CN1675209A - Dihydropyrazolopyridine compounds - Google Patents

Abstract

The present invention provides dihydropyrazolopyridine compounds represented by the formula (I): wherein each symbol is as defined in the specification, optically active forms thereof, and pharmaceutically acceptable salts thereof and hydrates thereof. The compounds of the present invention show a selective and strong inhibitory activity on glycogen synthase kinase-3 beta (GSK-3beta), and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications and neurodegenerative diseases or as immunopotentiators.

Description

Dihydropyrazolopyridine compounds

technical field

The present invention relates to novel pharmaceutical compounds having glycogen synthase kinase-3β (GSK-3β) inhibitory activity and their use.

Background technique

Glycogen synthase kinase-3β (GSK-3β), a protein kinase, has been reported to be involved in the cause of various diseases described below.

Type II diabetes is a disease in which the insulin activity of pancreatic beta cells becomes low and glucose in the blood increases. Therefore, it induces complications such as diabetic nephropathy, retinal degeneration, heart disease and the like. GSK-3β inhibits glycogen accumulation in peripheral tissues, reduces insulin response and increases blood glucose by phosphorylating glycogen synthase. Lithium, which has GSK-3β inhibitory activity, actually lowers glucose in blood through GSK-3β inhibitory activity (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 II diabetes and its complications.

The mechanism of development of Alzheimer's dementia has not been elucidated. However, amyloid aggregation and neurofibrillary changes are thought to be closely related to its development. As described below, GSK-3β is associated with both amyloid aggregation and neurofibrillary changes. (1) It binds to mutant presenilin and increases the production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It induces the phosphorylation of Tau protein, leads to changes in neurofibrils, and weakens the neuron skeleton to induce neuron death (Neurosci. Lett., 128, 195 (1991)). In addition to the above, (3) it has been reported that GSK-3β is directly involved in inactivating pyruvate dehydrogenase through phosphorylation to reduce the production of acetylcholine required to maintain cell activity, thereby causing neuron death.

In addition, efficacy against AIDS encephalopathy, which is a neurodegenerative disease different from Alzheimer's dementia, has also been proposed. Tat, as a protein produced by HIV virus that causes AIDS, enhances GSK-3β activity in neurons, inducing neuron death (J. Neurochem., 73, 578 (1999)). From the above, GSK-3β inhibitors are considered to be effective drugs for improving neurodegenerative diseases including Alzheimer's dementia.

Lithium and valproic acid, which have antimanic-depressive activity, have GSK-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The relationship between antimanic depressive activity and GSK-3β inhibitory activity is unclear, but it is considered that the inhibitory activity against glutamate toxicity is partly responsible for maintaining neuronal activity (Proc.Nat.Acad.Sci., 95, 2642 (1998)). Based on the above, it is believed that GSK-3β inhibitors are effective drugs for improving manic-depressive psychosis.

NF-AT is a transcription factor that is dephosphorylated by calcineurin to increase immune response (Science, 275, 1930 (1997)). GSK-3β acts to suppress immune function by conversely phosphorylating NF-AT. Therefore, GSK-3β inhibitors are considered to be effective drugs for immunopotentiation.

Incidentally, JP-A-3-272189 (invention relating to an improved method for synthesizing mevalolactone (mevalolacton) intermediate), JP-A-2-275878 (involving use in hyperlipoproteinemia and arterial Therapeutic agent for atherosclerosis) and JP-A-1-272584 (therapeutic agent for hyperlipoproteinemia) disclose pyrazolo[3, 4-b] Pyridine compounds. These documents do not disclose or suggest any effect of these compounds on GSK-3β or the central nervous system.

Specifications of JP-A-59-65089, JP-A-59-118786, JP-A-60-56979, JP-A-60-197685, etc. disclose 6-methyl-4- substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate compounds, and prepared them by a similar method. The present inventors repeated Reaction A shown below according to the method described in JP-A-59-65089, but could not obtain the compound shown in Example 14 (hereinafter formula (IV)) described herein. They confirmed that only pyrazolo[1,5-a]pyrimidine derivatives represented by formula (V) could be produced. The IR, NMR and melting point of the compound of formula (V) were measured and found to be the same as those described in the specification of the publication. It was therefore concluded that the wrong structural formula was disclosed in these documents. In other words, 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylates could not be synthesized according to the methods described in these documents.

The compound shown in above-mentioned formula (IV) can be synthesized according to the method described in J.Chem.Soc., Perkin Trans.1,947 (1996), and this publication discloses 4-(2-chlorophenyl)-6- Methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester, etc.

invention disclosure

The object of the present invention is to provide novel compounds having selective and potent inhibitory activity against glycogen synthase kinase-3β (GSK-3β), and additionally to provide medicaments comprising them and pharmaceutical compositions comprising them.

In order to achieve the above object, the present inventors conducted in-depth research and found that 4,7-dihydropyrazolo[3,4-b]pyridine derivatives have selective and strong GSK-3β inhibitory activity, based on this The present invention has been accomplished. That is, the present invention relates to a drug comprising a dihydropyrazolopyridine compound represented by the following formula (I), its optical isomer, its pharmaceutically acceptable salt or Its hydrate acts as the active ingredient.

The present invention provides the following.

[1] A dihydropyrazolopyridine compound represented by formula (I), or an optically active form thereof, or a pharmaceutically acceptable salt thereof:

in

^R is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthio Carbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl , acyloxyalkyl, optionally substituted phenyl, optionally substituted aromatic heterocyclic group, optionally substituted phenylalkyl, or the formula -COOR ⁸ shown group (wherein ^R is hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl);

R ¹ is hydrogen;

^R is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxyl, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acyl Amino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, Alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, optionally with Substituent phenyl, aromatic heterocyclic group or phenylalkyl;

^R3 is

(1) Alkyl or haloalkyl,

(2) cycloalkyl,

(3) A phenyl group optionally having a substituent,

(4) aromatic heterocyclic group,

(5) A group derived from a benzene ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic ring,

(6) A group derived from a benzene ring fused to a 5- to 7-membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatoms, or

(7) A group derived from a 5- to 7-membered saturated or unsaturated carbocycle containing 1 to 3 heteroatoms, which is fused to a benzene ring,

wherein the groups listed in (2) to (7) may have one or more substituents, or

Groups selected from the following formulas (II) and (III):

Wherein R ⁶ and R ⁷ are each optionally substituted phenyl or aromatic heterocyclic group,

or R and ^R combine to form a ring optionally comprising heteroatoms, wherein ^the ring may be fused to an optionally substituted benzene ring;

^R4 is

Alkoxycarbonyl,

Alkylcarbonyl,

Alkylsulfonyl,

Alkylsulfinyl,

Phenylsulfinyl,

phenylsulfonyl,

Dialkylphosphinyl,

Dialkylphosphono,

Optionally substituted phenyl,

An aromatic heterocyclic group optionally having substituents,

cyano, or

Nitro; and

R ⁵ is

alkyl,

Phenylaminoalkyl,

Acyl,

acylalkyl,

aminocarbonyl,

Arylaminocarbonyl,

4- to 7-membered saturated or unsaturated heterocycle optionally having substituents,

3 to 7 membered saturated carbocycles with substituents,

An alkyl group substituted by a 4 to 7 membered saturated or unsaturated ring containing 1 or 2 nitrogen atoms (the ring may optionally have substituents), or

A group represented by the formula -(CR ^a R ^b ) _n NR ¹¹ R ¹² , wherein n is an integer from 1 to 4, R ^a is hydrogen or an alkyl group, R ^b is hydrogen or an alkyl group, R ¹¹ is hydrogen, Alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, Phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and ^R is hydrogen or alkyl,

with the proviso that when R ⁰ , R ¹ and R ² are each hydrogen, R ⁴ is methoxycarbonyl and R ⁵ is methyl, then R ³ should not be phenyl, 2-chlorophenyl, 3-nitrobenzene base, 4-carboxyphenyl or ⁴ -methoxycarbonylphenyl, and when R is alkyl ^, then R is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl Acyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphono, cyano or nitro.

[2] The dihydropyrazolopyridine compound of the above [1], or an optically active form thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylene Sulfonyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphono, optionally substituted phenyl, substituted aromatic heterocyclic group, cyano or Nitro, and

R is ^alkyl , phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, optionally substituted 4 to 7 membered saturated or unsaturated heterocycle, substituted 3 to 7 A 7-membered saturated carbocyclic ring, an alkyl group substituted by a 4- to 7-membered saturated or unsaturated ring containing 1 or 2 nitrogen atoms (the ring optionally has a substituent), or as in the formula -(CH ₂ ) _n NR ¹¹ The group represented by R ¹² , wherein n is an integer from 1 to 4, and R ¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, benzene sulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and ^R is hydrogen or alkyl.

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

[4] The dihydropyrazolopyridine compound of the above-mentioned [1] or [2], or an optically active form thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is phenyl (which optionally has 1 to 3 substitutions yl), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl.

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

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

[7] The dihydropyrazolopyridine compound of the above-mentioned [1] or [2], or an optically active form thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is hydrogen or a group represented by the formula -COOR ⁸ : (wherein R is ^alkyl , optionally substituted aryl or optionally substituted aralkyl.

[8] The dihydropyrazolopyridine compound of the above-mentioned [1] or [2], which is selected from the following compounds, their tautomers, their optically active forms, or their pharmaceutically acceptable salts:

(2) 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazole And[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 -tetrahydropyridin-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-benzoxadiazol-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-tetrahydropyridine- 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-pyrazole And[3,4-b]pyridine,

(53) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylsulfonylpiperidin-4-yl)-2H-pyrazole And[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-pyrazole And[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-6-phenylaminocarbonyl-4,7-dihydro-2H-pyrazolo[3, 4-b]pyridine,

(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.

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

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

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

[12] The medicament of the above-mentioned [9], which is used for the prevention and/or treatment of diseases caused by excessive activity of glycogen synthase kinase-3β.

[13] The drug of the above-mentioned [9], which is used for preventing and/or treating neurodegenerative diseases.

[14] The drug of the above-mentioned [13], wherein the disease is selected from Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral ischemia caused by cerebral amyloid angiopathy, progressive nuclear Upper paralysis, subacute sclerosing panencephalitis, parkinsonian neurological dysfunction, postencephalitic parkinsonian neurological dysfunction, boxer's encephalopathy, Guam Parkinson's dementia syndrome, Levy Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, and manic-depressive psychosis.

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

[16] The drug of the above-mentioned [9], which is used as an immunopotentiator.

[17] 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-cell or B-cell leukemia or virus-induced tumors.

Detailed description of the invention

Formula (I) represents the existence of tautomers represented by the following formulas (I-a) and (I-b) based on the position of the hydrogen atom of the pyrazole ring. The present invention includes each of the isomers represented by formulas (I-a) and (I-b), as well as mixtures of these isomers.

Hereinafter, the compound represented by formula (I) in this specification is described in detail.

"Alkyl" means a straight or branched hydrocarbon chain having from 1 to 8 carbon atoms, which includes methyl, ethyl, propyl, butyl, pentyl, hexyl, or structural isomers thereof, such as Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, etc., preferably an alkyl group having 1 to 4 carbon atoms. The alkyl group for R ² is preferably an alkyl group having 1 to 4 carbon atoms. The alkyl group for R ⁵ is preferably an alkyl group having 2 to 8 carbon atoms. "Alkyl having 2 to 8 carbon atoms" specifically includes ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, or structural isomers thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, etc. An alkyl group having 2 to 4 carbon atoms is more preferred, and a propyl group is particularly preferred.

"Acyl" means C ₂ -C ₁₄ acyl, which includes "alkylcarbonyl" having 2 to 8 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl , heptanoyl, etc., for R ⁴ preferably an acyl group having 2 to 5 carbon atoms, "C ₇ -C ₁₂ arylcarbonyl" such as benzoyl, naphthoyl, etc.; and "C ₇ -C ₁₂ aralkylcarbonyl "Such as benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, etc., etc. The benzene ring and the naphthalene ring may have 1 to 5 substituents, and there is no specific limitation on the substitution position.

"Acylalkyl" is an acylalkyl group consisting of the aforementioned C ₁ -C ₈ alkyl groups and the aforementioned C ₂ -C ₁₄ acyl groups, which include, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyryl Methyl, pentanoylmethyl, pivaloylmethyl, 2-acetylethyl, 2-propionylethyl, 3-acetylpropyl, etc.

"Cycloalkyl" means a cyclic hydrocarbon of 3 to 8 carbon atoms. The cycloalkyl group specifically includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., preferably a cycloalkyl group having 3 to 6 carbon atoms. The cycloalkyl group may have 1 to 5 substituents, and there is no specific limitation on the substitution position.

"Halo"means fluorine, chlorine, bromine or iodine.

"Amino" refers to a primary, secondary or tertiary amine having the above-mentioned C ₁ -C ₈ alkyl, which includes, for example, amino, mono- or di-C ₁ -C ₈ alkyl substituted amino such as methylamino, dimethyl Amino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino, etc.

"Alkylthio" is a linear or branched alkylthio group having 1 to 6 carbon atoms, which includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio , and its structural isomers, such as isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-amylthio etc., preferably an alkylthio group having 1 to 3 carbon atoms.

"Phenylthio" means a phenylthio group optionally having 1 to 5 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Haloalkyl" is the above C ₁ -C ₈ alkyl substituted by 1 to 5 halogens, which represents fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoro Ethyl, 2,2,3,3,3-pentafluoropropyl, etc.

"Aminoalkyl" is a C ₁ -C ₈ alkyl group having a primary amino group, which includes, for example, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, etc., preferably containing 1 to 4 aminoalkyl groups of carbon atoms.

"Acylamino" is an acylamino group having the above-mentioned C ₂ -C ₁₄ acyl group, which represents, for example, acetylamino, propionylamino, butyrylamino, valerylamino, pivalylamino, benzoylamino, phenylacetylamino, Phenylpropionylamino, phenylbutyrylamino, etc.

"Alkoxy" is an alkoxy group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and structures thereof Isomers, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, tert-pentoxy, etc., preferably having 1 to 4 carbon atoms alkoxy.

"Cycloalkoxy" is a cycloalkoxy group having the above-mentioned C ₃ -C ₈ cycloalkyl group, which includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc., preferably containing Cycloalkoxy of a cycloalkyl group of 3 to 6 carbon atoms.

"Phenoxy" means a phenoxy group optionally having 1 to 5 substituents on a phenyl group, and there is no specific limitation on the substitution position.

"Phenylalkoxy" is phenylalkoxy having the above-mentioned C ₁ -C ₈ alkoxy, which includes, 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-phenylpropoxy, etc., preferably containing 1 Phenylalkoxy to an alkoxy group of 4 carbon atoms. The phenylalkoxy group optionally has 1 to 5 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Aminoalkoxy" is an aminoalkoxy group composed of the above-mentioned amino group and C ₁ -C ₈ alkoxy group, which includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2 -(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, 4-(dimethylamino)butoxy, etc., preferably composed of an alkyl group having 1 to 4 carbon atoms Aminoalkoxy consisting of a tertiary amino group and an alkoxy group having 1 to 4 carbon atoms.

"Alkoxyalkyl" is an alkoxyalkyl group composed of the above-mentioned C ₁ -C ₈ alkoxy and C ₁ -C ₈ alkyl, which includes, for example, methoxymethyl, ethoxymethyl, 2 - methoxyethyl, propoxymethyl, isopropoxymethyl, etc., preferably an alkoxy group consisting of an alkoxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms alkyl.

"Phenoxyalkyl" is a phenoxyalkyl group consisting of the above-mentioned phenoxy group and C ₁ -C ₈ alkyl group, which includes, for example, phenoxymethyl group, 2-phenoxyethyl group, 3-phenoxy group propyl group and the like, preferably a phenoxyalkyl group containing an alkyl group having 1 to 4 carbon atoms. The phenoxyalkyl group optionally has a substituent on the phenyl group, and there is no specific limitation on the position of substitution.

"Hydroxyalkyl" is a hydroxyalkyl group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, etc., preferably containing 1 to 4 carbon atoms Alkyl hydroxyalkyl.

"Alkoxycarbonyl" is an alkoxycarbonyl group having the above-mentioned C ₁ -C ₈ alkoxy group, which includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl , hexyloxycarbonyl, and its structural isomers, such as isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, t-Amyloxycarbonyl and the like, preferably alkoxycarbonyl in which the alkoxy moiety has 1 to 4 carbon atoms. The alkoxycarbonyl group for R ⁴ is preferably an alkoxycarbonyl group having 2 to 5 carbon atoms.

"Phenoxycarbonyl" is a phenoxycarbonyl group optionally having 1 to 5 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Aminocarbonyl" is an aminocarbonyl group having the above-mentioned amino group including a mono- or di-C ₁ -C ₈ alkyl substituted amino group, which includes, for example, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, di Ethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl and the like.

"Alkylthiocarbonyl" is alkylthiocarbonyl having the above-mentioned C ₁ -C ₆ alkylthio, which includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl, and structural isotopes thereof. Constituents such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec-butylthiocarbonyl, tert-butylthiocarbonyl, etc., preferably alkylthiocarbonyl in which the alkyl moiety has 1 to 3 carbon atoms.

"Carboxyalkyl" is a carboxyalkyl group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, carboxymethyl, carboxyethyl, carboxypropyl, etc., preferably a carboxy group containing an alkyl group having 1 to 4 carbon atoms alkyl.

"Cycloalkoxyalkyl" is cycloalkoxyalkyl composed of the above-mentioned C ₃ -C ₈ cycloalkoxy and C ₁ -C ₈ alkyl, which includes, for example, cyclopropoxymethyl, cyclopropoxy ethyl, cyclobutoxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, etc., preferably cycloalkoxy having 3 to 6 carbon atoms and alkane having 1 to 4 carbon atoms Cycloalkoxyalkyl composed of groups. The cycloalkoxyalkyl group optionally has 1 to 3 substituents on the cycloalkyl group, and there is no specific limitation on the substitution position.

"Alkylsulfinyl" is an alkylsulfinyl group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl Acyl and the like, preferably an alkylsulfinyl group containing an alkyl group of 1 to 5 carbon atoms. Preferably, the alkylsulfinyl group for R ⁴ is an alkylsulfinyl group having 1 to 4 carbon atoms.

"Phenylsulfinyl" means a phenylsulfinyl group optionally having 1 to 5 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Alkylsulfonyl" is an alkylsulfonyl group having the above-mentioned C ₁ -C ₈ alkyl, which includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, etc., preferably containing 1 Alkylsulfonyl to an alkyl group of 5 carbon atoms. Preferably, the alkylsulfonyl group of R ⁴ is an alkylsulfonyl group having 1 to 4 carbon atoms.

"Phenylsulfonyl" means a phenylsulfonyl group optionally having 1 to 5 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Mercaptoalkyl" is a mercaptoalkyl group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl, etc., preferably a mercaptoalkyl group containing an alkyl group of 1 to 4 carbon atoms .

"Alkylthioalkyl" is an alkylthioalkyl group consisting of the above-mentioned C ₁ -C ₆ alkylthio and C ₁ -C ₈ alkyl groups, which include, for example, methylthiomethyl, methylthioethyl, methyl Thiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl, etc., preferably alkylthioalkyl consists of an alkylthio group having 1 to 3 carbon atoms and an alkylthio group having 1 to 4 carbon atoms the alkyl composition.

"Aryl" is an aryl group having 6 to 14 carbon atoms, which includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthracenyl, 2-anthracenyl and the like. They may have 1 to 5 substituents, and there is no specific limitation on the substitution position.

"Aralkyl" is an aralkyl group in which the above-mentioned C ₁ -C ₈ alkyl group is substituted by the above-mentioned C ₆ -C ₁₄ aryl group, which includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1 -naphthylmethyl, 2-naphthylmethyl, etc. These may have 1 to 5 substituents on the aryl moiety, and there is no specific limitation on the substitution position.

"Acyloxyacetyl" is an acyloxyacetyl group having the above-mentioned C ₂ -C ₁₄ acyl group, which includes, for example, acetoxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxy Acetyl, etc.

"Acyloxyalkyl" is an acyloxyalkyl group having the above C ₂ -C ₁₄ acyl and C ₁ -C ₈ alkyl, which includes, for example, acetoxymethyl, propionyloxymethyl, butyryloxy methyl, benzoyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-benzoyloxyethyl, etc.

The substituent of "phenyl optionally having substituents" is, for example, "substituents" described below, wherein the number of substituents is usually 1 to 5, preferably 1 to 3. A phenyl group having 1 or 2 substituents is particularly preferred, and there is no specific limitation on the substitution position.

"Aromatic heterocyclic group" is, for example, a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, which includes, for example, thienyl, furyl, pyrrolyl , imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl (such as 1,3,4- Oxadiazolyl 1,2,4-oxadiazolyl, etc.) etc. The aromatic heterocyclic group may have 1 to 6 substituents, and there is no specific limitation on the substitution position.

The "saturated or unsaturated 4- to 7-membered heterocyclic ring optionally having substituents" includes the following groups and the like:

Wherein R ^are each independently hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, amidine hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthio ylalkyl, acyloxyacetyl, acyloxyalkyl, optionally substituted aryl, optionally substituted aromatic heterocyclic group or optionally substituted phenylalkyl .

"3- to 7-membered saturated carbocyclic ring having a substituent" includes the following groups, etc.:

wherein R is ^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, optionally substituted aromatic heterocyclic group, or optionally substituted phenylalkyl, and 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, any An aromatic heterocyclic group optionally having a substituent, or a phenylalkyl group optionally having a substituent.

The substituents in the "aromatic heterocyclic group optionally having substituents" are, for example, those "substituents" mentioned below, wherein the number of substituents is usually 1 to 6, and there is no specific limitation on the position of substitution .

"Phenylalkyl" is a phenylalkyl group consisting of phenyl and the above C ₁ -C ₈ alkyl groups, which include, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenyl Butyl, 1-phenylethyl, 1-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1- Methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl, etc., preferably a phenylalkyl group consisting of a phenyl group and an alkyl group having 1 to 4 carbon atoms.

The kind and number of substituents in the "phenylalkyl group optionally having substituents" are the same as those in the above-mentioned "aromatic heterocyclic group", and there are no specific limitations on the substitution position.

"Dialkylphosphinyl" is a dialkylphosphinyl group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl, etc. , preferably a dialkylphosphinyl group containing an alkyl group of 1 to 4 carbon atoms.

"Dialkylphosphono" is a dialkylphosphono group having the above-mentioned C ₁ -C ₈ alkyl group, which includes, for example, dimethylphosphono, diethylphosphono, dipropylphosphono, etc., preferably containing 1 to A dialkylphosphono group with an alkyl group of 4 carbon atoms.

In this specification, "substituent" includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic group, phenylalkyl, hydroxyl, carboxyl, thiol, halogen, amino, formyl, carbamoyl , cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl , phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl, etc.

The "ring optionally containing a heteroatom" is a 5- or 6-membered carbon ring optionally containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and a ring containing a sulfur atom is particularly preferred. The ring may be substituted with one or more of the above substituents or oxo groups. There is no specific limitation on the substitution position. The ring is formed by ^R2 and ^R3 in formula (I) together with the carbon atom to which they are attached. By forming such a ring, a spiro ring is formed in the compound represented by formula (I). The above-mentioned ring may be fused with a benzene ring optionally having a substituent and there is no specific limitation on the substitution position. Such rings include, for example, 2,3-dihydrobenzo[b]thiophene, 2,3-dihydrobenzo[b]thiophene-1-oxide, and the like.

"A group derived from a benzene ring fused to a 5- or 6-membered saturated or unsaturated carbocyclic ring" means a group derived from naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydro A group of naphthalene, 2,3-indane, etc. Among them, naphthyl groups such as naphthalen-1-yl and the like, and indanyl groups such as indan-4-yl and the like are preferable. This group may have 1 to 4 substituents, and there is no specific limitation on the substitution position.

"A group derived from a benzene ring fused to a 5- to 7-membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatoms" includes the following groups, etc.:

Among them, 2,1,3-benzoxadiazole, dihydrobenzo[b]furan, methylenedioxyphenyl and 3,4-dihydro-2H-benzopyran are preferred, and 2 , 1,3-benzoxadiazol-4-yl, 2,3-dihydrobenzo[b]furan-7-yl, 2,3-(methylenedioxy)phenyl and 3,4- Dihydro-2H-benzopyran-8-yl. This group may have 1 to 3 substituents, and there is no specific limitation on the position of the substituents.

"A group derived from a 5- to 7-membered saturated or unsaturated carbocycle containing 1 to 3 heteroatoms, which is fused to a benzene ring" includes the following groups and the like:

This group may have 1 to 5 substituents, and there is no specific limitation on the substitution position.

"Alkylcarbonylalkyl" is, for example, C ₁ -C ₄ -alkylcarbonyl-C ₁ -C ₄ alkyl, which includes, for example, methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butyl Carbonylmethyl etc.

"Arylaminocarbonyl" is C ₆ -C ₁₀ aryl-aminocarbonyl, which includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl and the like. The arylaminocarbonyl group optionally has 1 to 3 substituents on the aryl group, and there is no specific limitation on the substitution position.

"Aralkylaminocarbonyl" is C ₇ -C ₁₄ aralkyl-aminocarbonyl, which includes, for example, benzylaminocarbonyl and the like. The aralkylaminocarbonyl group optionally has 1 to 3 substituents on the aryl group, and there is no specific limitation on the substitution position.

"Alkyl group substituted by a saturated or unsaturated 4- to 7-membered ring containing 1 or 2 nitrogen atoms, the 4- to 7-membered ring optionally having one substituent" means substituted by "containing 1 or 2 nitrogen atoms Saturated or unsaturated 4 to 7-membered ring" substituted C ₁ -C ₈ alkyl, said saturated or unsaturated 4 to 7-membered ring such as pyrrole, pyrroline, pyrazole, pyridine, piperidine, piperazine, homo Piperazine (homopiperazine) or morpholine, etc., and it optionally has substituents such as C ₁ -C ₄ alkyl, C ₆ -C ₁₀ aryl (such as phenyl, naphthyl, etc.), "contained 1 or 2 A saturated or unsaturated 4- to 7-membered ring-substituted alkyl group of nitrogen atoms, said ring optionally having a substituent "including, for example, (4-phenylpiperazin-1-yl)methyl, 2-(4 -Phenylpiperazin-1-yl)ethyl, 3-(4-phenylpiperazin-1-yl)propyl, (4-(naphthalen-1-yl)piperazin-1-yl)methyl, 2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl, (4-methylhomopiperazin-1-yl)methyl, etc.

"Phenylaminoalkyl" is phenylamino-C ₁ -C ₄ alkyl, which includes, for example, phenylaminomethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylamino Butyl, etc. The phenylaminoalkyl group optionally has 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Phenylalkylcarbonyl" is phenyl-C ₁ -C ₄ alkylcarbonyl, which includes, for example, benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl wait. The phenylalkylcarbonyl group optionally has 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

The "alkyl" in R ¹¹ is C ₁ -C ₄ alkyl, which includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.

"Alkylsulfonyl" in R ¹¹ is C ₁ -C ₄ alkyl-sulfonyl, which includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.

The "phenylsulfonyl group" in R ¹¹ is a phenylsulfonyl group optionally having 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Phenylalkylsulfonyl" in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-sulfonyl, which includes, for example, benzylsulfonyl, 2-phenylethylsulfonyl, 3-phenylpropyl Sulfonyl, 4-phenylbutylsulfonyl, etc. The phenylalkylsulfonyl group optionally has 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Alkylsulfinyl" in R ¹¹ is C ₁ -C ₄ alkyl-sulfinyl, which includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.

The "phenylsulfinyl group" in R ¹¹ is a phenylsulfinyl group optionally having 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

The "phenylalkylsulfinyl" in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-sulfinyl, which includes, for example, benzylsulfinyl, 2-phenylethylsulfinyl, 3- Phenylpropylsulfinyl, 4-phenylbutylsulfinyl and the like. The phenylalkylsulfinyl group optionally has 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Alkoxycarbonyl" in R ¹¹ is C ₁ -C ₄ alkoxycarbonyl, which includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.

The "phenylalkoxycarbonyl" in R ¹¹ is phenyl-C ₁ -C ₄ alkoxycarbonyl, which includes, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl , 4-phenylbutoxycarbonyl, etc. The phenylalkoxycarbonyl group optionally has 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Alkylcarbonyl" in R ¹¹ is C ₁ -C ₄ alkylcarbonyl, which includes, for example, acetyl, propionyl, butylcarbonyl and the like.

The "phenylcarbonyl" in R ¹¹ is a phenylcarbonyl group optionally having 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

"Phenylalkylcarbonyl" in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-carbonyl, which includes, for example, benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4- Phenylbutylcarbonyl, etc. The phenylalkylcarbonyl group optionally has 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

The "phenoxycarbonyl" in R ¹¹ means a phenoxycarbonyl group optionally having 1 to 3 substituents on the phenyl group, and there is no specific limitation on the substitution position.

The "alkyl" in R ¹² is C ₁ -C ₄ alkyl, which includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-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 the present invention also includes such acid addition salt. Such acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as 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. When an asymmetric carbon atom is present, optical isomers and racemates thereof may exist, all of which are included in the present invention.

As for the compound (I) of the present invention, as shown below, a compound wherein R ⁰ is hydrogen can be synthesized according to the method described in J. Chem. Soc., Perkin Trans. 1, 947 (1996) and the like.

First preparation method

wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.

In the presence of ammonium acetate, the melindelentic acid (2,2-dimethyl-1,3-dioxane-4,6-dione) shown in formula (VI) and formula (VII) The carbonyl derivative shown and the carbonyl derivative shown in formula (VIII) are reacted to obtain the amide derivative shown in formula (IX). 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 generally used. The reaction is carried out at any temperature, for example from 0°C to 200°C, preferably from 60°C to 100°C.

wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.

The obtained amide derivative represented by the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to obtain a formyl derivative represented by the 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, dimethylsulfoxide and the like are generally used. The reaction is carried out at any temperature, for example from 0°C to 200°C, preferably from 0°C to 60°C.

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

Compound (I) of the present invention can be produced by reacting the resulting formyl derivative of formula (X) in the presence of hydrazine. 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, methylene chloride, dimethylformamide, dimethylsulfoxide, pyridine, alcohol, etc. are generally used. The reaction is carried out at any temperature, for example from 0°C to 200°C, preferably from 60°C to 100°C.

The carbonyl derivatives represented by the formula (VII) as raw materials can be obtained according to J.Org.Chem., 46,783(1981), Eur.J.Med.Chem., 31,3(1996) and TetrahedronLett., 24, Synthesized by the method described in 5023 (1983). The carbonyl derivative represented by formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993).

Second preparation method

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

Compound (I) of the present invention can be produced by reacting aminopyrazole represented by formula (XI) with carbonyl derivatives represented by formula (VII) and carbonyl derivatives represented by formula (VIII). 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, dimethylsulfoxide, alcohol and the like are generally used. The reaction is carried out at any temperature, for example from 0°C to 200°C, preferably from 60°C to 100°C.

For the compound (I) of the present invention, a compound wherein R ⁰ is a substituent other than hydrogen can be synthesized as follows.

The third preparation method

wherein R ⁰ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above and X represents halogen with the proviso that R ⁰ is other than hydrogen.

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

Fourth preparation method

wherein R ⁰ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, with the proviso that R ⁰ is not hydrogen.

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

It will be understood by those skilled in the art that the above preparation methods can be modified according to 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 and purification are carried out by conventional chemical processes such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various chromatography methods, and the like. When the purified product thus obtained is a racemate, the desired optically active compound can be isolated by, for example, fractional recrystallization using an optically active acid, or passing it through a column filled with an optically active carrier. The present invention also includes optically active compounds. The compound of the present invention obtained by the above method has weak inhibitory activity on kinases other than GSK-3β such as CaM kinase II, MAP kinase, casein kinase, PKA, PKC and ROCK, but has strong inhibitory activity on GSK-3β . Therefore, the compound of the present invention has selective GSK-3β inhibitory activity, and can be used as a medicine with little side effects for 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 panencephalitic parkinsonian neurological dysfunction, postencephalitic parkinsonian neurological dysfunction, boxer Encephalopathy, Guam Parkinson's dementia syndrome, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, and manic-depressive psychosis, etc.), alopecia , breast cancer, non-small cell lung cancer, thyroid cancer, T-cell or B-cell leukemia, and several virus-induced tumors. In addition, the compounds of the present invention are useful as immunopotentiators.

A formulation containing the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients and other additives generally used in formulations. Formulation carriers and excipients may be solid or liquid and include, for example, lactose, magnesium stearate, starches such as corn starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethyl alcohol, Glycols and other commonly used substances. Administration can be oral administration of tablets, pills, capsules, granules, powders, solutions, etc.; or parenteral injections (intravenous injections, intramuscular injections, etc.), suppositories, transdermal agents, etc. . Although the dose can be appropriately determined for each case in consideration of the symptoms, age, sex, etc. of the subject to be administered, it is usually 1-1,000 mg per day for adults, preferably 50-200 mg per day, administered orally once to several times per day; or For adults, 1-500mg per day, administered intravenously once to several times a day; or administered continuously intravenously for 1 to 24 hours a day.

Example

Hereinafter, the present invention is described in detail 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-tert-butoxycarbonyl-piperidin-4-yl)-5-cyano-4,7-dihydro -2H-pyrazolo[3,4-b]pyridine

To a solution of ethyl 4-piperidinecarboxylate (10.0 g) in THF (200 mL) was added triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di-tert-butyl dicarbonate at 0°C ester (15.3 g), and the mixture was stirred for one hour. The mixture was extracted with ethyl acetate and the solvent was distilled off 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-butyllithium (44 mmol) at -78°C, and stirred for three hours. Then ethyl N-Boc-piperidine 4-carboxylate (16.3 g) was added and the mixture was stirred for one hour. After acidification with hydrochloric acid, the compound was extracted with ethyl acetate, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (5:1)) to obtain 1-(N-Boc- Piperidin-4-yl)-2-cyanoethan-1-one (11.6 g) as a colorless oil. 2,1,3-Benzoxadiazole-4-aldehyde (1.0g), 3-aminopyrazole (0.6g) and 2-(N-Boc-piperidin-4-yl)-1-cyano A solution of ethane-2-one (1.7 g) in acetonitrile (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain the title compound (2.0 g) as colorless crystals.

MP: 226°C.

Elemental analysis, _calculated for: _{C23H25N7O3 :} C, 61.73; H, 5.63; _N , 21.97.

Found values: C, 61.45; H, 5.82; N, 21.61.

MS (EI): 447 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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

At 0°C, 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4 , 7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.7 g) was added to trifluoroacetic acid (20 mL), and the mixture was stirred for one hour. The solvent was evaporated under reduced pressure. After basification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure and 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°C.

MS (EI): 348 (M ⁺ ).

¹ H-NMR (400MHz, 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=9.0 Hz), 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-pyridine Azolo[3,4oxa-b]pyridine

At room temperature, to 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H- Add 37% formaldehyde (0.18g), sodium cyanoborohydride (0.19g) and acetic acid (0.36g) to a solution of pyrazolo[3,4-b]pyridine (0.7g) in MeOH (200mL) and stir The mixture was left overnight. After basification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure and 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°C.

MS (EI): 361 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz and 6.6 Hz), 7.91 (1H, d, J = 9.0 Hz), 9.76 (1H, brs), 12.17 (1H, brs).

Example 4

4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonyl-piperidin-3-yl)-5-cyano-4,7-dihydro -2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 229°C.

Elemental analysis, _calculated for: _{C23H25N7O3 :} C, 61.73; H, 5.63; _N , 21.97.

Found values: C, 61.56; H, 5.66; N, 21.67.

MS (EI): 447 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 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

In the same method as in Example 2, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonylpiperidin-3-yl)-5- Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: 202°C.

Elemental analysis, calculated for: C ₁₈ H ₁₇ N ₇ O: C, 62.24; H, 4.93; N, 28.23.

Found values: C, 61.97; H, 5.13; N, 27.89.

MS (EI): 347 (M ⁺ ).

¹ H-NMR (400MHz, 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=9.0 Hz), 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-pyridine Azolo[3,4-b]pyridine

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidine-3- yl)-2H-pyrazolo[3,4-b]pyridine to prepare the title compound.

MP: 228°C.

MS (EI): 361 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonyl-piperidin-2-yl)-5-cyano-4,7-dihydro -2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 2-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MS (EI): 447 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 2, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonylpiperidin-2-yl)-5- Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MS (EI): 347 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 1, the title compound was prepared from ethyl morpholine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MS (EI): 449 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 2, from 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.

MS (EI): 349 (M ⁺ ).

¹ H-NMR (400MHz, 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-pyridine Azolo[3,4-b]pyridine

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(morpholine-2- yl)-2H-pyrazolo[3,4-b]pyridine to prepare the title compound.

MP: 143°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 = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.80 (1H, brs), 12.20 (1H, brs).

Example 12

4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-5- Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, prepared from 1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole title compound.

MP: 222°C.

MS (EI): 445 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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-pyrazolo[3,4-b]pyridine

In the same method as in Example 2, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonyl-1,2,3,6-tetra (Hydropyridin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: 180°C.

MS (EI): 345 (M ⁺ ).

¹ H-NMR (400MHz, 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=9.0 Hz), 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-tetrahydro Pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

In the same method as in Example 3, from 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 The title compound was prepared.

MP: 218°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 = 9.0 Hz), 9.87 (1H, brs), 12.17 (1H, brs).

Example 15

4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-(N-tert-butoxycarbonyl-N-methyl-amino)ethyl)-5-cyano- 4,7-Dihydro-2H-pyrazolo[3,4-b]pyridine

To a solution of ethyl 3-alanine propionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di-tert-butyl dicarbonate ( 30 g) and the mixture was stirred at 40°C for four hours. The mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure to give ethyl N-Boc-3-aminopropanoate (16.7 g) as a colorless oil. To a solution of N-Boc-3-alanine ethyl ester (5.0 g) in THF (50 mL) was added t-BuOK (2.8 g) and iodomethane (4.9 g) at 0 °C and the mixture was stirred at room temperature for one hour . The mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure to give ethyl 3-(N-Boc-N-methylamino)propanoate (4.3 g) as a colorless oil. Then, in the same manner as in Example 1, from ethyl 3-(N-Boc-N-methylamino)propanoate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyridine azole to prepare the title compound.

MP: 240°C.

Elemental analysis, _calculated for: _{C21H23N7O3 :} C, 59.85; _H , 5.50; N, 23.26.

Found values: C, 59.69; H, 5.45; N, 23.22.

MS (EI): 421 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 2, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(2-(N-tert-butoxycarbonyl-N-methylamino) Ethyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: 174°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 = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.91 (1 H, d, J = 9.0 Hz).

Example 17

4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-(N-tert-butoxycarbonylamino)ethyl)-5-cyano-4,7-dihydro -2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 3-aminopropanoate hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 231°C.

Elemental analysis, _calculated for: _{C20H21N7O3 :} C, 58.96; _H , 5.20; N, 24.06.

Found values: C, 58.81; H, 5.19; N, 23.82.

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 2, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(2-(N-tert-butoxycarbonylamino)ethyl)-5 -Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MS (EI): 307 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 2.50-2.54 (2H, m), 2.88 (2H, t, J=7.3Hz), 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

In the same method as in Example 3, from 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 was prepared.

MP: 215°C.

MS (EI): 335 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 10.04 (1H, brs), 12.16 (1H, brs).

Example 20

4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-tert-butoxycarbonyl-N-methyl-amino)methyl)-5-cyano-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 15, the title compound was prepared from glycine ethyl ester hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 207°C.

Elemental analysis, _calculated for: _{C20H21N7O3 :} C, 58.96; _H , 5.20; N, 24.06.

Found values: C, 58.80; H, 5.12; N, 24.38.

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400MHz, 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-pyrazole And[3,4-b]pyridine trifluoroacetate

4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-tert-butoxycarbonyl-N-methylamino)methyl)-5-cyano Dihydro-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.6 g) was added to trifluoroacetic acid (10 mL), and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure and the residue was crystallized from ethanol, and the precipitated crystals were collected by filtration to give the title compound (0.1 g) as yellow crystals.

MP: 174°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

Prepared from ethyl 4-aminocyclohexanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 15 and then according to the method of Example 2 title compound.

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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

In the same method as in Example 3, from 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.

MP: 241°C.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400MHz, 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-pyridine Azolo[3,4-b]pyridine

To a solution of ethyl 4-piperidinecarboxylate (8.9 g) in _CH2Cl2 (500 mL) was added triphenylbismuth (25 g) and copper(II) acetate (10.3 g ₎ at room temperature, and the mixture was stirred overnight. After filtration _the mixture was extracted with _CH2Cl2 . The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (10:1)) to obtain ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as Colorless crystals. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-butyllithium (41 mmol) at -78°C. Then ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for one 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: n-hexane-ethyl acetate (10:1)) to give 1-(1-phenylpiperidin-4-yl)-2-cyano Ethan-1-one (2.0 g), as colorless crystals. 2,1,3-Benzoxadiazole-4-aldehyde (0.3g), 3-aminopyrazole (0.2g) and 1-(1-phenylpiperidin-4-yl)-2-cyano A solution of ethane-1-one (0.5 g) in acetonitrile (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain the title compound (0.6 g) as colorless crystals.

MS (FAB): 424 (M ⁺ +1).

¹ H-NMR (400MHz, 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-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyridine Azolo[3,4-b]pyridine

To a solution of ethyl 4-piperidinecarboxylate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0 °C, and The mixture was stirred for one hour. The mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-butyllithium (57 mmol) at -78°C. Then ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added, and the mixture was stirred for one 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: n-hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyano Ethan-1-one (7.5 g) as a colorless oil. 2,1,3-Benzoxadiazole-4-aldehyde (0.3g), 3-aminopyrazole (0.17g) and 1-(1-acetylpiperidin-4-yl)-2-cyano A solution of ethane-1-one (0.4 g) in acetonitrile (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain the title compound (0.49 g) as yellow crystals.

MP: 248°C.

MS (FAB): 340 (M ⁺ +1).

¹ H-NMR (400MHz, 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 = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 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

In the same manner as in Example 25, the title compound was prepared from benzoyl chloride, ethyl 4-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 228°C.

MS (FAB): 452 (M ⁺ +1).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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

In the same manner as in Example 25, from acetyl chloride, 1,2,3,6-ethyl tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-amino Pyrazole Preparation of the title compound.

MP: 237°C.

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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

In the same manner as in Example 25, the title compound was prepared from ethyl chloroformate, ethyl 4-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MS (EI): 419 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.19 (3H, t, J=7.3Hz), 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 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.80 (1H, brs), 12.17 (1H, brs).

Example 29

4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylsulfonylpiperidin-4-yl)-2H- Pyrazolo[3,4-b]pyridine

In the same manner as in Example 25, the title compound was prepared from methanesulfonyl chloride, ethyl 4-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 243°C.

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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)piperidine -4-yl)-2H-pyrazolo[3,4-b]pyridine

In the same method as in Example 25, from 1-chloro-N, N-dimethylformamide, ethyl 4-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3- Aminopyrazoles to prepare the title compound.

MS (EI): 418 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.86 (1H, brs), 12.18 (1H, brs).

Example 31

4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-amidinopiperidin-4-yl)-2H-pyridine Azolo[3,4-b]pyridine

To 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyridine at room temperature Azolo[3,4-b]pyridine (1.5g) in MeOH (30mL) was added diisopropylethylamine (4.2g), and 1H-pyrazole-1-amidine hydrochloride (0.96g) , and the mixture was stirred overnight. Precipitated crystals were collected by filtration to obtain the title compound (1.0 g) as yellow crystals.

MP: >270°C.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz and 6.6 Hz), 7.91 (1H, d, J = 9.0 Hz), 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-pyridine Azolo[3,4-b]pyridine

In the same manner as in Example 25, the title compound was prepared from acetyl chloride, ethyl 3-piperidinecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 219°C.

Elemental analysis, _calculated for: _{C20H19N7O2 :} C, 61.69; _H , 4.92; N, 25.18.

Found values: C, 61.36; H, 4.90; N, 25.12.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400MHz, 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-pyridine Azolo[3,4-b]pyridine

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidine-4- (yl)-2H-pyrazolo[3,4-b]pyridine and acetaldehyde to prepare the title compound.

MP: 231°C.

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.99 (3H, t, J=7.3Hz), 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 = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 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-pyridine Azolo[3,4-b]pyridine

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidine-4- (yl)-2H-pyrazolo[3,4-b]pyridine and propionaldehyde to prepare the title compound.

MP: 246°C.

Elemental analysis, _calculated for: _{C21H23N7O :} C, 64.76; H, 5.95; N, 25.18.

Found values: C, 64.23; H, 5.87; N, 24.86.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J=7.3Hz), 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

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidine-4- The title compound was prepared from (1)-2H-pyrazolo[3,4-b]pyridine and acetone.

MP: 260°C.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.22 (6H, d, J=7.3Hz), 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-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 4-piperidinecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: >270°C.

Elemental analysis, _calculated for: _{C24H25BrN6O2 :} C, 56.59; _H , 4.95; N, 16.50.

Found values: C, 56.47; H, 4.87; N, 16.52.

MS (EI): 509 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 2, from 4-(2-bromo-3-cyanophenyl)-6-(1-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine Preparation of the title compound.

MP: >270°C.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 3, from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H- Pyrazolo[3,4-b]pyridine to prepare the title compound.

MP: >270°C.

MS (EI): 423 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpiperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: 238°C.

Elemental analysis, _calculated for: _{C24H25BrN6O2 :} C, 56.56; _H , 4.95; N, 16.50.

Found values: C, 56.49; H, 4.85; N, 16.50.

MS (EI): 509 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 21, from 4-(2-bromo-3-cyanophenyl)-6-(1-tert-butoxycarbonylpiperidin-3-yl)-5-cyano-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine Preparation of the title compound.

MP: 225°C.

Elemental analysis, calculated for: C ₁₉ H ₁₇ BrN ₆ CF ₃ COOH: C, 48.20; H, 3.47; N, 16.06.

Found values: C, 47.98; H, 3.52; N, 15.97.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 3, from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-3-yl)-2H- Pyrazolo[3,4-b]pyridine trifluoroacetate salt Preparation of the title compound.

MP: 174°C.

MS (EI): 423 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 2-piperidinecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MS (EI): 509 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 1.3 5 (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

In the same manner as in Example 21, from 4-(2-bromo-3-cyanophenyl)-6-(1-tert-butoxycarbonylpiperidin-2-yl)-5-cyano-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine Preparation of the title compound.

MP: 232°C.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylmorpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo [3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl morpholine-2-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazole.

MP: 219°C.

MS (EI): 511 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 21, from 4-(2-bromo-3-cyanophenyl)-6-(4-tert-butoxycarbonylmorpholin-2-yl)-5-cyano-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine Preparation of the title compound.

MP: 236°C.

MS (EI): 411 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 3, from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H- Pyrazolo[3,4-b]pyridine trifluoroacetate salt Preparation of the title compound.

MP: 180°C.

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400MHz, 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-pyridine Azolo[3,4-b]pyridine

In the same method as in Example 1 and then according to the method of Example 2, from 1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyridine azole to prepare the title compound.

MP: 226°C.

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydro Pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: 233°C.

MS (EI): 421 (M ⁺ ).

¹ H-NMR (400MHz, 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-((N-tert-butoxycarbonyl-N-methyl-amino)methyl)-5-cyano-4,7-dihydro- 2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 15, the title compound was prepared from glycine ethyl ester hydrochloride, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MS (EI): 469 (M ⁺ ).

¹ H-NMR (400MHz, 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-methyl-amino)methyl)-2H-pyrazolo[3, 4-b]pyridine trifluoroacetate

In the same manner as in Example 21, from 4-(2-bromo-3-cyano-phenyl)-6-((N-tert-butoxycarbonyl-N-methylamino)methyl)-5- Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: 258°C.

MS (EI): 369 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 25, the title compound was prepared from acetyl chloride, ethyl 4-piperidinecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: >280°C.

MS (EI): 451 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 7.3 Hz), 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

In the same manner as in Example 25, the title compound was prepared from benzoyl chloride, ethyl 4-piperidinecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: >280°C.

MS (FAB): 514 (M ⁺ +1).

¹ H-NMR (400MHz, 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-methylsulfonylpiperidin-4-yl)-2H-pyrazolo[3 , 4-b]pyridine

In the same manner as in Example 25, the title compound was prepared from methanesulfonyl chloride, ethyl 4-piperidinecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: >280°C.

MS (EI): 487 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpiperidin-4-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4- b] pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 4-piperidinecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole.

MP: >280°C.

Elemental analysis, calculated for: _{C23H26ClN5O2 :} C, 62.79; H, 5.96; _N , _15.92 .

Found values: C, 62.81; H, 5.87; N, 16.01.

MS (EI): 439 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 2, from 6-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro- 2H-Pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: 221°C.

MS (EI): 339 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3 , 4-b] Pyridine trifluoroacetate salt to prepare the title compound.

MP: >270°C.

Elemental analysis, calculated for: _C19H20ClN5 ; C, _64.49 ; H, 5.70; N _, 19.79.

Found values: C, 64.71; H, 5.68; N, 19.59.

MS (EI): 353 (M ⁺ ).

¹ H-NMR (400MHz, 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]pyridine

To 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine at room temperature To a solution of (1.0 g) in pyridine (1.2 mL) was added acetic anhydride (0.42 mL), and the mixture was stirred for two hours. The mixture was evaporated under reduced pressure and 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 (400MHz, 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]pyridine

Ethylene glycol (10.1 g) and p-toluenesulfonic acid (2.8 g) were added to a solution of ethyl 2-cyclohexanone carboxylate (25 g) in toluene (200 mL) at room temperature, using Dean-Stark (Dean-Stark) The Stark apparatus was heated to reflux the mixture for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate (10:1)) to obtain 1,4-dioxaspiro[4, 5] Ethyl decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-butyllithium (160 mmol) at -78°C. Then ethyl 1,4-dioxaspiro[4,5]decane-6-carboxylate (31 g) was added, and the mixture was stirred for one hour. After acidifying with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxaspiro[4 ,5] Decane-6-yl)ethan-2-one (14.5 g) as a colorless oil. 2,1,3-Benzoxadiazole-4-aldehyde (0.8g), 3-aminopyrazole (0.5g) and 1-cyano-2-(1,4-dioxaspiro[4, 5] A solution of decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-( 1,4-dioxaspiro[4,5]decane-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g), as colorless crystals.

To 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxaspiro[4, 5] Add 4N HCl in dioxane (6.0 mL) to a solution of 5] decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in methanol (30 mL), And the mixture was heated at 60°C for two hours. After basifying 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: n-hexane-ethyl acetate (1:1)) to obtain the title compound (20 mg) as colorless crystals.

MP: >270°C.

MS (EI): 360 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 58, the title compound was prepared from ethyl 4-cyclohexanonecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MS (FAB): 361 (M ⁺ +1).

¹ H-NMR (400MHz, 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-oxocyclopentane-1-yl)-2H- Pyrazolo[3,4-b]pyridine

In the same manner as in Example 58, the title compound was prepared from ethyl 2-cyclopentanonecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MS (FAB): 347 (M ⁺ +1).

¹ H-NMR (400MHz, 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

In the same manner as in Example 58, the title compound was prepared from ethyl acetoacetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MP: 200°C.

MS (FAB): 321 (M ⁺ +1).

¹ H-NMR (400MHz, 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 = 6.6 Hz), 7.61 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.94 (1H, d, J = 9.0 Hz), 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

In the same manner as in Example 58, the title compound was prepared from ethyl 2-cyclohexanonecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: 273°C.

MS (EI): 422 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 58, the title compound was prepared from ethyl acetoacetate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP: 230°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-tert-butoxycarbonylpiperidin-4-yl)-2H-pyrazolo [3,4-b]pyridine (2.0 g) was added to a solution of 4N-HCl in dioxane (20 mL), and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and 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 (400MHz, 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 hydrochloride

In the same manner as in Example 64, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonylpiperidin-4-yl)-5- Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: >270°C.

Elemental analysis, calculated for: _{C18H17N7OHCl :} C, 56.09; H, 5.20; _N , 24.10.

Found values: C, 55.80; H, 5.00; N, 23.80.

MS (EI): 347 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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

In the same manner as in Example 64, from 4-(2-bromo-3-cyanophenyl)-6-(1-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine Preparation of the title compound.

MP: >270°C.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo [3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 1-tert-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

In the same manner as in Example 2, from 4-(2-bromo-3-cyanophenyl)-5-cyano-6-(1-tert-butoxycarbonylpyrrolidin-2-yl)-4, 7-Dihydro-2H-pyrazolo[3,4-b]pyridine Preparation of the title compound.

MP: >240°C.

MS (EI): 395 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpyrrolidin-2-yl)-5-cyano-4,7-dihydro- 2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 1-tert-butoxycarbonylpyrrolidine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole .

MS (EI): 433 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.6 Hz), 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

In the same method as in Example 2, from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-tert-butoxycarbonylpyrrolidin-2-yl)-5- Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MP: >240°C.

MS (EI): 333 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.3 Hz), 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

In the same manner as in Example 1, the title compound was prepared from ethyl 1-tert-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-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-2H- Pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate, 2,3-(methylenedioxy)benzaldehyde and 3-aminopyrazole.

MS (EI): 449 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 1.7 Hz), 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

In the same manner as in Example 2, from 6-(1-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-(methylene Dioxy)phenyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MS (EI): 390 (M ⁺ ).

¹ H-NMR (400MHz, 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-6-phenylaminocarbonyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl N-phenyloxamate, 2-chlorobenzaldehyde and 3-aminopyrazole.

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 5.50 (1H, s), 7.13 (1H, dd, J = 7.1 Hz and 7.6 Hz), 7.25-7.46 (7H, m), 7.66 ( 2H, dd, J = 8.3 Hz), 10.4 (1H, s), 10.76 (1H, s), 12.3 (1H, s).

Example 75

4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-phenylaminocarbonyl-4,7-dihydro-2H-pyrazolo[3,4-b ]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl N-phenyloxamate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole.

MS (EI): 383 (M ⁺ ).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 5.59 (1H, s), 7.11-7.15 (1H, dd, J = 7.3Hz and 7.6Hz), 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-(naphthalene-1-yl)piperazin-1-yl]methyl-2H-pyrazolo[ 3,4-b]pyridine trihydrochloride

Preparation of 4-(2-chlorophenyl)-5-cyano from tert-butyldimethylsilyloxyethyl acetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1 yl-6-(tert-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine. To 4-(2-chlorophenyl)-5-cyano-6-(tert-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4 -b] To a solution of pyridine (20 g) in tetrahydrofuran (200 mL) 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 saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated 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) as a white solid. 4-(2-Chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) and tetra To a solution of carbon bromide (15.4 g) in dichloromethane (340 mL) was added a solution of triphenylphosphine (12.2 g) in dichloromethane (100 mL), and the mixture was stirred at room temperature for 13 hr. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-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) 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 min. To the reaction mixture was added 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine under ice cooling (500 mg) solution, and the mixture was stirred under ice-cooling for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride 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 resulting oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals.

MP: 203-205°C (decomposition)

MS (EI): 481 (M ⁺ ).

¹ H-NMR (400MHz, 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=7.1Hz), 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

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 to prepare the title compound.

MP: 204-206°C (decomposition).

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 = 8.0 Hz), 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

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 1-phenylpiperazine to prepare the title compound.

MP: 217-220°C (decomposition).

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

Addition of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.8g) under ice cooling To a DMF (10 mL) solution was added potassium phthalimide (445 mg), and the mixture was stirred under ice-cooling for 4 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-n-hexane (2:1)) to obtain the title compound (285 mg) as white crystals.

MP: >250°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

Prepare 4-(2-chlorophenyl)-5-cyano-4 from 2,2-dimethoxypropionic acid methyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1 , 7-dihydro-6-(1,1-dimethoxyethyl)-2H-pyrazolo[3,4-b]pyridine. 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(1,1-dimethoxyethyl)-2H-pyrazolo[3,4 -b] To a solution of pyridine (1.0 g) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the mixture was stirred under ice-cooling for 1 hour. The solvent was distilled off and the resulting residue was crystallized from ethyl acetate to give the title compound (370 mg) as white crystals.

MP: 225-228°C (decomposition).

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

In the same manner as in Example 1, the title compound was prepared from 2-bromo-3-cyanobenzaldehyde, 3-aminopyrazole and methyl 2,2-dimethoxypropionate.

MP: >230°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 = 1.7 Hz and 7.3 Hz), 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

In the same manner as in Example 1, the title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and methyl 2,2-dimethoxypropionate.

MP: 230°C (decomposition).

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=6.6Hz), 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

In the same manner as in Example 1, the title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and 1-benzyl-2-oxopyrrolidine-4-carboxylic acid methyl ester.

MP: >230°C.

Elemental analysis, calculated for: _{C24H20ClN5O :} C, 67.05; H, 4.69; _N , 16.29.

Found values: 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

To a solution of 2-picoline (10 g) in THF (75 mL) was added n-butyllithium (113 mmol) at -40°C. Methyl butyrate (15.8 mL) was then added and the mixture was stirred for 1 hour, then 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: n-hexane-ethyl acetate (1:1)) to give 2-(2-oxopentyl)pyridine (4.8 g) as yellow Oil. Acetic acid ( 7 mL) solution was heated to reflux for 11 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)), so that the obtained residue was crystallized from ethyl acetate, Colorless crystals (520 mg) were obtained. To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the obtained crystals (520 mg) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous solution of sodium acetate (3.4 g) was added and the mixture was stirred for 1 hr. The mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure to obtain an oil. The resulting oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to obtain a yellow solid (530 mg). To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred under heating for 4 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to obtain an oil. Water was added to the obtained oil, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was crystallized from ethyl acetate to give the title compound (145 mg) as pale yellow crystals.

MP: 205-208°C (decomposition).

Elemental analysis _, calculated for: _C21H18BrN5 : C, _60.01 ; H, 4.32; N, 16.66.

Found values: 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

To a solution of methyl 1-benzyl-2-oxopyrrolidine-4-carboxylate (10.9 g) in THF (50 mL) was added 1.0 M borane-THF (84 mL) under ice-cooling, and the mixture was refluxed for 1 hour . 30 mL of methanolic hydrochloride was added dropwise, followed by reflux for 1 hour to decompose excess borane and boron complex, after removal of the solvent under reduced pressure, another 30 mL of methanolic hydrochloride was added, and the mixture was refluxed for another 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 evaporated and the residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)) to give methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 g) as light 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) was refluxed for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to give methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) was added dimethylaminopyridine (161 mg) and di-tert-butyl dicarbonate (3.4 g) at 0° C. and the mixture was stirred for 13 Hour. The mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (2:1)) to give methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate, It is a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added n-butyllithium (12.4 mmol) at -78°C. A solution of methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was then added, 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: n-hexane-ethyl acetate (2:1)) to give 1-(1-tert-butoxycarbonylpyrrolidin-3-yl)- 2-Cyanoethan-1-one (2.35 g) as a colorless oil. 2-Chlorophenylaldehyde (1.4g), 3-aminopyrazole (819mg) and 1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-2-cyanoethane-1-one ( 2.35 g) in acetonitrile (10 mL) 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 obtain the title compound (2.18 g) as colorless crystals.

Elemental _analysis , calculated for: _C22H24ClN5O2 : C, 62.04; H, 5.68; _N , _16.44 .

Found values: 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-butoxycarbonylpyrrolidin-3-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[ 3,4-b]pyridine (706 mg) was added to a solution of 4N-HCl in dioxane (5 mL), and the mixture was stirred for 2 hr. The solvent was evaporated under reduced pressure and the residue was washed with ethanol-ethyl acetate, and the precipitated crystals were collected by filtration to obtain the title compound (460 mg) as colorless crystals.

MP: 210-215°C (decomposition).

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

In the same manner as in Example 84, the title compound was prepared from 2,1,3-benzoxadiazol-4-al, melindelen's acid, 2-(2-oxopentyl)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-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-indan-4-yl)-2H-pyrazole And[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 4-piperidinecarboxylate, 2,3-indane-4-carbaldehyde and 3-aminopyrazole.

MS (EI): 445 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-dihydrobenzo[b]furan-7-yl) -2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 4-piperidinecarboxylate, 7-(2,3-dihydrobenzo[b]furan)carbaldehyde and 3-aminopyrazole.

MS (EI): 445 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 6.6 Hz), 7.22 (1H, s), 9.52 (1H, s), 12.06 (1H, s).

Example 90

6-(1-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl )-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 4-piperidinecarboxylate, 8-(3,4-dihydro-2H-chromene)carbaldehyde and 3-aminopyrazole.

MS (EI): 461 (M ⁺ ).

¹ H-NMR (400MHz, 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-tert-butoxycarbonylpiperidin-4-yl)-4-(2-chloro-3-trifluoromethylphenyl)-5-cyano-4,7-dihydro-2H-pyridine Azolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 4-piperidinecarboxylate, 2-chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole.

MS (EI): 461 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 2, from 6-(1-tert-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.

MS (EI): 361 (M ⁺ ).

¹ H-NMR (400MHz, 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-(2,3-indan-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b ]pyridine hydrochloride

In the same manner as in Example 2, from 6-(1-tert-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-indane -4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MS (EI): 345 (M ⁺ ).

¹ H-NMR (400MHz, 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-(2,3-indan-4-yl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3 , 4-b]pyridine

In the same method as in Example 3, from 5-cyano-4,7-dihydro-4-(2,3-indan-4-yl)-6-(piperidin-4-yl)-2H - Pyrazolo[3,4-b]pyridine hydrochloride Preparation of the title compound.

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-(piperidine- 4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared.

¹ H-NMR (400MHz, 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-methylsulfonylpiperidin-2-yl)-2H- Pyrazolo[3,4-b]pyridine

In the same manner as in Example 25, the title compound was prepared from methanesulfonyl chloride, ethyl 2-piperidinecarboxylate, 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-pyridine Azolo[3,4-b]pyridine hydrochloride

In the same manner as in Example 64, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiper Pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

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= 6.6 Hz), 7.59 (1H, dd, J=9.0 Hz and 6.6 Hz), 7.93 (1H, d, J=9.0 Hz), 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 Substituted pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

In the same method as in Example 1, from 1,2-dihydro-1-methyl-2-oxopyridine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-Aminopyrazole Preparation of the title compound.

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=9.0 Hz), 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

In the same method as in Example 1 and Example 2, from 1,2,3,4-ethyl tetrahydropyridine-3-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3- Aminopyrazoles to prepare the title compound.

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 = 9.0 Hz), 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-tetrahydro Pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4,5 , 6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

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-pyrazole And[3,4-b]pyridine 2 hydrochloride

In the same manner as in Example 15 and Example 2, the title compound was prepared from ethyl 2-methylglycine, 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-oxopyridine-4- base)-2H-pyrazolo[3,4-b]pyridine

In the same method as in Example 1, from 1,2-dihydro-1-methyl-2-oxopyridine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole Preparation of the title compound.

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 2 hydrochloride

In the same manner as in Example 15 and Example 2, the title compound was prepared from ethyl 4-aminocyclohexanecarboxylate, 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-pyridine Azolo[3,4-b]pyridine 2 hydrochloride

In the same manner as in Example 1 and Example 2, the title was prepared from ethyl 1,2,5,6-tetrahydropyridine-3-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole compound.

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

In the same manner as in Example 3, from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-(methylamino)cyclohexyl) -2H-Pyrazolo[3,4-b]pyridine to prepare the title compound.

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

In the same method as in Example 3, from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,4,5,6-tetrahydro Pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

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-(external form-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 2 hydrochloride

In the same method as in Example 1 and Example 2, from exo-2-azabicyclo[2,2,2]octane-6-ethyl carboxylate, 2,1,3-benzoxadiazole- 4-Aldehyde and 3-aminopyrazole to prepare the title compound.

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400MHz, 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-(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 2 hydrochloride

In the same method as in Example 1 and Example 2, from endo-2-azabicyclo[2,2,2]octane-6-ethyl carboxylate, 2,1,3-benzoxadiazole- 4-Aldehyde and 3-aminopyrazole to prepare the title compound.

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-(external form-2-methyl-2-azabicyclo[2 ,2,2]octane-6-yl)-2H-pyrazolo[3,4-b]pyridine

In the same method as in Example 3, from 6-(external form-2-azabicyclo[2,2,2]octane-6-yl)-4-(2,1,3-benzoxadiazole -4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400MHz, 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

4-(2,1,3-Benzoxadiazol-4-yl)-4,7-dihydro-5-ethoxycarbonyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b]pyridine 2 hydrobromide

Make 2,1,3-benzoxadiazole-4-aldehyde (3.0g), melindron's acid (3.0g), 3-keto-3-(1-benzylcarbonylpiperidin-4-yl)propane A solution of ethyl acetate (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) were added phosphorus oxychloride (3.4 mL) and a solution of colorless crystals (4.7 g) in chloroform (10 mL) under ice-cooling, and the mixture was stirred overnight . Under ice-cooling, an aqueous solution of sodium acetate (37.8 g) was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oily substance. The obtained oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (8:2)) to obtain colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.4 g), and the mixture was stirred under heating for 3 hr. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain an oil. The oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)) to obtain the title compound (840 mg) as colorless crystals. To a solution of the obtained colorless crystals in acetic acid (10 mL) was added HBr-AcOH solution (10 mL), and the mixture was stirred for 3 hr. The solvent was distilled off under reduced pressure to obtain colorless crystals. The crystals were recrystallized 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

In the same method as in Example 3, from 6-(endotype-2-azabicyclo[2,2,2]octane-6-yl)-4-(2,1,3-benzoxadiazole -4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

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

4-(2,1,3-Benzoxadiazol-4-yl)-4,7-dihydro-5-ethoxycarbonyl-6-(1-methylpiperidin-4-yl)-2H -Pyrazolo[3,4-b]pyridine 2 hydrochloride

In the same method as in Example 3, from 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-5-ethoxycarbonyl-6-(piperidine- 4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared.

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

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-bromobenzaldehyde and 3-aminopyrazole.

MS (EI): 383 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 7.3 Hz), 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 Salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-methoxybenzaldehyde and 3-aminopyrazole.

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 = 7.3 Hz), 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]pyridinium salt salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole.

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same manner as in Example 3, from 4-(2-bromophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3 ,4-b]pyridine to prepare the title compound.

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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b]pyridine Preparation of the title compound.

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

In the same method as in Example 3, from 5-cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazole Do[3,4-b]pyridine hydrochloride to prepare the title compound.

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

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-fluorobenzaldehyde and 3-aminopyrazole.

MS (EI): 323 (M ⁺ ).

¹ H-NMR (400MHz, 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]pyridinium salt salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2,3-difluorobenzaldehyde and 3-aminopyrazole.

MS (EI): 341 (M ⁺ ).

¹ H-NMR (400MHz, 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]pyridinium salt salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2,6-difluorobenzaldehyde and 3-aminopyrazole.

MS (EI): 341 (M ⁺ ).

¹ H-NMR (400MHz, 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 2-salt salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-methylthiobenzaldehyde and 3-aminopyrazole.

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]pyridinium salt salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2,6-dichlorobenzaldehyde and 3-aminopyrazole.

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 = 7.3 Hz), 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 2 Hydrochloride

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-trifluoromethylbenzaldehyde and 3-aminopyrazole.

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-4-(2-fluorophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3 , 4-b] Pyridine hydrochloride to prepare the title compound.

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

In the same manner as in Example 3, from 5-cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazole Do[3,4-b]pyridine hydrochloride to prepare the title compound.

MS (EI): 355 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 5-cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazole Do[3,4-b]pyridine hydrochloride to prepare the title compound.

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 2 hydrochloride Salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-nitrobenzaldehyde and 3-aminopyrazole.

MS (EI): 351 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 7.3 Hz), 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 2 hydrochloride

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, benzaldehyde and 3-aminopyrazole.

MS (EI): 305 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b]pyridine 2 hydrochloride to prepare the title compound.

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

In the same method as in Example 3, from 5-cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazole Do[3,4-b]pyridine hydrochloride to prepare the title compound.

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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazole Do[3,4-b]pyridine 2 hydrochloride to prepare the title compound.

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

In the same manner as in Example 3, from 5-cyano-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[ 3,4-b]pyridine 2 hydrochloride to prepare the title compound.

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

In the same manner as in Example 3, from 5-cyano-4,7-dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b] Pyridine 2 hydrochloride to prepare the title compound.

MS (EI): 319 (M ⁺ ).

¹ H-NMR (400MHz, 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-pyrazole And[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl butyrate, 2,2-difluoro-1,3-benzodioxol-4-al 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 2 hydrochloride

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole.

MS (EI): 363 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz), 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 2 hydrochloride

In the same method as in Example 1 and Example 2, from 3-piperidinecarboxylic acid ethyl ester, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-amino Pyrazole Preparation of the title compound.

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 = 7.3 Hz), 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-pyridine Azolo[3,4-b]pyridine

In the same method as in Example 3, from 4-(2,1,3-benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidine-4- The title compound was prepared from (1)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride.

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 = 9.0 Hz and 6.6 Hz), 7.98 (1H, d, J = 9.0 Hz), 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-methylpiperidine -4-yl)-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 3, from 5-cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro -6-(Piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared.

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 2 hydrochloride Salt

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, 2-cyanobenzaldehyde and 3-aminopyrazole.

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 = 7.3 Hz), 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

In the same manner as in Example 3, from 5-cyano-4-(2-cyanophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[ 3,4-b]pyridine 2 hydrochloride to prepare the title compound.

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 3 hydrochloride

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, pyridine-4-aldehyde and 3-aminopyrazole.

MS (EI): 306 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 6.8 Hz), 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 3 hydrochloride

In the same manner as in Example 1 and Example 2, the title compound was prepared from ethyl 3-piperidinecarboxylate, pyridine-3-aldehyde and 3-aminopyrazole.

MS (EI): 306 (M ⁺ ).

¹ H-NMR (400MHz, 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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo[3 , 4-b] Pyridine 3 hydrochloride to prepare the title compound.

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

In the same method as in Example 3, from 5-cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo[3 , 4-b] Pyridine 3 hydrochloride to prepare the title compound.

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 = 8.2 Hz), 8.42-8.45 (2H, m), 9.64 (1H, brs), 12.23 (1H, brs).

Example 146

6-(external form-2-azabicyclo[2,2,2]octane-6-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7- Dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride

In the same method as Example 1 and Example 2, from exo-2-azabicyclo[2,2,2]octane-6-formic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3 -Aminopyrazole Preparation of the title compound.

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-(endo-2-azabicyclo[2,2,2]octane-6-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7- Dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride

In the same method as in Example 1 and Example 2, from endo-2-azabicyclo[2,2,2]octane-6-formic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3 -Aminopyrazole Preparation of the title compound.

MS (EI): 435 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 7.3 Hz), 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-(external form-2-methyl-2-azabicyclo[2,2,2] Octane-6-yl)-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 3, from 6-(external form-2-azabicyclo[2,2,2]octane-6-yl)-4-(2-bromo-3-cyanophenyl) - 5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared.

MS (EI): 449 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 7.3 Hz and 7.2 Hz), 9.83 (1H, brs), 12.37 (1H, brs).

Example 149

4-(2,2-Difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-5-ethoxycarbonyl-6-propyl-2H- Pyrazolo[3,4-b]pyridine

2,2-difluoro-1,3-benzodioxol-4-aldehyde (2.0g), melindron's acid (1.6g), 3-keto-hexanoic acid ethyl ester (1.7g ) and ammonium acetate (0.91 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 (2.4 g). To a chloroform (10 mL) solution of dimethylformamide (1.9 g) were added phosphorus oxychloride (4.0 g) and a chloroform (10 mL) solution of the obtained colorless crystals (2.4 g) under ice-cooling, and the mixture was stirred overnight . Under ice-cooling, an aqueous solution of sodium acetate (27 g) was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oily substance. The obtained oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (8:2)) to obtain colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.0 g), and the mixture was stirred with heating for 3 hr. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain an oil. The oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)) to obtain 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

4-(2-Bromo-3-cyanophenyl)-4,7-dihydro-5-ethoxycarbonyl-6-(piperidin-4-yl)-2H-pyrazolo[3,4- b] Pyridine 2 hydrochloride

In the same manner as in Example 110, the title compound was prepared 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

4-(2-bromo-3-cyanophenyl)-4,7-dihydro-5-ethoxycarbonyl-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[ 3,4-b]pyridine

In the same manner as in Example 3, from 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-5-ethoxycarbonyl-6-(piperidin-4-yl)- 2H-Pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared.

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-oxopiperidin-4-yl )-2H-pyrazolo[3,4-b]pyridine

In the same manner as in Example 1, prepared from 1-methyl-2-oxopiperidine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole title compound.

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400MHz, 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 = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.88 (1H, brs), 12.22 (1H, brs).

Example 153

4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-2-oxopiperidin-4-yl)-2H-pyridine Azolo[3,4-b]pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl 1-methyl-2-oxopiperidine-4-carboxylate, 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]pyridine

A solution of 2-chlorobenzaldehyde (21 g), melindelen's acid (21 g), 3-keto-hexanoic acid-2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was heated at 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 a solution of the obtained colorless crystals (1.0 g) in DMF (5 mL) were added hydrazine (0.22 g) and CDI (0.66 g), and the mixture was stirred for 3 hr. The precipitated crystals were collected by filtration to give colorless crystals (0.7 g). To a solution of the obtained colorless crystals (1.0 g) in DMF (5 mL) was added triethyl orthoacetate (3.7 g) and the mixture was heated for 3 hr. The precipitated crystals were collected by filtration to give colorless crystals (0.6 g). To a solution of dimethylformamide (0.55 g) in chloroform (3 mL) were added phosphorus oxychloride (1.2 g) and the resulting solution of colorless crystals in chloroform (6 mL) under ice-cooling, and the mixture was stirred overnight. An aqueous solution of sodium acetate (7.7 g) was added under ice-cooling, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oily substance. The obtained oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (8:2)) to obtain colorless crystals. To a solution of the obtained colorless crystals in pyridine (10 mL) was added hydrazine (0.15 g), and the mixture was heated and stirred for 3 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain an oil. The oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)) to obtain 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 2 hydrochloride

In the same manner as in Example 15 and Example 2, the title compound was prepared from ethyl 2-methylglycine, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MS (EI): 384 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.49 (3H, d, J = 7.3 Hz), 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]pyridine

A solution of 2-chlorobenzaldehyde (21 g), melindelenic 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 a DMF (20 mL) solution of the obtained colorless crystals (4.2 g) were added ammonia solution (3.0 g) and CDI (2.8 g), followed by stirring overnight. The reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain an oil. A solution of the residue in N,N-dimethylacetamide dimethyl acetal (30 mL) was heated for 2 hours, and the solvent was evaporated under reduced pressure. Hydroxyammonium (1.4 g), 1N NaOH (20 mL), dioxane (20 mL) and acetic acid (28 mL) were added to the residue, and the mixture was heated for one hour. The reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain an oil. The oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)) to obtain colorless crystals (1.3 g). To a solution of dimethylformamide (1.7 g) in chloroform (10 mL) were added phosphorus oxychloride (3.5 g) and the resulting solution of colorless crystals in chloroform (20 mL) under ice-cooling, and the mixture was stirred overnight. An aqueous solution of sodium acetate (23 g) was added under ice-cooling, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure to obtain an oily substance. The obtained oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (8:2)) to obtain colorless crystals. To a solution of the obtained colorless crystals in pyridine (15 mL) was added hydrazine (0.6 g), and the mixture was heated and stirred for 3 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain an oil. The oil was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate (1:1)) to obtain 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

In the same manner as in Example 154, the title compound was prepared from 2,1,3-benzoxadiazole-4-al.

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=9.0 Hz), 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

In the same manner as in Example 154, the title compound was prepared 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

In the same manner as in Example 15 and Example 2, the title compound was prepared from ethyl 2,2-dimethylglycine, 2-chlorobenzaldehyde and 3-aminopyrazole.

Example 1 Example 2 Example 3 Example 4

Example 5 Example 6 Example 7 Example 8

Example 9 Example 10 Example 11 Example 12

Example 13 Example 14 Example 15 Example 16

Example 17 Example 18 Example 19 Example 20

Example 21 Example 22 Example 23 Example 24

Example 25 Example 26 Example 27 Example 28

Example 29 Example 30 Example 31 Example 32

Example 33 Example 34 Example 35 Example 36

Example 37 Example 38 Example 39 Example 40

Example 41 Example 42 Example 43 Example 44

Example 45 Example 46 Example 47 Example 48

Example 49 Example 50 Example 51 Example 52

Example 53 Example 54 Example 55 Example 56

Example 57 Example 58 Example 59 Example 60

Example 61 Example 62 Example 63 Example 64

Example 65 Example 66 Example 67 Example 68

Example 69 Example 70 Example 71 Example 72

Example 73 Example 74 Example 75 Example 76

Example 77 Example 78 Example 79 Example 80

Example 81 Example 82 Example 83 Example 84

Example 85 Example 86 Example 87 Example 88

Example 89 Example 90 Example 91 Example 92

Example 93 Example 94 Example 95

Example 96 Example 97 Example 98 Example 99

Example 100 Example 101 Example 102 Example 103

Example 104 Example 105 Example 106 Example 107

Example 108 Example 109 Example 110 Example 111

Example 112 Example 113 Example 114 Example 115

Example 116 Example 117 Example 118 Example 119

Example 120 Example 121 Example 122 Example 123

Example 124 Example 125 Example 126 Example 127

Example 128 Example 129 Example 130 Example 131

Example 132 Example 133 Example 134 Example 135

Example 136 Example 137 Example 138 Example 139

Example 140 Example 141 Example 142 Example 143

Example 144 Example 145 Example 146 Example 147

Example 148 Example 149 Example 150 Example 151

Example 152 Example 153 Example 154 Example 155

Example 156 Example 157 Example 158 Example 159

Formulation Example 1

The compound of Example 1 (0.5 parts), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were thoroughly mixed and kneaded with a binder made of corn starch (2 parts). The kneaded product was passed through a 16 mesh screen, dried in an oven at 50°C and passed through a 24 mesh screen. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were thoroughly mixed and compression punched to obtain tablets each containing 0.5 mg of the active ingredient.

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. Aseptically transfer the filtrate into ampoules. After sterilization, the ampoule was welded and sealed to obtain an injection solution containing 1.0 mg of the active ingredient.

The effect of compounds of the invention on glycogen synthase kinase-3β (GSK-3β) was evaluated and demonstrated as follows.

Test Example 1: GSK-3β inhibitory activity

CREB phosphopeptide (4.6 nmol), rabbit GSK-3β (0.5 unit), ATP (5 nmol), [γ- ³² P]ATP (12.3 kBq) and test compounds were incubated at 30°C in GSK containing 1% DMSO -3β buffer (25 μL) (20 mmol/L Tris-HCl (pH 7.5), 10 mmol/L magnesium chloride, 5 mmol/L dithiothreitol) was reacted for 20 minutes. The reaction product (10 μL) was adsorbed onto P81 ion exchange paper, the ion exchange paper was washed with phosphoric acid (100 mmol/L) and cpm was measured on a scintillation counter. As a result, the compounds of the present invention exhibited IC ₅₀ from 1 nmol/L to 1000 nmol/L. For example, the _IC50 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.

Table 1 Example number _IC50 (nmol/L) 2 10 3 2.5 8 3.7 11 14 twenty three 4.1 58 1.8 63 3.0 146 0.61 148 3.2 155 2.2 158 0.65

Test Example 2: GSK-3β inhibitory activity in artificially cultured rat hippocampal neurons

Hippocampal neurons were obtained from rat embryos at day eighteen post gestation. After 7 days of culturing hippocampal neurons, the neurons were treated with amyloid-β(25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor) and incubated for an additional 3 hours to induce phosphorylation of Tau protein . After completion of the culture, the phosphorylation level of Tau protein was measured by EIA method using phosphorylated Tau recognition antibody (by the position of GSK-3β phosphorylation), and the inhibitory effect of GSK-3β inhibitor on neurons was evaluated.

Test Example 3: Effects on amyloid β-induced cytotoxicity in artificially cultured rat hippocampal neurons

Hippocampal neurons were obtained from rat embryos at day eighteen post gestation. After 7 days of culturing hippocampal neurons, they were treated with amyloid-β(25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor) and cultured for 24 hours, thereby inducing cytotoxicity (intracellular decreased dehydrogenase activity). After completion of the culture, intracellular dehydrogenase activity was determined and the effect of GSK-3β inhibitors on amyloid β-induced cytotoxicity was evaluated.

Test Example 4: Inhibition of GSK-3β in Gerbil Cerebral Ischemia Model

Tau protein phosphorylation in the brain was induced by intraperitoneal injection of the test compound (GSK-3[beta] inhibitor) into gerbils 30 minutes later by ischemia by closing all carotid arteries (4 minutes). Evaluation of GSK based on the determination of the phosphorylation level of Tau protein by western blotting using an antibody recognizing phospho-Tau (site of phosphorylation by GSK-3β) in hippocampus obtained from gerbil brain three hours after cerebral ischemia GSK-3β inhibitory effects of -3β inhibitors in gerbil brain.

Industrial Applicability

The compounds of the present invention exhibit selective and potent inhibitory activity against glycogen synthase kinase-3β (GSK-3β), and are useful as medicines for the prevention and/or treatment of diabetes, diabetic complications, neurodegeneration Diseases (Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral ischemia caused by cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis, Parkinson's neurological Dysfunction, postencephalitic Parkinsonian neurological dysfunction, boxer's encephalopathy, Guam-type Parkinson's dementia syndrome, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, and manic-depressive psychosis, etc.), hair loss, breast cancer, non-small cell lung cancer, thyroid cancer, T-cell or B-cell leukemia or virus-induced tumors, or as an immune enhancer.

This application is based on Patent Application No. 2002-230581 filed in Japan, the contents of which are incorporated herein by reference.

Claims (17)

1. the dihydro-pyrazolo pyridine compounds of formula (I) expression, or its optical activity form, or its pharmacologically acceptable salt:

Wherein

R ⁰Be hydrogen; alkyl; aralkyl; acyl group; cycloalkyl; formyl radical; haloalkyl; aminoalkyl group; alkoxyalkyl; phenoxyalkyl; hydroxyalkyl; aminocarboxyl; the alkylthio carbonyl; carboxyalkyl; the cycloalkyloxy alkyl; alkyl sulphinyl; alkyl sulphonyl; phenyl sulfonyl; the phenyl sulfinyl; mercaptoalkyl; alkylthio alkyl; the acyloxy ethanoyl; the acyloxy alkyl; randomly has substituent phenyl; randomly has substituent aromatic heterocycle group; randomly has substituent phenylalkyl; or formula-COOR ⁸Shown group (R wherein ⁸For hydrogen, alkyl, randomly have substituent aryl or randomly have substituent aralkyl);

R ¹Be hydrogen;

R ²Be hydrogen, alkyl, aralkyl, acyl group, cycloalkyl, hydroxyl, thiol, halogen, amino, formyl radical, carboxyl, cyano group, nitro, alkylthio, haloalkyl, aminoalkyl group, amido, alkoxyl group, cycloalkyloxy, phenoxy group, the phenyl alkoxyl group, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxy carbonyl, aminocarboxyl, the alkylthio carbonyl, carboxyalkyl, the cycloalkyloxy alkyl, thiophenyl, alkyl sulphinyl, alkyl sulphonyl, phenyl sulfonyl, mercaptoalkyl, alkylthio alkyl, randomly has substituent phenyl, aromatic heterocycle group or phenylalkyl;

R ³For

(1) alkyl or haloalkyl,

(2) cycloalkyl,

(3) randomly have substituent phenyl,

(4) aromatic heterocycle group,

(5) derived from the group of phenyl ring, described phenyl ring and saturated or undersaturated 5 or 6 yuan carbocyclic fused,

(6) derived from the group of phenyl ring, described phenyl ring condenses with comprising 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, or

(7) derived from the group that comprises 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, described carbocyclic ring and phenyl ring condense,

Wherein (2) to (7) listed group can have one or more substituting groups; Or

The group that is selected from following formula (II) and (III) represents:

R wherein ⁶And R ⁷Respectively doing for oneself randomly has substituent phenyl or aromatic heterocycle group,

Perhaps, R ²And R ³Randomly comprise heteroatomic ring in conjunction with forming, wherein said ring can with randomly have substituent phenyl ring and condense;

R ⁴For

Alkoxy carbonyl,

Alkyl-carbonyl,

Alkyl sulphonyl,

Alkyl sulphinyl,

The phenyl sulfinyl,

Phenyl sulfonyl,

The dialkyl group phosphinyl,

The dialkyl phosphine acyl group,

Randomly have substituent phenyl,

Randomly have substituent aromatic heterocycle group,

Cyano group, or

Nitro; And

R ⁵For

Alkyl,

The phenyl amino alkyl,

Acyl group,

The acyl group alkyl,

Aminocarboxyl,

Aromatic yl aminocarbonyl,

Randomly have substituent 4 to 7 yuan of saturated or unsaturated heterocycles,

Have substituent 3 to 7 yuan of saturated carbon rings,

Saturated or unsaturated 4 to 7 yuan of cyclosubstituted alkyl of involved 1 or 2 nitrogen-atoms, described 4 to 7 yuan of rings can randomly have substituting group, or

Suc as formula-(CR ^aR ^b) _nNR ¹¹R ¹²Shown group, wherein n is 1 to 4 integer, R ^aBe hydrogen or alkyl, R ^bBe hydrogen or alkyl, R ¹¹Be hydrogen, alkyl, alkyl sulphonyl, phenyl sulfonyl, phenylalkyl alkylsulfonyl, alkyl sulphinyl, phenyl sulfinyl, phenylalkyl sulfinyl, alkoxy carbonyl, phenyloxycarbonyl, phenyl alkoxy carbonyl, alkyl-carbonyl, phenylcarbonyl group or phenylalkyl carbonyl, and R ¹²Be hydrogen or alkyl,

Condition is to work as R ⁰, R ¹And R ²Hydrogen, R respectively do for oneself ⁴Be methoxycarbonyl and R ⁵During for methyl, R then ³Be not phenyl, 2-chloro-phenyl-, 3-nitrophenyl, 4-carboxyl phenyl or 4-methoxycarbonyl phenyl, and work as R ⁵During for alkyl, R then ⁴Be not alkoxy carbonyl, alkyl sulphonyl, alkyl sulphinyl, phenyl sulfinyl, phenyl sulfonyl, dialkyl group phosphinyl, dialkyl phosphine acyl group, cyano group or nitro.

2. the dihydro-pyrazolo pyridine compounds of claim 1, or its optical activity form, or its pharmacologically acceptable salt, wherein

R ⁴Be alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl, alkyl sulphinyl, phenyl sulfinyl, phenyl sulfonyl, dialkyl group phosphinyl; the dialkyl phosphine acyl group, randomly have substituent phenyl, have substituent aromatic heterocycle group, cyano group or nitro, and

R ⁵For alkyl, phenyl amino alkyl, acyl group, acyl group alkyl, aminocarboxyl, aromatic yl aminocarbonyl, randomly have substituent saturated or unsaturated 4 to 7 yuan of heterocycles, have substituent saturated 3 to 7 yuan of carbocyclic rings, involved 1 or 2 nitrogen-atoms and randomly have substituent saturated or unsaturated 4 to 7 yuan of cyclosubstituted alkyl, or suc as formula-(CH ₂) _nNR ¹¹R ¹²Shown group, wherein n is 1 to 4 integer, R ¹¹Be hydrogen, alkyl, alkyl sulphonyl, phenyl sulfonyl, phenylalkyl alkylsulfonyl, alkyl sulphinyl, phenyl sulfinyl, phenylalkyl sulfinyl, alkoxy carbonyl, phenyloxycarbonyl, phenyl alkoxy carbonyl, alkyl-carbonyl, phenylcarbonyl group or phenylalkyl carbonyl, and

R ¹²Be hydrogen or alkyl.

3. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R ²Be hydrogen or alkyl.

4. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R ³For randomly having 1 to 3 substituent phenyl, naphthyl, 2,1,3-Ben Bing oxadiazole-4-base or 3,4-dihydro-2H-chromene-8-base.

5. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R ⁴For alkoxy carbonyl, alkyl-carbonyl with 2 to 5 carbon atoms with 2 to 5 carbon atoms, have the alkyl sulphonyl of 1 to 4 carbon atom or have the alkyl sulphinyl of 1 to 4 carbon atom.

6. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R ⁵For suc as formula-(CH ₂) _nNR ¹¹R ¹²Shown group, wherein n is 1 to 4 integer, R ¹¹Be hydrogen, alkyl or alkoxy carbonyl, and R ¹²Be hydrogen or alkyl.

7. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R ⁰For hydrogen or suc as formula-COOR ⁸Shown group, wherein R ⁸For alkyl, randomly have a substituent aryl or randomly have substituent aralkyl.

8. claim 1 or 2 dihydro-pyrazolo pyridine compounds, its tautomer, its optical activity form or its pharmacologically acceptable salt, described compound is selected from:

(2) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(3) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(11) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine,

(14) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(23) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-(N, N-dimethylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine,

(27) 6-(1-ethanoyl-1,2,3,6-tetrahydropyridine-4-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(33) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-ethyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(37) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(38) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(41) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-3-yl)-2H-pyrazolo [3,4-b] pyridine,

(46) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine,

(48) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(51) 6-(1-ethanoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(52) 6-(1-benzoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(53) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methylsulfonyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(59) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine,

(62) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(2-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine,

(63) 6-ethanoyl methyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(73) 5-cyano group-4,7-dihydro-4-(2,3-(methylene-dioxy) phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,

(75) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-6-phenyl amino carbonyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(78) 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(4-phenylpiperazine-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine,

(81) 6-ethanoyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(82) 6-ethanoyl-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,

(84) 4-(2-bromo-3-cyano-phenyl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine,

(86) 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(tetramethyleneimine-3-yl)-2H-pyrazolo [3,4-b] pyridine and

(87) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine.

9. medicine, it comprises dihydro-pyrazolo pyridine compounds, its optical activity form or its pharmacologically acceptable salt of claim 1 or 2.

10. pharmaceutical composition, it comprises dihydro-pyrazolo pyridine compounds, its optical activity form or its pharmacologically acceptable salt of claim 1 or 2, and pharmaceutically acceptable additive.

11. a glycogen synthase kinase-3 beta inhibitor, it comprises the compound of the dihydro-pyrazolo pyridine compounds, its optical activity form and the pharmacologically acceptable salt thereof that are selected from claim 1.

12. the medicine of claim 9, it is used to prevent and/or treat by the too high disease that causes of glycogen synthase kinase-3 'beta ' activity.

13. the medicine of claim 9, it is used to prevent and/or treat the nerve degeneration disease.

14. the medicine of claim 13, wherein said disease are selected from Parkinson's neurological dysfunction after cerebral ischemia that Alzheimer, ischemic cerebral vascular disorder, Down's syndrome, brain amyloid blood vessel disease cause, stein-leventhal syndrome, subacute sclerosing panencephalitis Parkinson neurological dysfunction, the encephalitis, boxer's encephalopathic, Guam type Parkinson chronic brain syndrome, thunder dimension corpusculum disease, Pick's disease, the sex change of cortex Basal ganglia, volume temporal lobe type dementia, AIDS encephalopathic, Huntington's disease and manic depressive psychosis.

15. the medicine of claim 9, it is used to prevent and/or treat diabetes and diabetic complication.

16. the medicine of claim 9, it is as immunostimulant.

17. the medicine of claim 9, it is used to prevent and/or treat the tumour of alopecia, mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T cell or B cell leukemia or virus induction.