI): 409 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.92 (2H, m), 2.07-2.10 (2H, m), 2.92-2.98 (5H, m), 5.48 (1H, s) , 7.34 (1H, s), 7.57-7.59 (2H, m), 7.84 (1H, dd, J = 7.3Hz and 7.2Hz), 8.30 (1H, br), 9.04 (1H, br), 9.90 (1H, brs), 12.35 (1H, br).

Example 67
4- (2-Bromo-3-cyanophenyl) -5-cyano-6- (1-t-butoxycarbonylpyrrolidin-2-yl) -4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl 1-t-butoxycarbonylpyrrolidine-2-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MS (EI): 495 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.47 (9H, s), 1.82-1.97 (4H, m), 2.31 (1H, m), 3.50 (1H, m), 4.53 (1H , m), 5.47 (1H, s), 7.51-7.91 (4H, m), 9.83 (1H, m), 12.26 (1H, s).

Example 68
4- (2-Bromo-3-cyanophenyl) -5-cyano-6- (pyrrolidin-2-yl) -4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Example from 2-bromo-3-cyanophenyl) -5-cyano-6- (1-t-butoxycarbonylpyrrolidin-2-yl) -4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 was produced in the same manner.
MP:> 240 ^o C.
MS (EI): 395 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39-1.55 (1H, m), 1.97 (2H, m), 2.30 (1H, m), 3.32 (2H, m), 4.10-4.28 (1H, m), 5.41 (1H, s), 6.52 (1H, s), 7.34-7.47 (2H, m), 7.70 (1H, dd, J = 8.3Hz and 9.0Hz), 11.89 (1H, brs) .

Example 69
4- (2,1,3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpyrrolidin-2-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine In the same manner as in Example 1, from the title compound from ethyl 1-t-butoxycarbonylpyrrolidine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole. Manufactured.
MS (EI): 433 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.40 (9H, s), 1.78-1.89 (4H, m), 2.11-2.31 (1H, m), 3.72 (1H, m), 4.53 (1H, m), 5.40 (1H, s), 7.26 (1H, s), 7.30-7.40 (1H, m), 7.58 (1H, dd, J = 6.4Hz and 9.6Hz), 7.91 (1H, d, J = 9.6Hz), 9.86 (1H, s), 12.16 (1H, s).

Example 70
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (pyrrolidin-2-yl) -2H-pyrazolo [3,4-b] pyridine The title compound was converted to 4- (2,1,3-benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpyrrolidin-2-yl) -5-cyano-4,7-dihydro-2H- Prepared from pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MP:> 240 ^o C.
MS (EI): 333 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41-1.46 (1H, m), 1.97-2.14 (4H, m), 3.72 (1H, m), 4.11-4.32 (1H, m) , 5.52 (1H, s), 7.00 (1H, s), 7.26 (1H, s), 7.30-7.42 (1H, m), 7.58 (1H, dd, J = 6.4Hz and 9.6Hz), 7.91 (1H, d, J = 9.3Hz), 11.87 (1H, s).

Example 71
6- (1-tert-Butoxycarbonylpyrrolidin-2-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 1 from t-butoxycarbonylpyrrolidine-2-carboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole.
MS (EI): 425 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.36 (9H, s), 1.86 (4H, m), 2.32 (1H, m), 3.54 (1H, m), 4.57 (1H, m ), 5.38 (1H, s), 7.23-7.27 (4H, m), 7.42 (1H, d, J = 7.6Hz), 9.68 (1H, s), 12.17 (1H, s).

Example 72
6- (1-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -2H-pyrazolo [3,4-b The pyridine title compound was prepared in the same manner as Example 1 from ethyl 1-t-butoxycarbonylpiperidine-4-carboxylate, 2,3- (methylenedioxy) benzaldehyde and 3-aminopyrazole.
MS (EI): 449 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39 (1H, m), 1.97-2.13 (2H, m), 2.00 (2H, m), 2.78-3.15 (2H, m), 3.31 (1H, m), 3.96 (2H, s), 5.03 (1H, d, J = 9.5Hz), 6.00-6.02 (1H, m), 6.64 (1H, d, J = 2.9Hz), 6.78 (1H, d, J = 1.7Hz), 7.29 (1H, s), 9.46 (1H, s), 12.18 (1H, s).

Example 73
5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine -(1-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -2H-pyrazolo [3,4-b] Prepared from pyridine in the same manner as in Example 2.
MS (EI): 390 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27-1.88 (5H, m), 2.49-2.96 (5H, m), 5.02 (1H, s), 6.00-6.02 (2H, m) , 6.66 (1H, m), 6.76 (2H, m), 7.27 (1H, s), 9.98 (1H, s), 12.14 (1H, s).

Example 74
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine-6-carboxylic acid phenylamide The title compound is converted to N-phenyloxamic acid ethyl ester, 2- Prepared from chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI): 375 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 5.50 (1 H, s), 7.13 (1 H, dd, J = 7.1 Hz and 7.6 Hz), 7.25-7.46 (7 H, m), 7.66 ( 2H, dd, J = 8.3Hz), 10.4 (1H, s), 10.76 (1H, s), 12.3 (1H, s).

Example 75
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine-6-carboxylic acid phenylamide Prepared from N-phenyloxamic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI): 383 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 5.59 (1H, s), 7.11-7.15 (1H, dd, J = 7.3 Hz and 7.6 Hz), 7.33-7.36 (3H, m), 7.51 (1H, d, J = 6.6Hz), 7.63-7.68 (3H, m), 7.96 (1H, d, J = 9.0Hz), 10.52 (1H, s), 10.76 (1H, s), 12.3 (1H , s).

Example 76
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- [4- (naphthalen-1-yl) piperazin-1-yl] methyl-2H-pyrazolo [3,4-b] pyridine Hydrochloride 4- (2-chlorophenyl) -5-cyano-6- (t-butyldimethylsilyloxy) methyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine was treated with ethyl t-butyldimethylsilyl Prepared from oxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. 4- (2-Chlorophenyl) -5-cyano-6- (t-butyldimethylsilyloxy) methyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (20 g) in tetrahydrofuran (200 mL) To the solution was added 1.0 M tetrabutylammonium fluoride in THF (49.9 mL) and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (800 mL) was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was crystallized from ethyl acetate to give 4- (2-chlorophenyl) -5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo [3,4-b]. Pyridine (12.7 g) was obtained as a white solid. 4- (2-Chlorophenyl) -5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (12.7 g) and tetrabromide in methylene chloride (340 mL) To a solution of carbon (15.4 g) was added triphenylphosphine (12.2 g) in methylene chloride (100 mL) under ice cooling and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give 4- (2-chlorophenyl) -5-cyano-6-bromomethyl- 4,7-Dihydro-2H-pyrazolo [3,4-b] pyridine (3.84 g) was obtained as a pale yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mL) was added 1- (naphthalen-1-yl) piperazine (334 mg) and the mixture was stirred under ice cooling for 30 minutes. To this reaction mixture was added a solution of 4- (2-chlorophenyl) -5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (500 mg) under ice cooling, and the mixture Was stirred for 6 hours under ice-cooling. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol (1: 1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals.
MP: 203-205 ^o C (Disassembly)
MS (EI): 481 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.31-3.70 (8H, m), 4.33 (2H, m), 4.85 (3H, m), 5.54 (1H, s), 7.19 (1H , d, J = 7.3Hz), 7.29-7.54 (8H, m), 7.67 (1H, d, J = 8.1Hz), 7.92 (1H, d, J = 7.1Hz), 8.15 (1H, d, J = 7.3Hz), 10.35 (1H, s), 11.28 (1H, brs).

Example 77
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (4-methylhomopiperazin-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine dihydrochloride Prepared in the same manner as in Example 76 from 4- (2-chlorophenyl) -5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine and N-methylhomopiperazine.
MP: 204-206 ^o C (Disassembly)
MS (EI): 382 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.22 (2H, m), 2.78 (3H, s), 3.24-4.11 (12H, m), 5.48 (1H, s), 7.14-7.35 (4H, m), 7.45 (1H, d, J = 8.0Hz), 10.17 (1H, brs), 11.51 (1H, brs).

Example 78
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (4-phenylpiperazin-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine trihydrochloride Prepared in the same manner as Example 76 from-(2-chlorophenyl) -5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine and 1-phenylpiperazine.
MP: 217-220 ^o C (disassembly)
MS (EI): 430 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 3.20-4.00 (9H, m), 4.27 (2H, m), 5.51 (1H, s), 6.86 (1H, t, J = 7.1Hz ), 7.01 (2H, d, J = 8.0Hz), 7.24-7.39 (6H, m), 7.45 (1H, d, J = 9.9Hz), 9.50 (1H, brs), 10.37 (1H, s), 11.40 (1H, brs).

Example 79
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6-phthalimidomethyl-2H-pyrazolo [3,4-b] pyridine in DMF (10 mL) To a solution of cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (0.8 g) was added potassium phthalimide (445 mg) under ice cooling, and the mixture was added under ice cooling. Stir for hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane (2: 1)) to give the title compound (285 mg) as white crystals.
MP:> 250 ^o C
MS (EI): 416 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 4.66 (2H, d, J = 2.4Hz), 5.40 (1H, s), 7.24-7.45 (5H, m), 7.82-7.94 (4H , m), 10.04 (1H, s), 12.23 (1H, s).

Example 80
6-acetyl-4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 4- (2-chlorophenyl) -5-cyano-4,7-dihydro -6- (1,1-dimethoxyethyl) -2H-pyrazolo [3,4-b] pyridine from methyl 2,2-dimethoxypropionate, 2-chlorobenzaldehyde and 3-aminopyrazole as in Example 1 Manufactured with. 4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (1,1-dimethoxyethyl) -2H-pyrazolo [3,4-b] pyridine (1.0 g) in dichloromethane (10 mL) ) Was added to the solution of) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. The solvent was distilled off, and the obtained residue was crystallized from ethyl acetate to give the title compound (370 mg) as white crystals.
MP: 225-228 ^o C (disassembly)
MS (EI): 298 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.56 (3H, s), 5.49 (1H, s), 7.25-7.36 (4H, m), 7.45 (1H, d, J = 7.8Hz ), 10.12 (1H, s), 12.50 (1H, brs).

Example 81
6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine The title compound is 2-bromo-3-cyanobenzaldehyde, Prepared in the same manner as in Example 1 from 3-aminopyrazole and methyl 2,2-dimethoxypropionate.
MP:> 230 ^o C
MS (EI): 368 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.42 (3H, s), 5.54 (1H, s), 7.32 (1H, brs), 7.50-7.59 (2H, m), 7.80 (1H , dd, J = 1.7Hz and 7.3Hz), 10.19 (1H, s), 12.39 (1H, brs).

Example 82
6-acetyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine , 3-Benzoxadiazole-4-aldehyde, 3-aminopyrazole and methyl 2,2-dimethoxypropionate were prepared in the same manner as Example 1.
MP: 230 ^o C (disassembly)
MS (EI): 306 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.55 (3H, s), 5.54 (1H, s), 7.33 (1H, s), 7.49 (1H, d, J = 6.6 Hz), 7.61 (1H, dd, J = 6.6Hz and 8.6Hz), 7.96 (1H, d, J = 9.2Hz), 10.27 (1H, s), 12.36 (1H, brs).

Example 83
6- (1-Benzyl-2-oxopyrrolidin-4-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 1 from chlorobenzaldehyde, 3-aminopyrazole and methyl 1-benzyl-2-oxopyrrolidine-4-carboxylate.
MP:> 230 ^o C
Calculated for C ₂₄ H ₂₀ ClN ₅ O: C, 67.05; H, 4.69; N, 16.29.
Found: C, 66.86; H, 4.56; N, 16.31.
MS (EI): 429 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.60 (1H, dd, J = 9.5Hz and 16.4Hz), 2.81 (1H, dd, J = 10.5Hz and 16.4Hz), 3.39 (1H , m), 3.47 (1H, m), 4.42 (2H, m), 5.36 (1H, s), 7.23-7.43 (10H, m), 10.04 (1H, s), 12.21 (1H, s).

Example 84
4- (2-Bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine in THF (75 mL) N-BuLi (113 mmol) was added to a solution of 2-picoline (10 g) at -40 ° C. Further methyl butanoate (15.8 mL) was added, the mixture was stirred for 1 hour, and the mixture was quenched with water. The mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give 2- (2-oxopentanyl) pyridine (4.8 g) as a yellow oil. Got as. 2-Bromo-3-cyanobenzaldehyde (1.5 g), Meldrum acid (1.0 g), 2- (2-oxopentanyl) pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 ml). ) Was heated to reflux for 11 hours. The reaction mixture is cooled to room temperature, the solvent is distilled off under reduced pressure, the residue is purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)), and the resulting residue is crystallized from ethyl acetate, Colorless crystals (520 mg) were obtained. To a solution of dimethylformamide (384 mg) in chloroform (5 mL) was added a solution of phosphorus oxychloride (805 mg) and the resulting crystals (520 mg) under ice cooling, and the mixture was stirred overnight. An aqueous solution of sodium acetate (3.4 g) was added under ice cooling, and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain an oil. The obtained oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9: 1)) to obtain a yellow solid (530 mg). Hydrazine (120 mg) was added to a solution of the obtained solid pyridine (10 mL), and the mixture was stirred with heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain an oil. Water was added to the resulting oil and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as pale-yellow crystals.
MP: 205-208 ^o C (Disassembly)
Calculated for C ₂₁ H ₁₈ BrN ₅ : C, 60.01; H, 4.32; N, 16.66.
Found: C, 59.83; H, 4.42; N, 16.26.
MS (EI): 420 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.83 (3H, t, J = 7.6Hz), 1.62 (2H, m), 2.24 (1H, m), 2.33 (1H, m), 5.93 (1H, s), 6.98 (1H, dd, J = 4.9Hz and 7.3Hz), 7.05 (1H, d, J = 7.8Hz), 7.28 (1H, m), 7.39 (1H, m), 7.51- 7.60 (3H, m), 8.36 (1H, d, J = 3.6Hz), 8.52 (1H, s), 11.84 (1H, s).

Example 85
6- (1-tert-butoxycarbonylpyrrolidin-3-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine in THF (50 ml) To a solution of methyl 1-benzyl-2-oxopyrrolidine-4-carboxylate (10.9 g) was added 1.0 M borane in THF (84 mL) under ice cooling and the mixture was refluxed for 1 hour. Excess borane and boron complex were decomposed by dropwise addition of 30 mL of methanolic hydrogen chloride followed by reflux for 1 hour. After removing the solvent under reduced pressure, 30 mL of methanolic hydrogen chloride was further added, and the mixture was further refluxed for 1 hour. The solvent was again removed in vacuo and the residue was treated with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to obtain methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 g) Obtained as a yellow oil. A suspension of methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 mg), 5% palladium on carbon (300 mg) and ammonium formate (2.8 g) in methanol (50 mL) -water (5 mL) for 2 hours. Refluxed. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol (9: 1)) to obtain methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) at 0 ° C. is added dimethylaminopyridine (161 mg) and di-tert-butyl dicarbonate (3.4 g) and the mixture is stirred for 13 hours. did. The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1)) to give methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2. 6 g) was obtained as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added n-BuLi (12.4 mmol) at −78 ° C. Further methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1)) to give 1- (1-tert-butoxycarbonylpyrrolidin-3-yl) -2-cyanoethane. -1-one (2.35 g) was obtained as a colorless oil. 2-chlorophenylaldehyde (1.4 g), 3-aminopyrazole (819 mg) and 1- (1-tert-butoxycarbonylpyrrolidin-3-yl) -2-cyanoethane-1-one (2. 35 g) was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.18 g) as colorless crystals.
Calculated for C ₂₂ H ₂₄ ClN ₅ O ₂ : C, 62.04; H, 5.68; N, 16.44.
Found: C, 61.94; H, 5.69; N, 16.45.
MS (EI): 425 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.14 (9H, s), 2.07 (1H, m), 2.32 (1H, m), 3.29-3.58 (5H, m), 5.37 (1H , s), 7.22-7.34 (4H, m), 7.42 (1H, d, J = 8.3Hz), 9.78 (1H, s), 12.20 (1H, s).

Example 86
4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (pyrrolidin-3-yl) -2H-pyrazolo [3,4-b] pyridine 6- (1-tert-butoxycarbonylpyrrolidine- 3-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (706 mg) was added to 4N HCl dioxane solution (5 mL) at room temperature. The mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, the residue was washed with ethanol-ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (460 mg) as colorless crystals.
MP: 210-215 ^o C (disassembly)
MS (EI): 325 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.24 (2H, m), 3.15 (1H, m), 3.26-3.55 (3H, m), 3.64 (1H, m), 5.34 (1H , s), 5.40 (1H, brs), 7.23-7.32 (4H, m), 7.43 (1H, d, J = 7.3Hz), 9.38 (1H, brs), 9.51 (1H, brs), 9.97 (1H, s).

Example 87
4- (2,1,3-Benzoxadiazol-4-yl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 84 from 2,1,3-benzoxadiazole-4-aldehyde, meldrum acid, 2- (2-oxopentanyl) pyridine and ammonium acetate.
MS (EI): 358 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 7.3Hz), 1.64 (2H, m), 2.27 (1H, m), 2.35 (1H, m), 5.96 (1H, s), 6.95 (1H, m), 7.11-7.18 (3H, m), 7.40 (1H, m), 7.51 (1H, m), 7.69 (1H, d, J = 9.3Hz), 8.35 (1H, m), 8.54 (1H, s), 11.78 (1H, brs).

Example 88
6- (1-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (indan-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 1 from ethyl isonipecotate, 4-indanecarboxaldehyde and 3-aminopyrazole.
MS (EI): 445 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.56-1.59 (2H, m), 1.88-1.06 (4H, m), 2.58-2.83 (7H, m) , 4.06 (2H, m), 4.96 (1H, s), 6.90 (1H, m), 7.04-7.07 (2H, m), 7.14 (1H, s), 9.55 (1H, s), 12.08 (1H, s ).

Example 89
6- (1-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (2,3-dihydrobenzo [b] furan-7-yl) -2H-pyrazolo [3 , 4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl isonipecotate, 7- (2,3-dihydrobenzo [b] furan) carboxaldehyde and 3-aminopyrazole.
MS (EI): 445 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42 (9H, s), 1.57-1.66 (2H, m), 1.88 (4H, m), 2.73-2.90 (3H, m), 3.17 (2H, m), 4.09 (2H, m), 4.54 (2H, m), 5.01 (1H, s), 6.76 (1H, m), 6.84 (1H, d, J = 7.1Hz), 7.05 (1H, d, J = 6.6Hz), 7.22 (1H, s), 9.52 (1H, s), 12.06 (1H, s).

Example 90
6- (1-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (3,4-dihydro-2H-benzopyran-8-yl) -2H-pyrazolo [3 4-b] pyridine The title compound was prepared in the same manner as Example 1 from ethyl isonipecotate, 8- (3,4-dihydro-2H-benzopyran) carboxaldehyde and 3-aminopyrazole.
MS (EI): 461 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42 (9H, s), 1.58-1.69 (2H, m), 1.80-2.00 (4H, m), 2.73-2.95 (5H, m) , 4.09 (2H, m), 4.22 (2H, m), 5.14 (1H, s), 6.74 (1H, m), 6.84-6.89 (2H, m), 7.21 (1H, s), 9.48 (1H, s ), 12.03 (1H, s).

Example 91
6- (1-t-Butoxycarbonylpiperidin-4-yl) -4- (2-chloro-3-trifluoromethylphenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b The pyridine title compound was prepared in the same manner as Example 1 from ethyl isonipecotate, 2-chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole.
MS (EI): 461 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.62 (2H, m), 1.89 (2H, m), 2.60-2.90 (3H, m), 4.10 (2H , m), 5.54 (1H, s), 7.32 (1H, s), 7.52-7.56 (2H, m), 7.75 (1H, d, J = 9.3Hz), 9.79 (1H, s), 12.25 (1H, s).

Example 92
5-Cyano-4,7-dihydro-4- (3,4-dihydro-2H-benzopyran-8-yl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The salt title compound was converted to 6- (1-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (3,4-dihydro-2H-benzopyran-8-yl) -2H- Prepared from pyrazolo [3,4-b] pyridine in the same manner as in Example 2.
MS (EI): 361 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.83-1.98 (4H, m), 2.14 (2H, m), 2.74 (2H, m), 2.90-3.00 (3H, m), 4.22 (2H, m), 3.40-3.70 (5H, m), 4.16-4.27 (2H, m), 5.15 (1H, s), 6.74 (1H, m), 6.83-6.89 (2H, m), 7.22 (1H , s), 9.54 (1H, s).

Example 93
5-Cyano-4,7-dihydro-4- (indan-4-yl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride 6- (1 -T-Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (indan-4-yl) -2H-pyrazolo [3,4-b] pyridine as in Example 2 Manufactured with.
MS (EI): 345 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.80-1.99 (4H, m), 2.14 (2H, m), 2.58 (1H, m), 2.82-2.95 (6H, m), 3.30 -3.50 (2H, m), 4.97 (1H, s), 6.90 (1H, m), 7.04-7.09 (2H, m), 7.17 (1H, s), 8.37 (1H, m), 9.10 (1H, m ), 9.62 (1H, s), 12.18 (1H, brs).

Example 94
5-cyano-4,7-dihydro-4- (indan-4-yl) -6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine -4,7-Dihydro-4- (indan-4-yl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared from hydrochloride salt in the same manner as in Example 3. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.56 (2H, m), 1.84-1.98 (6H, m), 2.15 (2H, m), 2.58 (1H, m), 2.80-3.00 (6H, m), 3.20-3.40 (2H, m), 4.95 (1H, s), 6.90 (1H, m), 7.05-7.07 (2H, m), 7.14 (1H, s), 9.54 (1H, brs ), 12.10 (1H, brs).

Example 95
5-cyano-4,7-dihydro-4- (3,4-dihydro-2H-benzopyran-8-yl) -6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b ] Pyridine hydrochloride The title compound is converted to 5-cyano-4,7-dihydro-4- (3,4-dihydro-2H-benzopyran-8-yl) -6- (piperidin-4-yl) -2H-pyrazolo [3] , 4-b] pyridine Prepared from hydrochloride in the same manner as in Example 3.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.90-2.00 (4H, m), 2.24 (2H, m), 2.73-2.75 (5H, m), 2.94-3.08 (3H, m) , 3.40-3.48 (2H, m), 4.17-4.27 (2H, m), 5.15 (1H, s), 6.74 (1H, m), 6.84-6.89 (2H, m), 7.22 (1H, s), 9.58 (1H, s), 9.80 (1H, m), 12.15 (1H, s).

Example 96
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-2-yl) -2H-pyrazolo [3,4 -B ] pyridine The title compound was prepared in the same manner as Example 25 from methanesulfonyl chloride, ethyl pipecolate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (EI): 425 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.20-2.07 (7H, m), 2.95 and 2.98 (3H, s), 2.98-3.17 (1H, m), 3.63-3.68 (1H, m), 5.40 and 5.52 (1H, s), 7.24 and 7.27 (1H, s), 7.41-7.63 (2H, m), 7.90-7.93 (1H, m), 9.80 and 9.82 (1H, brs), 12.16 ( 1H, brs).

Example 97
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4 b] pyridine hydrochloride 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl)- Prepared from 2H-pyrazolo [3,4-b] pyridine in the same manner as in Example 64.
MS (EI): 361 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.90 (2H, m), 2.24-2.27 (2H, m), 2.48 (3H, s), 2.72-2.75 (2H, m) , 2.94-2.98 (2H, m), 3.20-3.33 (1H, br), 3.44-3.47 (1H, m), 5.40 (1H, s), 7.28 (1H, s), 7.44 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz), 7.93 (1H, d, J = 9.0Hz), 9.92 (1H, brs), 12.26 (1H, brs).

Example 98
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1,2-dihydro-1-methyl-2-oxo-pyridine-4- Yl) -2H-pyrazolo [3,4-b] pyridine The title compound is converted into ethyl 1,2-dihydro-1-methyl-2-oxo-pyridine-4-carboxylic acid, 2,1,3-benzoxadiazole. Prepared from -4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI): 371 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 3.46 (3H, s), 5.42 (1H, s), 6.34 (1H, d, J = 7.2Hz), 6.56 (1H, s), 7.33 (1H, s), 7.52 (1H, d, J = 7.2Hz), 7.61 (1H, dd, J = 9.0Hz and 6.6Hz), 7.80 (1H, d, J = 6.6Hz), 7.95 (1H, d, J = 9.0Hz), 10.33 (1H, brs), 12.29 (1H, brs).

Example 99
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1,2,5,6-tetrahydropyridin-3-yl) -2H- Pyrazolo [3,4-b] pyridine hydrochloride The title compound is converted to 1,2,3,4-tetrahydropyridine-3-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-amino. Prepared from pyrazole in the same manner as in Examples 1 and 2.
MS (EI): 345 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.42-2.44 (2H, m), 3.11-3.14 (2H, m), 3.84-3.87 (2H, m), 4.39 (1H, br) , 5.46 (1H, s), 6.36 (1H, s), 7.30 (1H, s), 7.49 (1H, d, J = 6.6Hz), 7.56 (1H, dd, J = 9.0Hz and 6.6Hz), 7.94 (1H, d, J = 9.0Hz), 9.39 (2H, br), 10.06 (1H, brs).

Example 100
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-1,4,5,6-tetrahydropyridin-3-yl ) -2H -pyrazolo [3,4-b] pyridine Prepared from 4,5,6-tetrahydropyridin-3-yl) -2H-pyrazolo [3,4-b] pyridine in the same manner as Example 3.
MS (EI): 359 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.18-2.20 (2H, m), 2.43-2.47 (2H, m), 3.02-3.11 (2H, m), 5.43 (1H, s) , 6.11 (1H, s), 7.26 (1H, s), 7.43 (1H, d, J = 6.6Hz), 7.59 (1H, dd, J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.87 (1H, brs), 12.16 (1H, brs).

Example 101
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1- (methylamino) ethyl) -2H-pyrazolo [3,4-b Pyridine dihydrochloride The title compound was prepared in the same manner as Examples 15 and 2 from 2-methylglycine ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.
MS (EI): 321 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.56 (3H, d, J = 6.8Hz), 3.07 (3H, s), 4.59-4.68 (3H, m), 5.66 (1H, s ), 7.29 (1H, d, J = 6.6Hz), 7.44 (1H, s), 7.52 (1H, dd, J = 9.0Hz and 6.6Hz), 7.87 (1H, d, J = 9.0Hz), 8.22 ( 1H, br), 8.44 (1H, br), 10.95 (1H, brs).

Example 102
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl) -2H-pyrazolo [3,4-b] pyridine The title compound was prepared from 1,2-dihydro-1-methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole. 1 in the same manner.
MS (EI): 433 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 3.46 (3H, s), 5.35 (1H, s), 6.37 (1H, d, J = 7.2Hz), 6.61 (1H, s), 7.38 (1H, s), 7.60 (1H, dd, J = 7.3Hz and 7.2Hz), 7.72-7.86 (3H, m), 10.31 (1H, brs), 12.37 (1H, brs).

Example 103
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4- (methylamino) cyclohexyl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The compound was prepared in the same manner as Examples 15 and 2 from 4-aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MS (EI): 436 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.39 (2H, m), 1.80-1.90 (4H, m), 2.15-2.16 (2H, m), 2.84-2.86 (1H, m) , 3.14-3.16 (1H, m), 4.20 (2H, br), 5.46 (1H, s), 7.33 (1H, s), 7.56-7.57 (2H, m), 7.82 (1H, d, J = 7.3Hz ), 8.98 (2H, br), 9.80 (1H, brs).

Example 104
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,2,5,6-tetrahydropyridin-3-yl) -2H-pyrazolo [3,4 b] Pyridine dihydrochloride The title compound is prepared from 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. Manufactured.
MS (EI): 407 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.43-2.44 (2H, m), 3.13-3.15 (2H, m), 3.70-3.72 (2H, br), 3.86-3.88 (2H, m), 5.54 (1H, s), 6.41 (1H, s), 7.36 (1H, s), 7.58 (1H, dd, J = 7.3Hz and 7.2Hz), 7.84 (1H, d, J = 7.3Hz) , 7.86 (1H, d, J = 7.3Hz), 9.32 (2H, br), 10.03 (1H, brs).

Example 105
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4- (dimethylamino) cyclohexyl) -2H-pyrazolo [3,4-b] pyridine Example 3 from-(2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4- (methylamino) cyclohexyl) -2H-pyrazolo [3,4-b] pyridine Produced in the same way.
MS (EI): 450 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.26-1.29 (2H, m), 1.76-1.93 (6H, m), 2.27 (6H, s), 2.34-2.36 (1H, m) , 2.63-2.66 (1H, m), 5.45 (1H, s), 7.33 (1H, s), 7.56-7.60 (2H, m), 7.82 (1H, d, J = 7.3Hz), 9.74 (1H, brs ), 12.27 (1H, s).

Example 106
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methyl-1,4,5,6-tetrahydropyridin-3-yl) -2H-pyrazolo [ 3,4-b] pyridine The title compound is converted to 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,4,5,6-tetrahydropyridin-3-yl. ) -2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as in Example 3.
MS (EI): 420 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.21-2.22 (2H, m), 2.28 (3H, s), 2.48-2.49 (2H, m), 3.08-3.12 (2H, m) , 5.49 (1H, s), 6.15 (1H, s), 7.33 (1H, s), 7.56-7.61 (2H, m), 7.84 (1H, dd, J = 7.3Hz and 7.2Hz), 9.87 (1H, brs), 12.26 (1H, brs).

Example 107
6- (exo-2-azabicyclo [2,2,2] octane-6-yl) -4- (2,1,3-benzooxadiazol-4-yl) -5-cyano-4,7-dihydro -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound is converted to exo-2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole- Prepared from 4-aldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 373 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.55 (1H, m), 1.75-1.77 (1H, m), 1.89-2.06 (4H, m), 2.21-2.23 (1H, m), 3.07-3.10 (2H, m), 3.43-3.48 (4H, m), 5.39-5.43 (1H, s), 7.26-7.28 (1H, m), 7.44-7.47 (1H, m), 7.57- 7.61 (1H, m), 7.93-7.95 (1H, m), 8.87-9.03 (1H, br), 9.46-9.52 (1H, br), 9.73 and 9.80 (1H, brs).

Example 108
6- (End-2-azabicyclo [2,2,2] octane-6-yl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound is converted to the endo-2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole- Prepared from 4-aldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 373 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.67-1.73 (3H, m), 2.03-2.13 (4H, m), 3.04-3.06 (1H, m), 3.34-3.57 (5H, m), 5.49 (1H, s), 7.30 (1H, s), 7.50-7.51 (1H, m), 7.58-7.60 (1H, m), 7.92-7.94 (1H, m), 8.07 (1H, br) , 9.79 (1H, br), 9.89 (1H, br).

Example 109
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (exo-2-methyl-2-azabicyclo [2,2,2] octane- 6-yl) -2H-pyrazolo [3,4-b] pyridine The title compound is converted to 6- (exo-2-azabicyclo [2,2,2] octane-6-yl) -4- (2,1,3- Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as Example 3.
MS (EI): 387 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.43-1.44 (1H, m), 1.70-1.90 (5H, m), 2.11-2.13 (1H, m), 2.38-2.46 (4H, m), 3.00-3.02 (1H, m), 3.32-3.36 (2H, m), 5.38 and 5.40 (1H, s), 7.25-7.27 (1H, m), 7.38-7.42 (1H, m), 7.56- 7.61 (1H, m), 7.90-7.93 (1H, m), 9.73 (1H, br), 12.23 (1H, br).

Example 110
Ethyl 4- (2,1,3-Benzoxadiazol-4-yl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine-5 Carboxylate dihydrobromide 2,1,3-benzoxadiazole-4-aldehyde (3.0 g), Meldrum acid (3.0 g), ethyl 3-keto-3- (1-benzylcarbonylpiperidine- A solution of 4-yl) propionate (6.8 g) and ammonium acetate (1.8 g) in acetic acid (20 mL) was stirred at reflux for 12 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain colorless crystals (4.7 g). To a solution of dimethylformamide (2.7 g) in chloroform (10 mL) was added phosphorus oxychloride (3.4 mL) and the resulting colorless crystals (4.7 g) in chloroform (10 mL) under ice-cooling, and the mixture was allowed to stand overnight. Stir. Under ice-cooling, an aqueous solution of sodium acetate (37.8 g) was added, and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to give colorless crystals. Hydrazine (1.4 g) was added to a solution of the obtained colorless crystals in pyridine (20 mL), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (840 mg) as colorless crystals. An HBr-AcOH solution (10 mL) was added to an acetic acid (10 mL) solution of the obtained colorless crystals, and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure to obtain colorless crystals. The crystals were purified by recrystallization from EtOH to give the title compound (630 mg) as colorless crystals.
MS (EI): 394 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.77 (3H, t, J = 7.3Hz), 1.80-2.16 (4H, m), 2.90-2.93 (2H, m), 3.40-3.43 (2H, m), 3.80 (2H, q, J = 7.3Hz), 4.12-4.15 (1H, m), 4.50 (2H, br), 5.67 (1H, s), 7.17 (1H, d, J = 6.6 Hz), 7.26 (1H, s), 7.51 (1H, dd, J = 9.0Hz and 6.6Hz), 7.79 (1H, d, J = 9.0Hz), 8.10 (1H, br), 8.74 (1H, br) , 9.38 (1H, brs).

Example 111
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (endo-2-methyl-2-azabicyclo [2,2,2] octane- 6-yl) -2H-pyrazolo [3,4-b] pyridine The title compound is converted to 6- (endo-2-azabicyclo [2,2,2] octane-6-yl) -4- (2,1,3- Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as Example 3.
MS (EI): 387 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.43-1.47 (2H, m), 1.60-1.64 (2H, m), 1.81-1.82 (1H, m), 1.79-2.06 (2H, m), 2.24-2.26 (1H, m), 2.36 (3H, s), 2.76-2.80 (2H, m), 3.19-3.22 (1H, m), 5.43 (1H, s), 7.25 (1H, s) , 7.42-7.46 (1H, m), 7.57-7.60 (1H, m), 7.90-7.94 (1H, m), 10.79 (1H, brs), 12.16 (1H, brs).

Example 112
Ethyl 4- (2,1,3-Benzoxadiazol-4-yl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine -5-Carboxylate dihydrochloride The title compound was converted to ethyl 4- (2,1,3-benzoxadiazol-4-yl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo Prepared in the same manner as in Example 3 from [3,4-b] pyridine-5-carboxylate.
MS (EI): 408 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.75 (3H, t, J = 7.3Hz), 1.55-1.56 (1H, m), 1.71-1.73 (1H, m), 1.87-2.06 (4H, m), 2.17 (3H, s), 2.84-2.87 (2H, m), 3.78 (2H, q, J = 7.3Hz), 3.93-3.96 (1H, m), 5.68 (1H, s), 7.12 (1H, d, J = 6.6Hz), 7.22 (1H, s), 7.49 (1H, dd, J = 9.0Hz and 6.6Hz), 7.77 (1H, d, J = 9.0Hz), 9.32 (1H, brs), 12.06 (1H, brs).

Example 113
4- (2-bromophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound was converted to ethyl nipecotate, Prepared in the same manner as Examples 1 and 2 from bromobenzaldehyde and 3-aminopyrazole.
MS (EI): 383 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.85-1.93 (2H, m), 2.14-2.20 (2H, m), 2.94-2.98 (2H, m), 3.32-3.36 (3H, m), 5.36 (1H, s), 7.16 (1H, dd, J = 7.3Hz and 7.2Hz), 7.23-7.27 (2H, m), 7.35 (1H, dd, J = 7.3Hz and 7.2Hz), 7.59 (1H, d, J = 7.3Hz), 8.41 (1H, br), 9.14 (1H, br), 9.73 (1H, brs), 12.21 (1H, brs).

Example 114
5-cyano-4,7-dihydro-4- (2-methoxyphenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound was converted to ethyl nipecotate, 2 Prepared from -methoxybenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 335 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.87-1.95 (2H, m), 2.14-2.20 (2H, m), 2.94-3.03 (3H, m), 3.32-3.36 (2H, m), 3.82 (3H, s), 5.21 (1H, s), 6.88 (1H, dd, J = 7.3Hz and 7.2Hz), 6.99 (1H, d, J = 7.3Hz), 7.05 (1H, d, J = 7.3Hz), 7.15-7.20 (2H, m), 8.44 (1H, br), 9.17 (1H, br), 9.53 (1H, brs), 12.11 (1H, brs).

Example 115
5-cyano-4- (2,3-dichlorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound is ethyl nipecotate, Prepared from 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 373 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.90 (2H, m), 2.16-2.20 (2H, m), 2.94-3.00 (3H, m), 3.32-3.38 (2H, m), 5.44 (1H, s), 7.24-7.36 (3H, m), 7.56 (1H, d, J = 7.3Hz), 8.52 (1H, br), 9.24 (1H, br), 9.79 (1H, brs ), 12.29 (1H, brs).

Example 116
4- (2-Bromophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine -Bromophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine was prepared in the same manner as Example 3.
MS (EI): 397 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.56-1.63 (2H, m), 1.85-1.90 (2H, m), 2.01-2.06 (2H, m), 2.17 (3H, s) , 2.62-2.65 (1H, m), 2.87-2.89 (2H, m), 5.34 (1H, s), 7.14-7.26 (3H, m), 7.36 (1H, dd, J = 7.3Hz and 7.2Hz), 7.60 (1H, d, J = 7.3Hz), 9.60 (1H, brs), 12.16 (1H, brs).

Example 117
5-cyano-4,7-dihydro-4- (2-methoxyphenyl) -6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared from 4,7-dihydro-4- (2-methoxyphenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine in the same manner as Example 3.
MS (EI): 349 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.56-1.66 (2H, m), 1.86-1.92 (2H, m), 2.01-2.04 (2H, m), 2.17 (3H, s) , 2.64-2.67 (1H, m), 2.86-2.88 (2H, m), 3.84 (3H, s), 5.20 (1H, s), 6.90 (1H, dd, J = 7.3Hz and 7.2Hz), 6.98 ( 1H, d, J = 7.3Hz), 7.05 (1H, d, J = 7.3Hz), 7.16-7.19 (2H, m), 9.41 (1H, brs), 12.01 (1H, brs).

Example 118
5-cyano-4- (2,3-dichlorophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine -4- (2,3-Dichlorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared from hydrochloride in the same manner as in Example 3. .
MS (EI): 387 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.57-1.65 (2H, m), 1.85-1.90 (2H, m), 2.01-2.06 (2H, m), 2.17 (3H, s) , 2.59-2.66 (1H, m), 2.86-2.89 (2H, m), 5.43 (1H, s), 7.23 (1H, d, J = 7.3Hz), 7.29 (1H, s), 7.35 (1H, dd , J = 7.3Hz and 7.2Hz), 7.51 (1H, d, J = 7.3Hz), 9.65 (1H, brs), 12.18 (1H, brs).

Example 119
5-cyano-4,7-dihydro-4- (2-fluorophenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound was converted to ethyl nipecotate, 2 -Prepared from fluorobenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 323 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.85-1.89 (2H, m), 2.12-2.20 (2H, m), 2.90-2.98 (3H, m), 3.33-3.39 (2H, m), 5.20 (1H, s), 7.14-7.28 (5H, m), 8.37 (1H, br), 9.09 (1H, br), 9.66 (1H, brs), 12.23 (1H, brs).

Example 120
5-Cyano-4- (2,3-difluorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound is ethyl nipecotate , 2,3-difluorobenzaldehyde and 3-aminopyrazole were prepared in the same manner as Examples 1 and 2.
MS (EI): 341 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.88 (2H, m), 2.14-2.19 (2H, m), 2.95-3.00 (3H, m), 3.33-3.38 (2H, m), 5.26 (1H, s), 7.03 (1H, d, J = 7.3Hz), 7.18 (1H, dd, J = 7.3Hz and 7.2Hz), 7.26-7.31 (2H, m), 8.80 (2H, br), 9.74 (1H, brs), 12.29 (1H, brs).

Example 121
5-cyano-4- (2,6-difluorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound is ethyl nipecotate , 2,6-difluorobenzaldehyde and 3-aminopyrazole were prepared in the same manner as Examples 1 and 2.
MS (EI): 341 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.76-1.84 (2H, m), 2.13-2.18 (2H, m), 2.91-2.95 (3H, m), 3.28-3.30 (2H, m), 5.35 (1H, s), 7.02-7.07 (2H, m), 7.31-7.38 (2H, m), 8.77 (2H, br), 9.68 (1H, brs), 12.22 (1H, brs).

Example 122
5-cyano-4,7-dihydro-4- (2-methylthiophenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound is ethyl nipecotate, Prepared from 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 351 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.93 (2H, m), 2.17-2.23 (2H, m), 2.50 (3H, s), 2.95-3.00 (3H, m) 3.36-3.40 (4H, m), 5.36 (1H, s), 7.14-7.33 (5H, m), 8.49 (1H, br), 9.22 (1H, br), 9.63 (1H, brs).

Example 123
5-cyano-4- (2,6-dichlorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride The title compound is ethyl nipecotate, Prepared from 2,6-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 373 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.80-1.84 (2H, m), 2.12-2.20 (2H, m), 2.90-2.98 (3H, m), 3.30-3.33 (2H, m), 5.92 (1H, s), 7.19 (1H, s), 7.29 (1H, dd, J = 7.3Hz and 7.2Hz), 7.38 (1H, d, J = 7.3Hz), 7.51 (1H, d, J = 7.3Hz), 8.41 (1H, br), 9.16 (1H, br), 9.73 (1H, brs), 12.18 (1H, brs).

Example 124
5-cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (2-trifluoromethylphenyl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound was converted to nipecotic acid. Prepared in the same manner as Examples 1 and 2 from ethyl, 2-trifluoromethylbenzaldehyde and 3-aminopyrazole.
MS (EI): 373 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.83-1.90 (2H, m), 2.18-2.26 (2H, m), 2.92-3.00 (3H, m), 3.38-3.43 (2H, m), 4.16 (2H, br), 5.22 (1H, s), 7.06 (1H, s), 7.42-7.44 (2H, m), 7.63-7.69 (2H, m), 8.57 (1H, br), 9.30 (1H, br), 9.77 (1H, br).

Example 125
5-cyano-4,7-dihydro-4- (2-fluorophenyl) -6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared from 4,7-dihydro-4- (2-fluorophenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine hydrochloride in the same manner as Example 3.
MS (EI): 337 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.55-1.59 (2H, m), 1.83-1.88 (2H, m), 1.96-2.00 (2H, m), 2.15 (3H, s) , 2.60-2.63 (1H, m), 2.84-2.88 (2H, m), 5.17 (1H, s), 7.13-7.24 (5H, m), 9.60 (1H, brs), 12.18 (1H, brs).

Example 126
5-cyano-4- (2,3-difluorophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Cyano-4- (2,3-difluorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine In the same manner as Example 3 from hydrochloride. Manufactured.
MS (EI): 355 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.55-1.59 (2H, m), 1.82-1.8 (2H, m), 1.99-2.02 (2H, m), 2.15 (3H, s) , 2.57-2.60 (1H, m), 2.84-2.88 (2H, m), 5.23 (1H, s), 7.00 (1H, dd, J = 7.3Hz and 7.2Hz), 7.16 (1H, d, J = 7.3 Hz), 7.27-7.30 (2H, m), 9.66 (1H, brs), 12.24 (1H, brs).

Example 127
5-Cyano-4- (2,6-difluorophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Cyano-4- (2,6-difluorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine In the same manner as Example 3 from hydrochloride. Manufactured.
MS (EI): 355 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.49-1.53 (2H, m), 1.82-1.86 (2H, m), 1.96-2.01 (2H, m), 2.15 (3H, s) , 2.48-2.51 (1H, m), 2.83-2.86 (2H, m), 5.31 (1H, s), 7.00-7.05 (2H, m), 7.29-7.31 (2H, m), 9.60 (1H, brs) , 12.15 (1H, brs).

Example 128
5-cyano-4,7-dihydro-4- (2-nitrophenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound is ethyl nipecotate, Prepared from 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 351 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.93 (2H, m), 2.17-2.23 (2H, m), 2.94-3.00 (3H, m), 3.35-3.38 (2H, m), 4.42 (2H, br), 5.40 (1H, s), 7.30 (1H, s), 7.46-7.51 (2H, m), 7.71 (1H, dd, J = 7.3Hz and 7.2Hz), 7.90 ( 1H, d, J = 7.3Hz), 8.61 (1H, br), 9.36 (1H, br), 9.87 (1H, brs).

Example 129
5-cyano-4,7-dihydro-4-phenyl-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound is converted to ethyl nipecotate, benzaldehyde and 3-amino Prepared from pyrazole in the same manner as in Examples 1 and 2.
MS (EI): 305 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.81-1.89 (2H, m), 2.14-2.20 (2H, m), 2.90-2.96 (3H, m), 3.32-3.35 (2H, m), 4.20 (2H, br), 4.89 (1H, s), 7.17-7.22 (4H, m), 7.28-7.31 (2H, m), 8.58 (1H, br), 9.32 (1H, br), 9.65 (1H, brs).

Example 130
5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (2-methylthiophenyl) -2H-pyrazolo [3,4-b] pyridine Prepared from 4,7-dihydro-4- (2-methylthiophenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride in the same manner as Example 3.
MS (EI): 366 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.58-1.66 (2H, m), 1.83-1.89 (2H, m), 1.97-2.02 (2H, m), 2.15 (3H, s) , 2.50 (3H, s), 2.62-2.65 (1H, m), 2.84-2.87 (2H, m), 5.32 (1H, s), 7.12-7.30 (5H, m), 9.57 (1H, brs), 12.18 (1H, brs).

Example 131
5-cyano-4- (2,6-dichlorophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine -4- (2,6-Dichlorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared from hydrochloride in the same manner as in Example 3. .
MS (EI): 387 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.52-1.56 (2H, m), 1.83-1.87 (2H, m), 1.99-2.06 (2H, m), 2.15 (3H, s) , 2.52-2.55 (1H, s), 2.83-2.87 (2H, m), 5.90 (1H, s), 7.17 (1H, s), 7.28 (1H, dd, J = 7.3Hz and 7.2Hz), 7.36 ( 1H, d, J = 7.3Hz), 7.48 (1H, d, J = 7.3Hz), 9.67 (1H, brs), 12.12 (1H, brs).

Example 132
5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (2-trifluoromethylphenyl) -2H-pyrazolo [3,4-b] pyridine Cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (2-trifluoromethylphenyl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride same procedure as Example 3 Manufactured with.
MS (EI): 387 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.57-1.62 (2H, m), 1.83-1.86 (2H, m), 1.97-2.03 (2H, m), 2.16 (3H, s) , 2.60-2.63 (1H, m), 2.84-2.87 (2H, m), 5.18 (1H, s), 7.05 (1H, s), 7.40-7.42 (2H, m), 7.62-7.68 (2H, m) , 9.69 (1H, brs), 12.23 (1H, brs).

Example 133
5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (2-nitrophenyl) -2H-pyrazolo [3,4-b] pyridine Prepared from 4,7-dihydro-4- (2-nitrophenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride in the same manner as Example 3.
MS (EI): 365 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.58-1.67 (2H, m), 1.86-1.90 (2H, m), 1.99-2.06 (2H, m), 2.16 (3H, s) , 2.58-2.61 (1H, m), 2.86-2.90 (2H, m), 5.36 (1H, s), 7.26 (1H, s), 7.42-7.48 (2H, m), 7.69 (1H, dd, J = 7.3Hz and 7.2Hz), 7.88 (1H, d, J = 7.3Hz), 9.72 (1H, brs), 12.26 (1H, brs).

Example 134
5-cyano-4,7-dihydro-4-phenyl-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine The title compound is converted to 5-cyano-4,7-dihydro Prepared in the same manner as Example 3 from -4-phenyl-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride.
MS (EI): 319 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.54-1.57 (2H, m), 1.81-1.87 (2H, m), 1.97-2.03 (2H, m), 2.15 (3H, s) , 2.58-2.60 (1H, m), 2.84-2.86 (2H, m), 4.87 (1H, s), 7.17-7.20 (4H, m), 7.27-7.32 (2H, m), 9.52 (1H, brs) , 12.13 (1H, brs).

Example 135
5-cyano-4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine title compound Was prepared in the same manner as in Example 1 from ethyl butanoate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole.
MS (EI): 322 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.93 (3H, t, J = 7.3Hz), 1.63-1.68 (2H, m), 2.34-2.45 (2H, m), 5.16 (1H , s), 7.02 (1H, d, J = 7.3Hz), 7.18 (1H, dd, J = 7.3Hz and 7.2Hz), 7.28 (1H, d, J = 7.2Hz), 9.88 (1H, brs), 12.22 (1H, brs).

Example 136
4- (2,1,3-Benzothiadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The salt title compound was prepared in the same manner as Examples 1 and 2 from ethyl nipecotate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole.
MS (EI): 363 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.89-1.98 (2H, m), 2.22-2.29 (2H, m), 2.98-3.05 (3H, m), 3.37-3.43 (2H, m), 5.20 (2H, br), 5.72 (1H, s), 7.24 (1H, s), 7.48 (1H, d, J = 6.6Hz), 7.72 (1H, dd, J = 9.0Hz and 6.6Hz) , 7.99 (1H, d, J = 9.0Hz), 8.68 (1H, br), 9.43 (1H, br), 9.86 (1H, brs).

Example 137
5-Cyano-4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4 -B] pyridine dihydrochloride The title compound was prepared in the same manner as Examples 1 and 2 from ethyl nipecotate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole.
MS (EI): 385 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.82-1.85 (2H, m), 2.16-2.22 (2H, m), 2.95-3.00 (3H, m), 3.34-3.39 (2H, m), 5.17 (1H, s), 5.65 (2H, br), 7.05 (1H, d, J = 7.3Hz), 7.19 (1H, dd, J = 7.3Hz and 7.2Hz), 7.29 (1H, d, J = 7.3Hz), 7.33 (1H, s), 8.65 (1H, br), 9.43 (1H, br), 9.86 (1H, brs).

Example 138
4- (2,1,3-Benzothiadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] The pyridine title compound was converted to 4- (2,1,3-benzothiadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b. Prepared from pyridine dihydrochloride in the same manner as in Example 3.
MS (EI): 377 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.64-1.73 (2H, m), 1.91-1.97 (2H, m), 2.05-2.09 (2H, m), 2.419 (3H, s) , 2.70-2.72 (1H, m), 2.90-2.93 (2H, m), 5.71 (1H, s), 7.22 (1H, s), 7.45 (1H, d, J = 6.6Hz), 7.72 (1H, dd , J = 9.0Hz and 6.6Hz), 7.98 (1H, d, J = 9.0Hz), 9.71 (1H, brs), 12.13 (1H, brs).

Example 139
5-cyano-4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [ 3,4-b] pyridine The title compound is converted to 5-cyano-4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6- (piperidine-4- Yl) -2H-pyrazolo [3,4-b] pyridine Prepared from dihydrochloride salt in the same manner as in Example 3.
MS (EI): 399 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.5-1.58 (2H, m), 1.86-1.90 (2H, m), 1.99-2.03 (2H, m), 2.16 (3H, s) , 2.59-2.62 (1H, m), 2.85-2.89 (2H, m), 5.15 (1H, s), 7.03 (1H, d, J = 7.3Hz), 7.17 (1H, dd, J = 7.3Hz and 7.2 Hz), 7.26-7.31 (2H, m), 9.71 (1H, brs), 12.26 (1H, brs).

Example 140
5-cyano-4- (2-cyanophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The title compound is ethyl nipecotate, Prepared from 2-cyanobenzaldehyde and 3-aminopyrazole in the same manner as Examples 1 and 2.
MS (EI): 330 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.90 (2H, m), 2.18-2.22 (2H, m), 2.92-2.98 (3H, m), 3.34-3.37 (2H, m), 5.10 (2H, br), 5.25 (1H, s), 7.27 (1H, s), 7.43-7.47 (2H, m), 7.68 (1H, dd, J = 7.3Hz and 7.2Hz), 7.82 ( 1H, d, J = 7.3Hz), 8.61 (1H, br), 9.41 (1H, br), 9.93 (1H, brs).

Example 141
5-cyano-4- (2-cyanophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 3 from 4- (2-cyanophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride.
MS (EI): 344 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.58-1.63 (2H, m), 1.82-1.87 (2H, m), 1.98-2.06 (2H, m), 2.16 (3H, s) , 2.59-2.61 (1H, m), 2.84-2.88 (2H, m), 5.23 (1H, s), 7.25 (1H, s), 7.39-7.46 (2H, m), 7.6 (1H, dd, J = 7.3Hz and 7.2Hz), 7.81 (1H, d, J = 7.3Hz), 9.77 (1H, brs), 12.26 (1H, brs).

Example 142
5-cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (pyridin-4-yl) -2H-pyrazolo [3,4-b] pyridine trihydrochloride The title compound is ethyl nipecotate , Pyridine-4-aldehyde and 3-aminopyrazole were prepared in the same manner as in Examples 1 and 2.
MS (EI): 306 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.92 (2H, m), 2.18-2.25 (2H, m), 2.93-3.00 (3H, m), 3.35-3.38 (2H, m), 5.41 (1H, s), 6.50 (3H, br), 7.42 (1H, s), 7.97 (2H, d, J = 6.8Hz), 8.90 (1H, br), 8.93 (2H, d, J = 6.8Hz), 9.60 (1H, br), 10.10 (1H, brs).

Example 143
5-cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (pyridin-3-yl) -2H-pyrazolo [3,4-b] pyridine trihydrochloride The title compound is ethyl nipecotate , Pyridine-3-aldehyde and 3-aminopyrazole were prepared in the same manner as in Examples 1 and 2.
MS (EI): 306 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.93 (2H, m), 2.19-2.25 (2H, m), 2.90-2.97 (3H, m), 3.35-3.38 (2H, m), 5.39 (1H, s), 6.50 (3H, br), 7.41 (1H, s), 8.09 (1H, dd, J = 8.2Hz and 5.4Hz), 8.49 (1H, d, J = 8.2Hz) , 8.72 (1H, br), 8.88 (1H, d, J = 5.4Hz), 8.92 (1H, s), 9.57 (1H, br), 10.02 (1H, brs).

Example 144
5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (pyridin-4-yl) -2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 3 from -4,7-dihydro-6- (piperidin-4-yl) -4- (pyridin-4-yl) -2H-pyrazolo [3,4-b] pyridine trihydrochloride did.
MS (EI): 320 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.56-1.64 (2H, m), 1.86-1.90 (2H, m), 1.99-2.03 (2H, m), 2.17 (3H, s) , 2.61-2.64 (1H, m), 2.86-2.89 (2H, m), 4.96 (1H, s), 7.23 (2H, d, J = 6.8Hz), 7.31 (1H, s), 8.50 (2H, d , J = 6.8Hz), 9.67 (1H, brs), 12.25 (1H, brs).

Example 145
5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (pyridin-3-yl) -2H-pyrazolo [3,4-b] pyridine Prepared in the same manner as Example 3 from -4,7-dihydro-6- (piperidin-4-yl) -4- (pyridin-3-yl) -2H-pyrazolo [3,4-b] pyridine trihydrochloride did.
MS (EI): 320 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.57-1.60 (2H, m), 1.84-1.89 (2H, m), 1.99-2.05 (2H, m), 2.17 (3H, s) , 2.58-2.61 (1H, m), 2.85-2.8 (2H, m), 4.98 (1H, s), 7.29 (1H, s), 7.35 (1H, dd, J = 8.2Hz and 5.4Hz), 7.55 ( 1H, d, J = 8.2Hz), 8.42-8.45 (2H, m), 9.64 (1H, brs), 12.23 (1H, brs).

Example 146
6- (exo-2-azabicyclo [2,2,2] octane-6-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine dihydrochloride The title compound was prepared from exo-2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole. And 2 in the same way.
MS (EI): 435 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.52-1.54 (1H, m), 1.74-2.18 (6H, m), 3.06-3.09 (2H, m), 3.50-3.52 (2H, m), 3.87 (2H, br), 5.51 (1H, s), 7.33 (1H, d, J = 7.3Hz), 7.55-7.60 (2H, m), 7.84 (1H, d, J = 7.3Hz), 8.97 (1H, br), 9.73 (1H, br), 9.78 (1H, brs).

Example 147
6- (End-2-azabicyclo [2,2,2] octane-6-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3 , 4-b] pyridine dihydrochloride The title compound was prepared from endo-2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole. And 2 in the same way.
MS (EI): 435 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.67-1.69 (3H, m), 2.02-2.12 (4H, m), 3.02-3.05 (1H, m), 3.31-3.35 (1H, m), 3.45-3.51 (2H, m), 4.04 (2H, br), 5.50 (1H, s), 7.34 (1H, s), 7.56 (1H, dd, J = 7.3Hz and 7.2Hz), 7.82 ( 1H, d, J = 7.3Hz), 8.16 (1H, br), 9.82 (1H, br), 9.93 (1H, brs).

Example 148
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (exo-2-methyl-2-azabicyclo [2,2,2] octane-6-yl) -2H The pyrazolo [3,4-b] pyridine title compound to 6- (exo-2-azabicyclo [2,2,2] octan-6-yl) -4- (2-bromo-3-cyanophenyl) -5 Prepared in the same manner as Example 3 from cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine dihydrochloride.
MS (EI): 449 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42-1.45 (1H, m), 1.72-1.88 (5H, m), 2.06-2.09 (1H, m), 2.46-2.51 (4H, m), 3.04-3.07 (1H, m), 3.45-3.48 (2H, m), 5.48 (1H, s), 7.34 (1H, s), 7.57-7.60 (2H, m), 7.83 (1H, dd, J = 7.3Hz and 7.2Hz), 9.83 (1H, brs), 12.37 (1H, brs).

Example 149
Ethyl 4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine-5-carboxylate 2,2-Difluoro-1,3-benzodioxol-4-aldehyde (2.0 g), Meldrum acid (1.6 g), ethyl 3-keto-hexanoate (1.7 g) and ammonium acetate (0.91 g) ) In acetic acid (20 mL) was stirred under reflux for 12 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain colorless crystals (2.4 g). To a solution of dimethylformamide (1.9 g) in chloroform (10 mL) was added phosphorus oxychloride (4.0 g) and the resulting colorless crystals (2.4 g) in chloroform (10 mL) under ice-cooling, and the mixture was overnight. Stir. Under ice cooling, an aqueous solution of sodium acetate (27 g) was added, and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to give colorless crystals. Hydrazine (1.0 g) was added to a solution of the obtained colorless crystals in pyridine (20 mL), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (190 mg) as colorless crystals.
MS (EI): 391 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.90-0.97 (6H, m), 1.58-1.64 (2H, m), 2.60-2.64 (1H, m), 2.83-2.86 (1H, m), 3.83 (2H, q, J = 7.3Hz), 5.32 (1H, m), 6.86 (1H, d, J = 7.3Hz), 7.03-7.11 (2H, m), 7.24 (1H, s), 9.61 (1H, brs), 12.06 (1H, brs).

Example 150
Ethyl 4- (2-bromo-3-cyanophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine-5-carboxylate dihydrobromide The acid salt title compound was prepared in the same way as Example 110 from 2-bromo-3-cyanobenzaldehyde.
MS (EI): 455 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 7.3Hz), 1.78-1.81 (1H, m), 1.98-2.14 (3H, m), 2.87-2.90 (2H, m), 3.40-3.42 (2H, m), 3.78 (2H, q, J = 7.3Hz), 3.80-4.25 (3H, m), 5.64 (1H, s), 7.35 (1H, s), 7.40-7.47 (2H, m), 7.70 (1H, d, J = 7.3Hz), 8.10 (1H, br), 8.73 (1H, br), 9.37 (1H, brs).

Example 151
Ethyl 4- (2-bromo-3-cyanophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine-5-carboxylate The compound was converted to ethyl 4- (2-bromo-3-cyanophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine-5-carboxylate 2 odors Prepared from the hydride salt in the same manner as in Example 3.
MS (EI): 469 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.85 (3H, t, J = 7.3Hz), 1.53-1.55 (1H, m), 1.70-1.72 (1H, m), 1.87-2.06 (4H, m), 2.16 (3H, s), 2.84-2.88 (2H, m), 3.78 (2H, q, J = 7.3Hz), 3.94-3.96 (1H, m), 5.63 (1H, s), 7.34-7.48 (3H, m), 7.68 (1H, d, J = 7.3Hz), 9.34 (1H, brs), 12.16 (1H, brs).

Example 152
4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-2-oxo-piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine The title compound was prepared from 1-methyl-2-oxo-piperidine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole. 1 in the same manner.
MS (EI): 375 (M ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.88-1.91 (1H, m), 2.26-2.33 (2H, m), 2.65-2.70 (1H, m), 2.82 (3H, m) , 3.17-3.20 (1H, m), 3.31-3.36 (2H, m), 5.40 (1H, s), 7.29 (1H, s), 7.44 (1H, d, J = 6.6Hz), 7.58 (1H, dd , J = 9.0Hz and 6.6Hz), 7.92 (1H, d, J = 9.0Hz), 9.88 (1H, brs), 12.22 (1H, brs).

Example 153
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methyl-2-oxo-piperidin-4-yl) -2H-pyrazolo [3,4-b The pyridine title compound was prepared in the same manner as Example 1 from 1-methyl-2-oxo-piperidine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MS (EI): 437 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.88-1.92 (1H, m), 2.25-2.36 (2H, m), 2.69-2.74 (1H, m), 2.84 (3H, s) , 3.18-3.36 (3H, m), 5.50 (1H, s), 7.37 (1H, s), 7.59-7.62 (2H, m), 7.85 (1H, d, J = 7.3Hz), 9.90 (1H, brs ), 12.33 (1H, brs).

Example 154
4- (2-Chlorophenyl) -4,7-dihydro-5- (5-methyl-1,3,4-oxadiazol-2-yl) -6-propyl-2H-pyrazolo [3,4-b] A solution of pyridine 2-chlorobenzaldehyde (21 g), meldrum acid (21 g), 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain colorless crystals (16 g). 1N NaOH solution (100 mL) was added and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was acidified. The reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain colorless crystals (9.6 g). Hydrazine (0.22 g) and CDI (0.66 g) were added to the obtained colorless crystals (1.0 g) in DMF (5 mL), and the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration to obtain colorless crystals (0.7 g). Orthoacetic acid triethyl ester (3.7 g) was added to the resulting colorless crystals (1.0 g) in DMF (5 mL) and the mixture was heated for 3 hours. The precipitated crystals were collected by filtration to obtain colorless crystals (0.6 g). To a solution of dimethylformamide (0.55 g) in chloroform (3 mL) was added phosphorus oxychloride (1.2 g) and a solution of the resulting colorless crystals in chloroform (6 mL) under ice-cooling, and the mixture was stirred overnight. Under ice cooling, an aqueous solution of sodium acetate (7.7 g) was added, and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to give colorless crystals. Hydrazine (0.15 g) was added to a solution of the obtained colorless crystals in pyridine (10 mL), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (170 mg) as colorless crystals.
MS (EI): 356 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.00 (3H, t, J = 7.3Hz), 1.67-1.74 (2H, m), 2.31 (3H, s), 2.70-2.83 (2H , m), 5.71 (1H, s), 7.07-7.12 (3H, m), 7.33-7.40 (2H, m), 9.49 (1H, brs), 12.04 (1H, brs).

Example 155
4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1- (methylamino) ethyl) -2H-pyrazolo [3,4-b] pyridine dihydrochloride The compound was prepared in the same manner as Examples 15 and 2 from 2-methylglycine ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.
MS (EI): 384 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.49 (3H, d, J = 7.3Hz), 3.09 (3H, s), 4.00 (2H, br), 4.60 (1H, q, J = 7.3Hz), 5.53 (1H, s), 7.48-7.53 (2H, m), 7.64 (1H, s), 7.82 (1H, d, J = 7.3Hz), 8.00-8.29 (2H, br), 10.97 (1H, brs).

Example 156
4- (2-Chlorophenyl) -4,7-dihydro-5- (5-methyl-1,2,4-oxadiazol-3-yl) -6-propyl-2H-pyrazolo [3,4-b] A solution of pyridine 2-chlorobenzaldehyde (21 g), meldrum acid (21 g), 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain colorless crystals (16 g). 1N NaOH solution (100 mL) was added and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was acidified. The reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain colorless crystals (9.6 g). To the resulting colorless crystals (4.2 g) in DMF (20 mL) was added ammonia solution (3.0 g) and CDI (2.8 g) and the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to give an oil. A solution of the residue in N, N-dimethylacetamide dimethylacetal (30 mL) was heated for 2 hours, and the solvent was distilled off under reduced pressure. To the residue was added hydroxyammonium (1.4 g), 1N NaOH (20 mL), dioxane (20 mL) and acetic acid (28 mL) and the mixture was heated for 1 h. The reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to obtain colorless crystals (1.3 g). To a solution of dimethylformamide (1.7 g) in chloroform (10 mL) was added phosphorus oxychloride (3.5 g) and a solution of the resulting colorless crystals in chloroform (20 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous solution of sodium acetate (23 g) was added, and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to give colorless crystals. Hydrazine (0.6 g) was added to a solution of the obtained colorless crystals in pyridine (15 mL), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (500 mg) as colorless crystals.
MS (EI): 356 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.99 (3H, s), 1.62 (3H, t, J = 7.3Hz), 1.66-1.73 (2H, m), 2.13 (3H, s ), 2.35-2.38 (2H, m), 2.84-3.05 (2H, m), 5.73 (1H, s), 7.06-7.17 (3H, m), 9.90 (1H, brs), 12.11 (1H, brs).

Example 157
4- (2,1,3-Benzoxadiazol-4-yl) -4,7-dihydro-5- (5-methyl-1,3,4-oxadiazol-2-yl) -6-propyl -2H -pyrazolo [3,4-b] pyridine The title compound was prepared in the same manner as Example 154 from 2,1,3-benzoxadiazole-4-aldehyde.
MS (EI): 364 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.01 (3H, t, J = 7.3Hz), 1.69-1.76 (2H, m), 2.31 (3H, s), 2.72-2.86 (2H , m), 5.82 (1H, s), 7.18 (1H, d, J = 6.6Hz), 7.32 (1H, s), 7.48 (1H, dd, J = 9.0Hz and 6.6Hz), 7.80 (1H, d , J = 9.0Hz), 9.65 (1H, brs), 12.07 (1H, brs).

Example 158
4- (2-Bromo-3-cyanophenyl) -4,7-dihydro-5- (5-methyl-1,3,4-oxadiazol-2-yl) -6-propyl-2H-pyrazolo [3 , 4-b] pyridine The title compound was prepared in the same manner as Example 154 from 2-bromo-3-cyanobenzaldehyde.
MS (EI): 425 (M ⁺ ).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.00 (3H, t, J = 7.3Hz), 1.66-1.73 (2H, m), 2.33 (3H, s), 2.74-2.78 (2H , m), 5.78 (1H, s), 7.40-7.47 (3H, m), 7.69 (1H, dd, J = 7.3Hz and 7.2Hz), 9.63 (1H, brs), 12.14 (1H, brs).

Example 159
6- (1-Amino-1-methylethyl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine hydrochloride Prepared in the same manner as Examples 15 and 2 from dimethylglycine ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole.

Formulation Example 1
The compound of Example 1 (0.5 parts), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were mixed well and kneaded well with a binder made with corn starch (2 parts). . The kneaded product is sieved with 16 mesh, dried in an oven at 50 ° C., and sieved with 4 mesh. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) are mixed well, compressed and tableted to contain 0.5 mg of active ingredient per tablet. Got.

Formulation Example 2
The compound of Example 1 (1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, and the solution was filtered to remove pyrogens. The filtrate was transferred to an ampoule under aseptic conditions. After sterilization, the ampule was melt-sealed to obtain an injection containing 1.0 mg of the active ingredient.
The action of the compound of the present invention on glycogen synthase kinase-3 beta (GSK-3β) was evaluated and confirmed as follows.

Test Example 1 : GSK-3β inhibitory activity In GSK-3β buffer solution (25 μL) containing 1% dimethyl sulfoxide (20 mmol / L Tris-HCl (pH 7.5), 10 mmol / L magnesium chloride, 5 mmol / L dithiothreitol) Reaction of CREB phosphopeptide (4.6 nmol), rabbit GSK-3β (0.5 unit), ATP (5 nmol), [γ- ³² P] ATP (12.3 kBq) and the test compound at 30 ° C. for 20 minutes I let you. The reaction product (10 μL) was adsorbed on ion exchange paper P81, this ion exchange paper was washed with phosphoric acid (100 mmol / L), and cpm was measured with a scintillation counter. As a result, the compound of the present invention showed an IC ₅₀ value of 1 to 1000 nmol / L. As an example, the IC ₅₀ values of the compounds are shown in Table 1 below.

  The CREB phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser-Arg-Arg-Pro-Ser (P) -Tyr-Arg.

Test Example 2 : GSK-3β Inhibitory Activity in Rat Hippocampal Cultured Neurons Hippocampal neurons were collected from embryonic day 18 rat embryos. After culturing hippocampal neurons for 7 days, the neurons were treated with β-amyloid (25-35) (20 μmol / L) and a test compound (GSK-3β inhibitor), and the culture was continued for 3 hours to thereby increase the tau protein concentration. Phosphorylation was induced. After completion of the culture, the phosphorylation level of tau protein was measured by the EIA method using a phosphorylated tau-recognizing antibody (phosphorylated site by GSK-3β), and the inhibitory action of a GSK-3β inhibitor in nerve cells was evaluated.

Test Example 3 : Effect on β-amyloid-induced cell damage in cultured rat hippocampal neurons Hippocampal neurons were collected from embryonic day 18 rat embryos. After culturing hippocampal neurons for 7 days, the neurons were treated with β-amyloid (25-35) (20 μmol / L) and a test compound (GSK-3β inhibitor), and the culture was continued for 24 hours to cause cytotoxicity. (Reduced activity of intracellular dehydrogenase) was induced. After completion of the culture, intracellular dehydrogenase activity was measured, and the effect of GSK-3β inhibitors on β-amyloid-induced cytotoxicity was evaluated.

Test Example 4 : GSK-3β inhibitory action in a gerbil cerebral ischemia model A test compound (GSK-3β inhibitor) is intraperitoneally administered to gerbils, and 30 minutes later, the common carotid artery is blocked (4 minutes). Produced cerebral ischemia, thereby inducing phosphorylation of tau protein in the brain. The hippocampus was collected from gerbil brain 3 hours after cerebral ischemia, and the phosphorylation level of tau protein was measured by Western blot using a phosphorylated tau recognition antibody (phosphorylated site by GSK-3β). The GSK-3β inhibitory action of the -3β inhibitor in the gerbil brain was evaluated.

(Industrial applicability)
The compound of the present invention exhibits a selective and potent inhibitory action against glycogen synthase kinase-3 beta (GSK-3β), and is associated with diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorder, Down syndrome) Cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalic Parkinson syndrome, post-encephalitic Parkinson syndrome, fighting encephalopathy, Guam-Parkinson dementia complex, Lewy body disease, Pick disease, Cortical base degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic depression, etc.), alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia, prevention against some virus-induced tumors And / or as a therapeutic or as an immunostimulant.
This application is based on Japanese Patent Application No. 2002-230581 filed in Japan, the contents of which are incorporated herein by reference.

Claims (17)

Formula (I):

[Where,
R ⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenyl Sulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, optionally substituted phenyl, optionally substituted aromatic heterocyclic group, substituted May be phenylalkyl, or —COOR ⁸ (wherein R ⁸ is hydrogen, alkyl, aryl optionally having substituent (s), or aralkyl optionally having substituent (s)). A group of
R ¹ is hydrogen;
R ² is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, amino Alkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, substituted Optionally phenyl, aromatic heterocyclic group or phenylalkyl;
R ³ is (1) alkyl or haloalkyl,
(2) cycloalkyl,
(3) phenyl optionally having substituent (s),
(4) an aromatic heterocyclic group,
(5) a group derived from a benzene ring fused with a saturated or unsaturated 5- or 6-membered carbocyclic ring,
(6) a group derived from a benzene ring fused with a saturated or unsaturated 5- to 7-membered carbon ring containing 1 to 3 heteroatoms, or (7) 1 to 3 fused with a benzene ring A group derived from a saturated or unsaturated 5- to 7-membered carbocyclic ring containing
The groups (2) to (7) may have one or more substituents, or
R ³ represents the following formulas (II) and (III):

(Wherein R ⁶ and R ⁷ are each an optionally substituted phenyl or aromatic heterocyclic group)
Or a group selected from the group represented by
R ² and R ³ are bonded to form a ring that may contain a hetero atom, and the ring may be condensed with an optionally substituted benzene ring;
R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, optionally substituted phenyl, optionally substituted. An aromatic heterocyclic group, cyano or nitro; and R ⁵ is alkyl,
Phenylaminoalkyl,
Acyl,
Acylalkyl,
Aminocarbonyl,
Arylaminocarbonyl,
A saturated or unsaturated 4- to 7-membered heterocyclic ring which may have a substituent,
A saturated 3- to 7-membered carbocyclic ring having a substituent,
Alkyl optionally substituted with a saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms, or
Formula: — (CR ^a R ^b ) _n NR ¹¹ R ¹² (wherein n is an integer of 1 to 4, R ^a is hydrogen or alkyl, R ^b is hydrogen or alkyl, and R ¹¹ is hydrogen) , Alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, R ¹² is hydrogen or Group which is alkyl).
Provided that when R ⁰ , R ¹ and R ² are each hydrogen, R ⁴ is methoxycarbonyl and R ⁵ is methyl, R ³ is phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxy When neither phenyl nor 4-methoxycarbonylphenyl and R ⁵ is alkyl, R ⁴ is alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano, nitro is not. ]
A dihydropyrazolopyridine compound, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof. R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, optionally substituted phenyl, substituted aromatic heterocyclic group , Cyano or nitro; and R ⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, an optionally substituted saturated or unsaturated 4- to 7-membered heterocyclic ring A saturated 3- to 7-membered carbocyclic ring having a substituent, an alkyl substituted with a saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms which may have a substituent Or the formula: — (CH ₂ ) _n NR ¹¹ R ¹² (where n is an integer of 1 to 4) R ¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl. And R ¹² is hydrogen or alkyl). The dihydropyrazolopyridine compound of claim 1, an optically active form thereof, or a pharmaceutically acceptable salt thereof. The dihydropyrazolopyridine compound according to claim 1 or 2, wherein R ² is hydrogen or alkyl, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof. R ³ may optionally have 1 to 3 substituents phenyl, naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl The dihydropyrazolopyridine compound according to claim 1 or 2, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof. R ⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms The dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, or a pharmaceutically acceptable salt thereof. R ⁵ is represented by the formula: — (CH ₂ ) _n NR ¹¹ R ¹² (wherein n is an integer of 1 to 4, R ¹¹ is hydrogen, alkyl or alkoxycarbonyl, and R ¹² is hydrogen or alkyl) The dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, or a pharmaceutically acceptable salt thereof. 2. R ⁰ is hydrogen or a group of the formula: —COOR ⁸ , wherein R ⁸ is alkyl, aryl optionally having substituent (s) or aralkyl optionally having substituent (s). Or 2 dihydropyrazolopyridine compounds, optically active forms thereof, or pharmaceutically acceptable salts thereof. (2) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4 b] pyridine,
(3) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(11) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(14) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridine- 4-yl) -2H-pyrazolo [3,4-b] pyridine,
(23) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4- (N, N-dimethylamino) cyclohexyl)- 2H-pyrazolo [3,4-b] pyridine,
(27) 6- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -4- (2,1,3-benzooxadiazol-4-yl) -5-cyano-4 , 7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(33) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-ethylpiperidin-4-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(37) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine,
(38) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine ,
(41) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2H-pyrazolo [3,4-b] pyridine ,
(46) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2H-pyrazolo [3,4-b] pyridine ,
(48) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -2H -Pyrazolo [3,4-b] pyridine,
(51) 6- (1-Acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine ,
(52) 6- (1-Benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine ,
(53) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-4-yl) -2H-pyrazolo [3,4-b] Pyridine,
(59) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-oxocyclohexane-1-yl) -2H-pyrazolo [3 , 4-b] pyridine,
(62) 4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexane-1-yl) -2H-pyrazolo [3,4-b] pyridine ,
(63) 6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(73) 5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -6- (piperidin-4-yl) -2H-pyrazolo [3,4-b] pyridine,
(75) 4- (2,1,3-Benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine-6-carboxylic acid phenylamide ,
(78) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (4-phenylpiperazin-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine,
(81) 6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(82) 6-acetyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(84) 4- (2-Bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine,
(86) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (pyrrolidin-3-yl) -2H-pyrazolo [3,4-b] pyridine, and (87) 4- ( 2,1,3-Benzoxadiazol-4-yl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2H-pyrazolo [3,4-b] pyridine The dihydropyrazolopyridine compound of claim 1 or 2, selected from: tautomers thereof, optically active forms thereof, or pharmaceutically acceptable salts thereof.   A medicament comprising the dihydropyrazolopyridine compound of claim 1 or 2, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the dihydropyrazolopyridine compound of claim 1 or 2, an optically active isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.   A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of the dihydropyrazolopyridine compound of claim 1, an optically active isomer thereof, and a pharmaceutically acceptable salt thereof.   The medicament according to claim 9, which is used for prevention and / or treatment of a disease caused by glycogen synthase kinase-3 beta hyperfunction.   The medicament according to claim 9, which is used for prevention and / or treatment of a neurodegenerative disease.   Diseases include Alzheimer's disease, ischemic cerebrovascular disorder, Down syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalic parkinsonism, post encephalitis parkinsonism, fighter encephalopathy, guam 14. The medicament of claim 13, selected from the group consisting of Parkinson dementia complex, Lewy body disease, Pick disease, cortical basal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic depression.   The medicament according to claim 9, which is used for prevention and / or treatment of diabetes and diabetic complications.   The medicament according to claim 9, which is used as an immunostimulant.   The medicament according to claim 9, which is used for prevention and / or treatment of alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia or virus-induced tumor.