KR20050069977A - Dihydropyrazolopyridine compounds - Google Patents

Abstract

The present invention relates to a dihydropyrazolopyridine compound of formula (I), an optically active agent thereof or a pharmaceutically acceptable salt thereof.

Wherein each symbol is as defined in the specification.

The compounds of the present invention exhibit selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3β) and are useful as agents for the prevention and / or treatment of diabetes and diabetic complications and neurodegenerative diseases, or as adjuvant Do.

Description

Dihydropyrazolopyridine Compound {DIHYDROPYRAZOLOPYRIDINE COMPOUNDS}

The present invention relates to novel compounds for pharmaceuticals having glycogen synthase kinase-3 beta (GSK-3β) -inhibitory activity and uses thereof.

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

Type-II diabetes is a disease in which the insulin reactivity of pancreatic β cells decreases and blood glucose increases. As a result, complications such as diabetic neuropathy, retinopathy, heart disease and the like are induced. GSK-3β functions to increase glucose in the blood by inhibiting glycogen accumulation in peripheral tissues, decreasing insulin response and phosphorylating glycogen synthase. Lithium with GSK-3β-inhibiting activity substantially lowers glucose in the blood by GSK-3β-inhibiting activity (Proc. Nat. Acad. Sci., 93, 8455 (1996)). Therefore, agents with GSK-3β-inhibiting activity are considered to be effective pharmaceutical agents for ameliorating type II diabetes and its complications.

The mechanism of development of Alzheimer's dementia is not yet clear. However, it is believed that amyloid aggregation and neurofibrillary tangles are closely related to the cause of development. GSK-3β is involved in both amyloid aggregation and neurofibrillary tangles, as described below. (1) It binds to variant presenilin and increases the production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It causes phosphorylation of the Tau protein, which causes fibrotic fiber changes and weakens the skeleton of the neurons, leading to neuronal death (Neurosci. Lett., 128, 195 (1991)). In addition, (3) it has been reported that GSK-3β is directly related to neuronal death by reducing the amount of acetylcholine needed to maintain cellular activity through inactivation of pyruvate dehydrogenase by phosphorylation. (Proc. Nat. Acad. Sci., 93, 2719 (1996)).

In addition, the effectiveness of AIDS encephalopathia as neurodegenerative diseases other than Alzheimer's dementia has been suggested. Tat, a protein produced by the HIV virus that causes AIDS, induces neuronal death by enhancing GSK-3β activity in neurons (J. Neurochem., 73, 578 (1999)). From the above, GSK-3β inhibitors are considered to be effective agents for ameliorating neurodegenerative diseases including Alzheimer's dementia.

Lithium and valproic acid with antidepressant activity have GSK-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The link between antidepressant activity and GSK-3β inhibitory activity is unclear, but it is believed that the suppressive activity against glutamic acid toxicity has some cause in maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642). (1998). Based on the above, GSK-3β inhibitors are considered to be effective agents for improving manic-depressive psychosis.

The transcription factor, NF-AT, is dephosphorylated by calcineurin to increase immune reactivity (Science, 275, 1930 (1997)). GSK-3β reversely functions to inhibit immune function by phosphorylating NF-AT. Therefore, it is believed that GSK-3β inhibitors may be effective agents for adjuvant.

Incidentally, JP-A-3-272189 (invention regarding improved synthesis method of mevalolactone intermediate), JP-A-2-275878 (treatment for hyperlipoproteinemia and atherosclerosis) and JP-A-1-272584 (Treatment for hyperlipoproteinemia) discloses a pyrazolo [3,4- b ] pyridine compound which is methyl, isopropyl or cyclopropyl at position 6. This document does not describe or suggest any action of the 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., include 6-methyl-4-substituted, useful for the treatment of cardiovascular diseases. Phenyl-4,7-dihydropyrazolo [3,4- b ] pyridine-5-carboxylate compounds are disclosed and they are prepared in a similar manner. We reproduced the following Scheme A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 described below (formula (IV) described below). It was confirmed that only pyrazolo [1,5- a ] pyrimidine derivatives represented by formula (V) can be produced. The IR, NMR and melting points of the compounds of formula (V) were measured to find that they were identical to the IR, NMR and melting points described herein. Therefore, it was concluded that the publication described incorrect structural formulas. That is, 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo [3,4- b ] pyridine-5-carboxylate cannot be synthesized according to the methods described in this publication.

Compounds of formula (IV) are described in J. Chem. Chem. Soc., Perkin Trans. 1, 947 (1996)], which can be synthesized according to the method described in methyl 4- (2-chlorophenyl) -6-methyl-4,7-dihydro-1 H -pyrazolo [3,4]. -b ] pyridine-5-carboxylate and the like.

Disclosure of the Invention

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

The present inventors earnestly studied to achieve the above object, and found that the 4,7-dihydropyrazolo [3,4- b ] pyridine derivative has selective and potent activity against GSK-3β and completed the present invention. It was. That is, the present invention provides, as an active ingredient, a dihydropyrazolopyridine compound represented by the following general formula (I), which has GSK-3β-inhibiting activity and can be used as a medicament, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or It relates to a medicament comprising a hydrate thereof.

The present invention provides the following.

[1] a dihydropyrazolopyridine compound of formula (I), an optically active agent thereof, or a pharmaceutically acceptable salt thereof:

[In the meal,

R ⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl , Alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl which may have substituent (s), may have substituent (s) Aromatic heterocyclic group, phenylalkyl which may have substituent (s), or the following group: -COOR ⁸ , wherein R ⁸ is hydrogen, alkyl, aryl or substituent (s) which may have substituent (s) Is an aralkyl which may have);

R ¹ is hydrogen;

R ² is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy , Phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsul Phonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl which may have substituent (s), aromatic heterocyclic group or phenylalkyl;

R ³ is

(1) alkyl or haloalkyl,

(2) cycloalkyl,

(3) phenyl which may have substituent (s),

(4) aromatic heterocyclic groups,

(5) groups derived from benzene rings fused with saturated or unsaturated 5 or 6 membered carbocyclic rings,

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

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

Wherein the groups of (2) to (7) are one or more substituents, or the following formulas (II) and (III):

Wherein R ⁶ and R ⁷ are each a phenyl or aromatic heterocyclic group which may have substituent (s), or R ² and R ³ together form a ring which may contain heteroatoms, wherein The ring may be fused with a benzene ring which may have substituent (s));

R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl which may have substituent (s), substituent (s) Aromatic heterocyclic group, cyano, or nitro;

R ⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4-7 membered heterocyclic ring which may have substituent (s), having substituent (s) Saturated 3 to 7 membered carbocyclic rings, alkyl substituted by saturated or unsaturated 4 to 7 membered rings containing 1 or 2 nitrogen atoms which may have substituent (s), or

The following groups:-(CR ^a R ^b ) _n NR ¹¹ R ¹² (wherein n is an integer from 1 to 4, R ^a is hydrogen or alkyl, R ^b is hydrogen or alkyl, R ¹¹ is hydrogen, alkyl , Alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenyl Alkylcarbonyl, R ¹² is hydrogen or alkyl),

Provided that when R ⁰ , R ¹ and R ² are each hydrogen, R ⁴ is methoxycarbonyl and R ⁵ is methyl, then R ³ is phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl Or 4-methoxycarbonylphenyl and when R ⁵ is alkyl, R ⁴ is alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosph Not phonyl, cyano or nitro].

[2] R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl which may have a substituent (s), Aromatic heterocyclic groups, cyano or nitro, which may have substituent (s),

R ⁵ represents alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4-7 membered heterocyclic ring, substituent (s) which may have substituent (s) A saturated 3 to 7 membered carbocyclic ring, an alkyl having a substituent (s) and substituted with a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atoms, or the following groups: (CH ₂ ) _n NR ¹¹ R ¹² wherein n is an integer from 1 to 4, R ¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, Phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R ¹² is hydrogen or alkyl) Pyrazolopyridine compounds, optically active agents thereof or pharmaceutically acceptable thereof One salt.

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

[4] phenyl, naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran, wherein R ³ may have from 1 to 3 substituent (s); The dihydropyrazolopyridine compound of [1] or [2], the optically active agent thereof or a pharmaceutically acceptable salt thereof, which is 8-day.

[5] The above [1] or [2], wherein R ⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, and alkylsulfinyl having 1 to 4 carbon atoms. ] Dihydropyrazolopyridine compounds, optically active agents thereof or pharmaceutically acceptable salts thereof.

[6] R ⁵ is a group:-(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 Dihydropyrazolopyridine compound of the above-mentioned [1] or [2], an optically active agent thereof, or a pharmaceutically acceptable salt thereof.

[7] The above [1], wherein R ⁰ is hydrogen or the following group: -COOR ⁸ , wherein R ⁸ is alkyl, aryl which may have substituent (s) or aralkyl which may have substituent (s). Or the dihydropyrazolopyridine compound of [2], an optically active agent thereof, or a pharmaceutically acceptable salt thereof.

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

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

(11) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2 H -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-tetra Hydropyridin-4-yl) -2 H -pyrazolo [3,4- b ] pyridine,

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

(33) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-ethylpiperidin-4-yl) -2 H -pyrazolo [3,4- b ] pyridine,

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

(38) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H - pyrazolo [3,4- b ] pyridine,

(41) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2 H - pyrazolo [3,4- b ] pyridine,

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

(51) 6- (1-acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine,

(52) 6- (1-benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine,

(53) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methanesulfonyloxy nilpi-4-yl) -2 H - pyrazol Zolo [3,4- b ] pyridine,

(59) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-oxocyclohexan-1-yl) -2 H -Pyrazolo [3,4- b ] pyridine,

(62) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexane-1-yl) -2 H -pyrazolo [ 3,4- b ] pyridine,

(63) 6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine,

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

(75) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine-6- Carboxylic acid phenylamide,

(78) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (4-phenylpiperazin-1-yl) methyl- 2H -pyrazolo [3,4- b ] Pyridine,

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

(82) 6-acetyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] Pyridine,

(84) 4- (2-bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2 H -pyrazolo [3,4- b ] Pyridine,

(86) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (pyrrolidin-3-yl) -2 H -pyrazolo [3,4- b ] pyridine, And

(87) 4- (2,1,3-benzoxadiazol-4-yl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2 H -pyrazolo [3 , 4- b ] pyridine,

The dihydropyrazolopyridine compound of [1] or [2], a tautomer thereof, an optically active agent thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

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

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

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

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

[13] The agent of [9], which is used for the prevention and / or treatment of neurodegenerative diseases.

[14] The diseases include Alzheimer's disease, ischemic cerebrovascular disorder, Down syndrome, cerebral infarction due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, encephalitis Postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, [13] The agent of [13], which is selected from the group consisting of frontotemporal dementia, AIDS encephalitis, Huntington's disease, and manic depression.

[15] The agent of [9], which is used for preventing and / or treating diabetes and diabetic complications.

[16] The agent of [9], which is used as an adjuvant.

[17] The agent of [9], which is used for preventing and / or treating alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell myeloma, or virus-induced tumor.

Detailed description of the invention

Formula (I) shows the presence 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 isomer of Formulas (I-a) and (I-b), and mixtures of such isomers.

Compounds represented by formula (I) in the present specification are described in detail below.

"Alkyl" means a straight or branched chain hydrocarbon of 1 to 8 carbon atoms, methyl, ethyl, propyl, butyl, pentyl (ie amyl), hexyl, or structural isomers thereof such as isopropyl, isobutyl, sec -Butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with alkyl having 1 to 4 carbon atoms being preferred. Alkyl of R ² is preferably alkyl having 1 to 4 carbon atoms. Alkyl of R ⁵ is preferably alkyl having 2 to 8 carbon atoms. "Alkyl having 2 to 8 carbon atoms" specifically refers to ethyl, propyl, butyl, pentyl (ie, amyl), hexyl, heptyl and octyl, or structural isomers thereof such as isopropyl, isobutyl, sec-butyl, tert -Butyl, isopentyl, neopentyl, tert-pentyl and the like. Alkyl having 2 to 4 carbon atoms is more preferred, and propyl is particularly preferred.

"Acyl" means C ₂ -C ₁₄ acyl, preferably in R ⁴ having 2 to 5 carbon atoms, "alkylcarbonyl" of 2 to 8 carbon atoms (e.g. acetyl, propionyl, butyryl, isobutyryl) , Valeryl, pivaloyl, hexanoyl, heptanoyl, etc.), "C ₇ -C ₁₂ arylcarbonyl" (eg benzoyl, naphtholyl, etc.), and "C ₇ -C ₁₂ aralkylcarbonyl" (eg : Benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, and the like). The benzene and naphthalene rings may have 1 to 5 substituent (s), and the position of substitution is not particularly limited.

"Acylalkyl" is an acylalkyl consisting of said C ₁ -C ₈ alkyl and said C ₂ -C ₁₄ acyl, for example acetylmethyl, propionylmethyl, butyrylmethyl, isobutyrylmethyl, valerylmethyl, pi Baloylmethyl, 2-acetylethyl, 2-propionylethyl, 3-acetylpropyl, and the like.

"Cycloalkyl" means a cyclic hydrocarbon chain having 3 to 8 carbon atoms. Cycloalkyl specifically includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with cycloalkyl having 3 to 6 carbon atoms being preferred. Cycloalkyl may have 1 to 5 substituent (s), and the position of substitution is not particularly limited.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" is secondary or tertiary amino with primary amino, C ₁ -C ₈ alkyl, for example amino, mono- or di-C ₁ -C ₈ alkyl-substituted amino (eg, methylamino, dimethylamino, Ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino and the like).

"Alkylthio" is a straight or branched chain alkylthio of 1 to 6 carbon atoms, for example methylthio, ethylthio, propylthio, butylthio, pentylthio (ie, amylthio), hexylthio and their structural isomers (eg Isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-pentylthio, etc.), and is preferably an alkylthio having 1 to 3 carbon atoms.

"Phenylthio" means phenylthio which may have 1 to 5 substituent (s) on phenyl, and the substitution position is not particularly limited.

"Haloalkyl" is said C ₁ -C ₈ alkyl substituted with 1 to 5 halogen, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like.

“Aminoalkyl” is C ₁ -C ₈ alkyl having primary amino, and includes, for example, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, and preferably 1 to 4 carbon atoms. Aminoalkyl containing alkyl.

"Acylamino" is acylamino having said C ₂ -C ₁₄ acyl, for example acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetylamino, phenylpropy Onylamino, phenylbutyrylamino and the like.

"Alkoxy" is alkoxy having said C ₁ -C ₈ alkyl, for example methoxy, ethoxy, propoxy, butoxy, pentyloxy (ie amyloxy), hexyloxy and its structural isomers (eg Isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy and the like), and preferably alkoxy having 1 to 4 carbon atoms.

"Cycloalkoxy" is cycloalkoxy having C ₃ -C ₈ cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, and preferably has 3 to 6 carbon atoms. Cycloalkoxy with cycloalkyl.

"Phenoxy" is phenyloxy which may have from 1 to 5 substituent (s) on phenyl, and the position of substitution is not particularly limited.

"Phenylalkoxy" is phenylalkoxy having said C ₁ -C ₈ alkoxy, for example benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1- Methyl-1-phenylethoxy, 1-methyl-2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 1-methyl-1-phenylpropoxy, 1-methyl-2-phenylpropoxy, Phenylalkoxy containing 1-methyl-3-phenylpropoxy and the like, and preferably containing alkoxy having 1 to 4 carbon atoms. Phenylalkoxy can have 1 to 5 substituent (s) on phenyl and the position of substitution is not particularly limited.

"Aminoalkoxy" is aminoalkoxy consisting of the above amino and C ₁ -C ₈ alkoxy, for example aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2- (dimethylamino) ethoxy, 3- (dimethyl Amino) propoxy, 4- (dimethylamino) butoxy and the like, preferably aminoaminoalk consisting of tertiary amino containing alkyl having 1 to 4 carbon atoms and alkoxy having 1 to 4 carbon atoms.

"Alkoxyalkyl" is an alkoxyalkyl consisting of C ₁ -C ₈ alkoxy and C ₁ -C ₈ alkyl, for example methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl And the like, and are preferably alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atoms and alkyl having 1 to 4 carbon atoms.

"Phenoxyalkyl" is a phenoxyalkyl consisting of the above phenoxy and C ₁ -C ₈ alkyl, and includes, for example, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl and the like, preferably carbon number Phenoxyalkyl containing 1-4 alkyl. Phenoxyalkyl may have 1 to 5 substituent (s) on phenyl, and the position of substitution is not particularly limited.

"Hydroxyalkyl" is hydroxyalkyl having C ₁ -C ₈ alkyl and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like, and preferably 1 to 4 carbon atoms. It is hydroxyalkyl containing the alkyl of.

"Alkoxycarbonyl" is alkoxycarbonyl having C ₁ -C ₈ alkoxy, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyl octa Cycarbonyl and their structural isomers (e.g. isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyl Oxycarbonyl and the like), and preferably alkoxycarbonyl having an alkoxy moiety having 1 to 4 carbon atoms. The alkoxycarbonyl of R ⁴ is preferably alkoxycarbonyl having 2 to 5 carbon atoms.

"Phenoxycarbonyl" is phenoxycarbonyl, which may have 1 to 5 substituent (s) on phenyl, and the position of substitution is not particularly limited.

“Aminocarbonyl” is aminocarbonyl having the above amino, including mono- or di-C ₁ -C ₈ alkyl-substituted amino, for example aminocarbonyl (ie carbamoyl), methylaminocarbonyl , Dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl and the like.

"Alkylthiocarbonyl" is alkylthiocarbonyl having said C ₁ -C ₆ alkylthio, for example methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and their structural isomers ( Such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec-butylthiocarbonyl, tert-butylthiocarbonyl, etc.), and is preferably alkylthiocarbonyl having an alkyl moiety having 1 to 3 carbon atoms. .

"Carboxyalkyl" is carboxyalkyl having C ₁ -C ₈ alkyl, for example carboxymethyl, carboxyethyl, carboxypropyl, and the like, and preferably carboxyalkyl containing alkyl having 1 to 4 carbon atoms.

"Cycloalkoxyalkyl" is cycloalkoxyalkyl consisting of C ₃ -C ₈ cycloalkoxy and C ₁ -C ₈ alkyl, for example cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclopentyloxymethyl , Cyclohexyloxymethyl and the like, and are preferably cycloalkoxyalkyl consisting of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atoms. Cycloalkoxyalkyl may have 1 to 3 substituent (s) on cycloalkyl, and the position of substitution is not particularly limited.

“Alkylsulfinyl” is alkylsulfinyl having the above C ₁ -C ₈ alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, and the like, and preferably has 1 to 1 carbon atoms. Alkylsulfinyl containing alkyl of 5; Alkylsulfinyl of R ⁴ is preferably alkylsulfinyl having 1 to 4 carbon atoms.

"Phenylsulfinyl" means phenylsulfinyl, which may have 1 to 5 substituent (s) on phenyl, and the position of substitution is not particularly limited.

"Alkylsulfonyl" is alkylsulfonyl having the C ₁ -C ₈ alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and the like, and preferably has 1 to 1 carbon atoms. Alkylsulfonyl containing alkyl of 5; The alkylsulfonyl of R ⁴ is preferably alkylsulfonyl having 1 to 4 carbon atoms.

"Phenylsulfonyl" may have 1 to 5 substituent (s) on phenyl, and the position of substitution is not particularly limited.

"Mercaptoalkyl" is a mercaptoalkyl having C ₁ -C ₈ alkyl and includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl, and the like, and preferably contains alkyl having 1 to 4 carbon atoms. Is mercaptoalkyl.

"Alkylthioalkyl" is alkylthioalkyl consisting of C ₁ -C ₆ alkylthio and C ₁ -C ₈ alkyl, for example methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl , Ethylthiopropyl and the like, preferably alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atoms and alkyl having 1 to 4 carbon atoms.

"Aryl" is aryl having 6 to 14 carbon atoms and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and the like. They may have 1 to 5 substituent (s), and the substitution position is not particularly limited.

"Aralkyl" is aralkyl wherein said C ₁ -C ₈ alkyl is substituted by said C ₆ -C ₁₄ aryl, benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthyl Methyl and the like. They may have 1 to 5 substituent (s) on the aryl moiety, and the position of substitution is not particularly limited.

"Acyloxyacetyl" is acyloxyacetyl having C ₂ -C ₁₄ acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.

"Acyloxyalkyl" is acyloxyalkyl having the above C ₂ -C ₁₄ acyl and C ₁ -C ₈ alkyl, for example acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2- Acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-benzoyloxyethyl and the like.

Substituents of “phenyl which may have a substituent (s)” may be exemplified by those referred to below as “substituents” and the number of substituents is generally 1 to 5, preferably 1 to 3. Phenyl having 1 to 2 substituent (s) is particularly preferred, and the position of substitution is not particularly limited.

"Aromatic heterocyclic group" is a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of, for example, nitrogen atoms, oxygen atoms and sulfur atoms, for example thio Phenyl, furanyl, pyrrolyl, imidazole, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxdiazolyl (i.e., 1,3 , 4-oxadiazolyl, 1,2,4-oxadiazolyl and the like). The aromatic heterocyclic group may have 1 to 6 substituent (s), and the substitution position is not particularly limited.

"Substituted or unsubstituted 4 to 7 membered heterocyclic ring" includes the following groups and the like.

Wherein R ⁹ is each independently hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl , Alkylthiocarbonyl, carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, substituent (s) Aryl which may have, an aromatic heterocyclic group which may have substituent (s), or phenylalkyl which may have substituent (s).

"Saturated 3 to 7 membered carbocyclic ring having substituent (s)" includes the following groups and the like.

Wherein R ¹⁰ is alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, Carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl which may have substituent (s), aromatic which may have substituent (s) Phenylalkyl which may have a heterocyclic group or substituent (s); 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, aryl which may have substituent (s), aromatic which may have substituent (s) Phenylalkyl which may have a heterocyclic group or substituent (s).

Substituents of the "aromatic heterocyclic group which may have a substituent (s)" may be exemplified by the following "substituents", and the number of substituents is generally 1 to 6, and the substitution position is not particularly limited.

"Phenylalkyl" is phenylalkyl consisting of phenyl and C ₁ -C ₈ alkyl, for example benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 1-methyl-2 -Phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl, preferably phenyl and carbon number It is phenylalkyl which consists of alkyl of 1-4.

The type and number of substituents of "phenylalkyl which may have a substituent (s)" are the same as those of the "aromatic heterocyclic group" mentioned above, and the substitution position is not particularly limited.

“Dialkylphosphinyl” is dialkylphosphinyl having the above C ₁ -C ₈ alkyl and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl, and the like, and preferably has 1 to 4 carbon atoms. Dialkylphosphinyl containing alkyl.

"Dialkylphosphonyl" is dialkylphosphonyl having said C ₁ -C ₈ alkyl and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl, and the like, and preferably has 1 to 4 carbon atoms. Dialkylphosphonyl containing alkyl.

As used herein, "substituent" is an alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic group, phenylalkyl, hydroxy, carboxy, thiol, halogen, amino, formyl, carbamoyl, cyano, nitro, alkyl Thio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthio Carbonyl and the like.

A ring which may contain a hetero atom is a 5 or 6 membered carbocyclic ring which may contain 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, particularly preferably sulfur atoms It is a ring containing. The ring may be substituted with one or more of the above substituents or oxo groups. The substitution position is not particularly limited. The ring is formed by R ² and R ³ in formula (I) together with the carbon atom to which it is attached. By forming the ring, the spiro ring is formed in the compound of formula (I). The ring may be fused with a benzene ring which may have substituent (s) and the position of substitution is not particularly limited. Such rings include, for example, 2,3-dihydrobenzo [ b ] thiophene, 2,3-dihydrobenzo [ b ] thiophene-1-oxide and the like.

“Groups derived from benzene rings fused with saturated or unsaturated 5 or 6 membered carbocyclic rings” are derived from naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indane and the like Represents a group. Of these, naphthyl (eg, naphthalen-1-yl and the like) and indanyl (indan-4-yl and the like) are preferable. The group may have 1 to 4 substituent (s) and the substitution position is not particularly limited.

"Group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatoms" includes the following groups and the like.

Among them, 2,1,3-benzoxadiazole, dihydrobenzo [ b ] furan, methylenedioxyphenyl, and 3,4-dihydro-2H-benzopyran are preferable, and 2,1,3-benzoxa Diazol-4-yl, 2,3-dihydrobenzo [ b ] furan-7-yl, 2,3- (methylenedioxy) phenyl and 3,4-dihydro-2H-benzopyran-8-yl Particularly preferred. These groups may have 1 to 3 substituent (s) and the substitution position is not particularly limited.

"Group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 carbon atoms fused with a benzene ring" includes the following groups and the like.

The group may have 1 to 5 substituent (s), and the substitution position is not particularly limited.

"Alkylcarbonylalkyl" is for example C ₁ -C ₄ alkyl-carbonyl-C ₁ -C ₄ alkyl, for example methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butylcarbonylmethyl And the like.

"Arylaminocarbonyl" is C ₆ -C ₁₀ aryl-aminocarbonyl and includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl, and the like. Arylaminocarbonyl may have 1 to 3 substituent (s) on aryl, and the position of substitution is not particularly limited.

"Aralkylaminocarbonyl" is C ₇ -C ₁₄ aralkyl-aminocarbonyl and includes, for example, benzylaminocarbonyl and the like. Aralkylaminocarbonyl may have 1 to 3 substituent (s) on aryl, and the position of substitution is not particularly limited.

"Alkyl substituted with saturated or unsaturated 4-7 membered rings containing 1 or 2 nitrogen atoms, which may have substituent (s)" is C ₁ -C ₄ alkyl, C ₆ -C ₁₀ aryl (eg Saturated or unsaturated 4 to 7 membered rings containing one or two nitrogen atoms (e.g., pyrrolo, pyrroline, pyrazole, pyridine, which may have substituent (s) such as phenyl, naphthyl, etc.) C ₁ -C ₈ alkyl substituted with " piperidine, piperazine, homopiperadine or morpholine, etc. ", for example (4-phenylpiperazin-1-yl) methyl, 2- (4-phenyl Piperazin-1-yl) ethyl, 3- (4-phenylpiperazin-1-yl) propyl, (4- (naphthalen-1-yl) piperazin-1-yl) methyl, 2- (4- (naphthalene -1-yl) piperazin-1-yl) ethyl, (4-methylhomopiperazin-1-yl) methyl, and the like.

“Phenylaminoalkyl” is phenylamino-C ₁ -C ₄ alkyl and includes, for example, phenylaminomethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl, and the like. Phenylaminoalkyl may have 1 to 3 substituent (s) on phenyl, and the position of substitution is not particularly limited.

“Phenylalkylcarbonyl” is phenyl-C ₁ -C ₄ alkyl-carbonyl and includes, for example, benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl, and the like. do. Phenylalkylcarbonyl may have 1 to 3 substituent (s) on phenyl, and the position of substitution is not particularly limited.

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

“Phenylsulfonyl” in R ¹¹ is phenylsulfonyl, which may have 1 to 3 substituent (s) on phenyl, and the position of substitution is not particularly limited.

“Phenylalkylsulfonyl” in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-sulfonyl, for example benzylsulfonyl, 2-phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl And the like. Phenylalkylsulfonyl may have 1 to 3 substituent (s) on phenyl, and the position of substitution is not particularly limited.

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

"Phenylsulfinyl" in R ¹¹ is phenylsulfinyl, which may have 1 to 3 substituent (s) on phenyl, and the substitution position is not particularly limited.

“Phenylalkylsulfinyl” in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-sulfinyl, for example benzylsulfinyl, 2-phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4-phenylbutylsulfinyl And the like. The phenylalkylsulfinyl may have 1 to 3 substituent (s) on phenyl and the position of substitution is not particularly limited.

“Alkoxycarbonyl” in R ¹¹ is C ₁ -C ₄ alkoxy-carbonyl and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.

"Phenylalkoxycarbonyl" in R ¹¹ is phenyl-C ₁ -C ₄ alkoxy-carbonyl, for example benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenyl Butoxycarbonyl and the like. The phenylalkoxycarbonyl may have 1 to 3 substituent (s) on phenyl and the position of substitution is not particularly limited.

“Alkylcarbonyl” in R ¹¹ is C ₁ -C ₄ alkyl-carbonyl and includes, for example, acetyl, propionyl, butylcarbonyl and the like.

“Phenylcarbonyl” in R ¹¹ is phenylcarbonyl, which may have 1 to 3 substituent (s) on phenyl, and the position of substitution is not particularly limited.

"Phenylalkylcarbonyl" in R ¹¹ is phenyl-C ₁ -C ₄ alkyl-carbonyl, for example benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl And the like. The phenylalkylcarbonyl may have 1 to 3 substituent (s) on phenyl and the position of substitution is not particularly limited.

"Phenoxycarbonyl" in R ¹¹ is phenoxycarbonyl which may have 1 to 3 substituent (s) on phenyl and the substitution position is not particularly limited.

“Alkyl” in R ¹² is C ₁ -C ₄ alkyl and 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 with a pharmaceutically acceptable acid, and the acid addition salt is also included in the present invention. The acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid. Salts with organic acids such as lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like. Where asymmetric carbon atoms are present, optical isomers and racemates thereof may be present, all of which are included in the present invention.

Among the compounds (I) of the present invention, compounds in which R ⁰ is hydrogen are described in J. Chem. Soc., Perkin Trans. 1, 947 (1996) et al. Can be synthesized as follows.

1st manufacturing method:

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

Meldrum's acid of formula (VI) and carbonyl derivative of formula (VII) are reacted with a carbonyl derivative of formula (VIII) in the presence of ammonium acetate to give an amide derivative of formula (IX). The reaction is carried out in the presence of a carboxylic acid which is 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 between 0 ° C and 200 ° C, preferably between 60 ° C and 100 ° C.

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

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

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described above].

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

Carbonyl derivatives of formula (VII) as starting materials are described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983). Carbonyl derivatives of formula (VIII) may be synthesized according to the methods described in Synthesis, 290 (1993).

2nd manufacturing method:

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described above].

Compounds (I) of the present invention can be prepared by reacting aminopyrazoles of formula (XI) and carbonyl derivatives of formula (VII) with carbonyl derivatives of formula (VIII). The reaction is carried out in the presence of a solvent which is inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used. The reaction is carried out at any temperature, for example between 0 ° C and 200 ° C, preferably between 60 ° C and 100 ° C.

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

Third manufacturing method:

[Wherein, R ⁰ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described above, X represents halogen, but R ⁰ is not hydrogen].

Compounds (I) of the present invention may be prepared by reacting a derivative with a halide of formula (XII) with dihydropyrazole of formula (XI) 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 which is inert to the reaction. As the solvent, those having no hydroxy group, for example, tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like are generally used. The reaction is carried out at any temperature, for example -10 ° C to 200 ° C, preferably 0 ° C to 100 ° C.

4th manufacturing method:

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

Compounds (I) of the present invention can be prepared by reacting a dihydropyrazolopyridine derivative of formula (XI) with anhydrides of 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 which is inert to the reaction. As the solvent, those having no hydroxy group, for example, tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like are generally used. The reaction is carried out at any temperature, for example -10 ° C to 200 ° C, preferably 0 ° C to 100 ° C.

Those skilled in the art should understand that the method of preparation may be modified to correspond to the desired compound.

The resulting compound (I) of the present invention can be isolated and purified as a free compound or salt thereof. Separation and purification can be carried out by conventional chemical methods such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography, and the like. If the purified compound obtained is a racemate, the desired optically active compound can be separated, for example, by fractional recrystallization with an optically active acid or by passing through a column packed with an optically active carrier. The invention also includes optically active compounds. The compounds of the present invention obtained by the above method have weak inhibitory activity against kinases such as CaM kinase II, MAP kinase II, casein kinase, PKA, PKC and ROCK other than GSK-3β, but strong inhibition against GSK-3β. Have activity. Therefore, the compounds of the present invention have GSK-3β-selective inhibitory activity and have few side effects, but have diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down syndrome, cerebral amyloid angiopathy) , Advanced upper nucleus palsy, subacute sclerosing encephalitis Parkinson's disease, post-encephalitis Parkinson's disease, boxer encephalitis, PDG (Parkinsonism dementia complex of Guam), Lewy body disease, peak disease, corticobasal degeneration, frontal temporal Dementia, AIDS encephalitis, Huntington's disease and manic depression, etc.), alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell myeloma, and virus-induced tumors. In addition, the compounds of the present invention can be used as adjuvant.

Formulations comprising the compounds of the present invention or salts thereof as active ingredients are prepared using carriers, excipients and other additives conventionally used in the formulations. Carriers and excipients for the preparation may be solid or liquid, for example lactose, magnesium stearate, starch (eg corn starch), talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cacao butter, Ethylene glycol and other commonly used materials. Oral administration of tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration by injection (intravenous injection, intramuscular injection, etc.), parenteral administration by suppositories, transdermal agents and the like. The dosage may be appropriately determined in each case in consideration of the symptoms, age, and sex of the subject to be administered, and generally 1 to 1,000 mg per day, preferably 1 to several times per day in an adult. 50-200 mg may be administered, or 1-500 mg per day, in adults, once to several times intravenously or intravenously for 1 to 24 hours per day.

The present invention is described in detail below based on Examples, Preparation Examples and Experimental Examples. The scope of the invention is not limited to these examples.

Example 1

4- (2,1,3-benzoxadiazol-4-yl) -6- (1- t -Butoxycarbonyl-piperidin-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

To a solution of ethyl isonipetate (10.0 g) in THF (200 mL), triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di- tert -butyldicarbonate (15.3 g) were added to 0 ° C. Was added and the mixture was stirred for one hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N- Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. n- BuLi (44 mmol) was added to a solution of acetonitrile (3.2 g) in THF (300 mL) at −78 ° C. and stirred for 3 hours. In addition, ethyl N- Boc-piperidine-4-carboxylate (16.3 g) was added and the mixture was stirred for one hour. The mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5: 1)) to give 1- ( N- Boc-piperidin-4-yl) -2 -Cyanoethan-1-one (11.6 g) was obtained as a colorless oil. 2,1,3-benzoxadiazol-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2- ( N- Boc-piperidin-4-yl) in acetonitrile (10 mL) The 1-cyanoethan-2-one (1.7 g) solution was heated overnight under reflux. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.

MP: 226 ^o C.

Calcd for C ₂₃ H ₂₅ N ₇ O ₃ : C, 61.73; H, 5.63; N, 21.97.

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

MS (EI): 447 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42 (9H, m), 1.59-1.62 (2H, m), 1.89-1.92 (2H, m), 2.62-2.86 (3H, m) , 4.05-4.08 (2H, m), 5.40 (1H, s), 7.26 (1H, s), 7.41 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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) -2 H -Pyrazolo [3,4- b ] Pyridine

4- (2,1,3-benzoxadiazol-4-yl) -6- (1- t -butoxycarbonyl-piperidin-4-yl) -5-cyano-4,7-di Hydro- 2H -pyrazolo [3,4- b ] pyridine (1.7 g) was added to trifluoroacetic acid (20 mL) at 0 ° C. and the mixture was stirred for one hour. The solvent was evaporated under reduced pressure. The mixture was basified with sodium bicarbonate and then extracted with ethyl acetate. The solvent was evaporated under reduced pressure, the residue was washed with acetonitrile and the precipitated crystals were collected by filtration to give the title compound (0.83 g) as yellow crystals.

MP: 216 ^o C.

MS (EI): 348 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.78-1.81 (2H, m), 2.07-2.11 (2H, m), 2.80-2.86 (3H, m), 3.27-3.30 (3H, m), 5.39 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.86 (1 H, brs), 12.24 (1 H, brs).

Example 3

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H in MeOH (200 mL) To a -pyrazolo [3,4- b ] pyridine (0.7 g) solution, 37% formaldehyde (0.18 g), sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) were added at room temperature, and The mixture was stirred overnight. The mixture was alkalized with sodium dicarbonate and then extracted with ethyl acetate. The solvent was evaporated under reduced pressure, the residue was washed with acetonitrile and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals.

MP:> 270 ^o C.

MS (EI): 361 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.57-1.60 (2H, m), 1.82-1.88 (2H, m), 2.01-2.06 (2H, m), 2.15 (3H, s) , 2.58-2.61 (1H, m), 2.85-2.88 (2H, m), 5.40 (1H, s), 7.26 (1H, s), 7.40 (1H, d, J = 6.6Hz), 7.58 (1H, dd , J = 9.0 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- t -Butyloxycarbonyl-piperidin-3-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 229 ^o C.

Calcd for C ₂₃ H ₂₅ N ₇ O ₃ : C, 61.73; H, 5.63; N, 21.97.

Found: C, 61.56; H, 5.06; N, 21.67.

MS (EI): 447 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.32-1.40 (2H, m), 1.39 (9H, s), 1.69-1.78 (2H, m), 2.69-2.76 (2H, m) , 3.16-3.19 (1H, m), 3.92-3.95 (2H, m), 5.42 (1H, s), 7.28 (1H, s), 7.42 (1H, d, J = 6.6Hz), 7.58 (1H, dd , J = 9.0 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 202 ^o C.

Calcd for C ₁₈ H ₁₇ N ₇ O: C, 62.24; H, 4.93; N, 28.23.

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

MS (EI): 347 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42-1.45 (1H, m), 1.72-1.88 (3H, m), 2.66-2.84 (5H, m), 2.94-3.02 (1H, m), 5.38 (1H, s), 7.26 (1H, s), 7.39 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 228 ^o C.

MS (EI): 361 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.76 (4H, m), 2.21 (3H, s), 2.47-2.55 (4H, m), 2.93-2.96 (1H, m) , 5.38 (1H, s), 7.27 (1H, s), 7.40 (1H, d, J = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 10.16 (1H, brs), 12.20 (1H, brs).

Example 7

4- (2,1,3-benzoxadiazol-4-yl) -6- (1- t -Butyloxycarbonyl-piperidin-2-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 447 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27 and 1.32 (9H, s), 1.42-1.97 (6H, m), 3.30-3.33 (1H, m), 3.53-3.61 (1H, m), 4.47-4.50 (1H, m), 5.37 and 5.39 (1H, s), 7.26 and 7.29 (1H, s), 7.38-7.44 (1H, m), 7.54-7.60 (1H, m), 7.90- 7.93 (1 H, m), 9.63 and 9.73 (1 H, brs), 12.16 (1 H, brs).

Example 8

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 347 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27-1.88 (6H, m), 3.12-3.16 (1H, m), 4.12-4.15 (1H, m), 4.48-4.58 (1H, m), 5.64 and 5.66 (1H, s), 7.22-7.28 (1H, m), 7.45-7.52 (2H, m), 7.87-7.90 (1H, m), 8.26 (1H, br), 10.92 and 10.94 ( 1 H, brs), 12.35 (1 H, brs).

Example 9

4- (2,1,3-benzoxadiazol-4-yl) -6- (4- t -Butyloxycarbonyl-morpholin-2-yl) -5-cyano-4,7-dihydro-2 H -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 (400 MHz, DMSO-d ₆ ) δ (ppm): 1.36 and 1.40 (9H, s), 2.95-3.06 (2H, m), 3.50-3.52 (1H, m), 3.75-3.95 (3H, m), 4.34-4.40 (1H, m), 5.44 and 5.48 (1H, s), 7.26 and 7.30 (1H, s), 7.42-7.45 (1H, m), 7.57-7.62 (1H, m), 7.93- 7.96 (1 H, m), 9.84 and 9.92 (1 H, brs), 12.23 (1 H, brs).

Example 10

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (morpholin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 2, 4- (2,1,3-benzoxadiazol-4-yl) -6- (4-t-butoxycarbonylmorpholin-2-yl) -5-sia The title compound was prepared from no-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine.

MS (EI): 349 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.64-2.95 (4H, m), 3.53 (1H, br), 3.55-3.57 (1H, m), 3.82-3.85 (1H, m) , 4.41-4.45 (1H, m), 5.43 and 5.44 (1H, s), 7.24 and 7.28 (1H, s), 7.38-7.41 (1H, m), 7.56-7.61 (1H, m), 7.91-7.94 ( 1 H, m), 9.74 and 9.76 (1 H, brs), 12.19 (1 H, brs).

Example 11

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 143 ^o C.

MS (EI): 363 (M ⁺ ).

¹ H-NMR (400 MHz, 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- t -Butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, titled from ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazol-4-aldehyde and 3-aminopyrazole The compound was prepared.

MP: 222 ^o C.

MS (EI): 445 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 2.35-2.39 (2H, m), 3.46-3.48 (2H, m), 3.90-3.92 (2H, m) , 5.43 (1H, s), 6.06-6.09 (1H, m), 7.28 (1H, s), 7.45 (1H, d, J = 6.6 Hz), 7.60 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 180 ^o C.

MS (EI): 345 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.26-2.32 (2H, m), 2.87-2.90 (2H, m), 3.30-3.36 (3H, m), 5.42 (1H, s) , 6.09-6.10 (1H, m), 7.30 (1H, s), 7.43 (1H, d, J = 6.6 Hz), 7.60 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.87 (1 H, brs), 12.18 (1 H, brs).

Example 14

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-1,2,3,6-tetrahydropyridine- 4-day) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 218 ^o C.

MS (EI): 359 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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 - t Butoxycarbonyl N -Methylamino) ethyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL), triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di- tert -butyldicarbonate (30 g) were added at 0 ° C. Was added and the mixture was stirred at 40 ° C. for 4 hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N- Boc-3-aminopropionate (16.7 g) as a colorless oil. t- BuOK (2.8 g) and methyl iodide (4.9 g) are added to a solution of ethyl N- Boc-3-aminopropionate (5.0 g) in THF (50 mL) at 0 ° C. and the mixture at room temperature. Stir for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 3- ( N- Boc- N -methylamino) propionate (4.3 g) as a colorless oil. Then, in the same manner as in Example 1, titled from ethyl 3- ( N- Boc- N -methylamino) propionate, 2,1,3-benzoxadiazol-4-aldehyde and 3-aminopyrazole The compound was prepared.

MP: 240 ^o C.

Calcd for C ₂₁ H ₂₃ N ₇ O ₃ : C, 59.85; H, 5.50; N, 23.26.

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

MS (EI): 421 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.26 and 2.32 (9H, s), 2.62-2.63 (2H, m), 2.81 (3H, s), 3.48-3.55 (2H, m) , 5.40 (1H, s), 7.27 (1H, s), 7.40 (1H, d, J = 6.6 Hz), 7.57 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 10.07 (1 H, brs), 12.15 (1 H, brs).

Example 16

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2- ( N -Methylamino) ethyl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 174 ^o C.

MS (EI): 321 (M ⁺ ).

¹ H-NMR (400 MHz, 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 (1H, d, J = 9.0 Hz).

Example 17

4- (2,1,3-benzoxadiazol-4-yl) -6- (2- ( N - t -Butoxycarbonylamino) ethyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 231 ^o C.

Calcd for C ₂₀ H ₂₁ N ₇ O ₃ : C, 58.96; H, 5.20; N, 24.06.

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

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.33 (9H, s), 2.55-2.60 (2H, m), 3.23-3.33 (2H, m), 5.41 (1H, s), 6.81 (1H, brs), 7.25 (1H, s), 7.44 (1H, d, J = 6.6 Hz), 7.57 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz ), 9.94 (1 H, brs), 12.14 (1 H, brs).

Example 18

6- (2-aminoethyl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 2, 4- (2,1,3-benzoxadiazol-4-yl) -6- (2- ( N- t-butoxycarbonylamino) ethyl) -5-sia The title compound was prepared from no-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine.

MS (EI): 307 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.50-2.54 (2H, m), 2.88 (2H, t, J = 7.3 Hz), 3.35 (4H, br), 5.40 (1H, s ), 7.25 (1H, s), 7.44 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz).

Example 19

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2- ( N , N -Dimethylamino) ethyl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 215 ^o C.

MS (EI): 335 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.19 (6H, s), 2.45-2.62 (4H, m), 5.41 (1H, s), 7.27 (1H, s), 7.43 (1H , d, J = 6.6 Hz, 7.58 (1 H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1 H, d, J = 9.0 Hz), 10.04 (1 H, brs), 12.16 (1 H, brs).

Example 20

4- (2,1,3-benzoxadiazol-4-yl) -6-(( N - t -Butoxycarbonyl-N-methylamino) methyl) -5-cyano-4,7-dihydro-2 H -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-benzoxadiazol-4-aldehyde and 3-aminopyrazole.

MP: 207 ^o C.

Calcd for C ₂₀ H ₂₁ N ₇ 0 ₃ : C, 58.96; H, 5.20; N, 24.06.

Found: C, 58.80; H, 5.22; N, 24.38.

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.33 and 1.39 (9H, s), 2.81 (3H, s), 4.13-4.20 (2H, m), 5.42 (1H, s), 7.29 (1H, s), 7.43 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.94 (1H, d, J = 9.0 Hz), 9.33 (1H, brs ), 12.15 (1 H, brs).

Example 21

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6-(( N -Methylamino) methyl) -2 H -Pyrazolo [3,4- b ] Pyridine trifluoroacetate

4- (2,1,3-benzoxadiazol-4-yl) -6-(( N - t -butoxycarbonyl- N -methylamino) methyl) -5-cyano-4,7-di Hydro- 2H -pyrazolo [3,4- b ] pyridine was added to trifluoroacetic acid (10 mL) at 0 ° C. and the mixture was stirred for one hour. The solvent was evaporated under reduced pressure, the residue was crystallized with ethanol and the precipitated crystals were collected by filtration to give the title compound (0.1 g) as yellow crystals.

MP: 174 ^o C.

MS (EI): 307 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.10 (3H, s), 4.51-4.68 (2H, m), 7.24 (1H, d, J = 6.6 Hz), 7.45 (1H, s ), 7.52 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.89 (1H, d, J = 9.0 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 15 and Example 2 above, the title compound was prepared from ethyl 4-aminocyclohexanecarboxylate, 2,1,3-benzoxadiazol-4-aldehyde and 3-aminopyrazole. .

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.32-1.35 (2H, m), 1.81-2.12 (6H, m), 2.57 (3H, s), 2.65-2.69 (1H, m) , 2.81-2.85 (1H, m), 5.39 (1H, s), 7.28 (1H, s), 7.41 (1H, d, J = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 241 ^o C.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.15-2.02 (9H, m), 2.15 and 2.21 (6H, s), 2.62-2.76 (1H, m), 5.38 and 5.43 (1H, s), 7.26 (1H, s), 7.38-7.44 (1H, m), 7.56-7.62 (1H, m), 7.90-7.96 (1H, m), 9.74 (1H, brs), 12.18 (1H, brs) .

Example 24

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-phenylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

To a solution of ethyl isonipekotate (8.9 g) in CH ₂ Cl ₂ (500 mL), triphenyl bismuth (25 g) and copper (II) acetate (10.3 g) were added at room temperature and the mixture was stirred overnight. The mixture was filtered and extracted with CH ₂ Cl ₂ . The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) Was obtained as colorless crystals. n- BuLi (41 mmol) was added to a solution of acetonitrile (1.9 g) in THF (200 mL) at −78 ° C. In addition, ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for one hour. The mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give 1- (1-phenylpiperidin-4-yl) -2- Cyanoethan-1-one (2.0 g) was obtained as colorless crystals. 2,1,3-benzoxadiazol-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1- (1-phenylpiperidin-4-yl)-in acetonitrile (10 mL) The 2-cyanoethan-1-one (0.5 g) solution was heated overnight under reflux. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.

MS (FAB): 424 (M ⁺ +1).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.73-1.76 (2H, m), 2.14-2.18 (2H, m), 2.62-2.66 (2H, m), 2.81-2.84 (1H, m), 3.80-3.84 (2H, m), 5.41 (1H, s), 6.75 (1H, dd, J = 7.3 Hz and 7.2 Hz), 6.94-6.96 (2H, m), 7.18-7.27 (3H, m) ), 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), 12.17 ( 1H, brs).

Example 25

6- (1-acetylpiperidin-4-yl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

To a solution of ethyl isonipekotate (8.0 g) in THF (100 mL), triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) were added at 0 ° C. and the mixture was Stir for hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to afford ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. n- BuLi (57 mmol) was added to a solution of acetonitrile (2.5 g) in THF (300 mL) at −78 ° C. In addition, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for one hour. The mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give 1- (1-acetylpiperidin-4-yl) -2- Cyanoethan-1-one (7.5 g) was obtained as a colorless oil. 2,1,3-benzoxadiazol-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1- (1-acetylpiperidin-4-yl)-in acetonitrile (10 mL) The 2-cyanoethan-1-one (0.4 g) solution was heated overnight under reflux. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.

MP: 248 ^o C.

MS (FAB): 340 (M ⁺ +1).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.62-1.64 (2H, m), 1.82-1.84 (1H, m), 2.00-2.02 (4H, m), 2.49-2.50 (1H, m), 2.94-3.07 (2H, m), 3.89-3.92 (1H, m), 4.48-4.51 (1H, m), 5.40 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J = 6.6 Hz), 7.59 (1 H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1 H, d, J = 9.0 Hz), 9.81 (1 H, brs), 12.18 (1 H, brs).

Example 26

4- (2,1,3-benzoxadiazol-4-yl) -6- (1-benzoylpiperidin-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 228 ^o C.

MS (FAB): 452 (M ⁺ +1).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.59-1.76 (2H, m), 2.04-2.08 (2H, m), 2.76-2.80 (1H, m), 3.01-3.09 (2H, m), 3.58-3.60 (1H, m), 4.60-4.63 (1H, m), 5.41 (1H, s), 7.28 (1H, s), 7.43-7.46 (6H, m), 7.56-7.59 (1H, m), 7.92 (1 H, d, J = 9.0 Hz), 9.90 (1 H, brs), 12.21 (1 H, 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-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 25, acetylchloride, ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazol-4-aldehyde and 3-aminopyra The title compound was prepared from the sol.

MP: 237 ^o C.

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.00 and 2.04 (3H, s), 2.46-2.49 (2H, m), 3.55-3.58 (2H, m), 4.00-4.06 (2H, m), 5.44 (1H, s), 6.10 (1H, s), 7.29 (1H, s), 7.45 (1H, d, J = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 419 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.19 (3H, t, J = 7.3 Hz), 1.61-1.63 (2H, m), 1.90-1.94 (2H, m), 2.84-2.88 (3H, m), 4.02-4.07 (4H, m), 5.40 (1H, s), 7.26 (1H, s), 7.41 (1H, d, J = 6.6 Hz), 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-methanesulfonylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 243 ^o C.

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.73-1.76 (2H, m), 2.04-2.08 (2H, m), 2.74-2.78 (3H, m), 2.88 (3H, s) , 3.66-3.69 (2H, m), 5.41 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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) piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 25, the title compound from 1-chloro- N, N -dimethylformamide, ethyl isonifecatetate, 2,1,3-benzoxadiazol-4-aldehyde and 3-aminopyrazole Was prepared.

MS (EI): 418 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.61-1.63 (2H, m), 2.00-2.06 (2H, m), 2.65-2.67 (2H, m), 2.75 (6H, s) , 2.81-2.85 (1H, m), 3.64-3.67 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.41 (1H, d, J = 6.6Hz), 7.59 (1H, dd , J = 9.0 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-guanylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 270 ^o C.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.56 (2H, m), 1.86-1.91 (2H, m), 2.47-2.50 (2H, m), 2.71-2.77 (1H, m), 3.00-3.03 (2H, m), 3.32-3.36 (3H, br), 5.39 (1H, s), 7.26 (1H, s), 7.39 (1H, d, J = 6.6 Hz), 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-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 219 ^o C.

Calcd for C ₂₀ H ₁₉ N ₇ O ₂ : C, 61.69; H, 4.92; N, 25.18.

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

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.25-1.49 (1H, m), 1.74-1.78 (2H, m), 2.00 (3H, s), 2.01-2.04 (1H, m) , 2.49-2.98 (3H, m), 3.78-3.81 (1H, m), 4.37-4.40 (1H, m), 5.29 and 5.42 (1H, s), 7.28 (1H, s), 7.41-7.48 (1H, m), 7.58-7.62 (1 H, m), 7.92-7.95 (1 H, m), 9.90 (1 H, brs), 12.21 (1 H, brs).

Example 33

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-ethylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 231 ^o C.

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.99 (3H, t, J = 7.3 Hz), 1.60-1.63 (2H, m), 1.85-1.88 (2H, m), 2.00-2.04 (2H, m), 2.31-2.34 (2H, m), 2.64-2.66 (1H, m), 2.97-3.00 (2H, m), 5.39 (1H, s), 7.26 (1H, s), 7.40 (1H , d, J = 6.6 Hz, 7.58 (1 H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1 H, d, J = 9.0 Hz), 9.75 (1 H, brs), 12.18 (1 H, brs).

Example 34

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-propylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 246 ^o C.

Calcd for C ₂₁ H ₂₃ N ₇ O: C, 64.76; H, 5.95; N, 25.18.

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

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 7.3 Hz), 1.40-1.45 (2H, m), 1.59-1.62 (2H, m), 1.82-1.86 (2H, m), 2.00-2.05 (2H, m), 2.21 (2H, t, J = 7.3 Hz), 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 = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.91 (1H, d, J = 9.0 Hz), 9.77 ( 1 H, brs), 12.18 (1 H, brs).

Example 35

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-isopropylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 260 ^o C.

MS (EI): 389 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.22 (6H, d, J = 7.3 Hz), 1.82-3.42 (10H, m), 5.40 (1H, s), 7.27 (1H, s ), 7.42 (1H, d, J = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.66 (1H, brs), 12.22 ( 1H, brs).

Example 36

4- (2-bromo-3-cyanophenyl) -6- (1- t -Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 270 ^o C.

Calcd for C ₂₄ H ₂₅ BrN ₆ O ₂ : C, 56.59; H, 4.95; N, 16.50.

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

MS (EI): 509 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.59-1.66 (2H, m), 1.85-1.90 (2H, m), 2.65-2.82 (3H, m) , 4.05-4.07 (2H, m), 5.47 (1H, s), 7.33 (1H, s), 7.56-7.60 (2H, m), 7.84 (1H, d, J = 7.3Hz), 9.81 (1H, brs ), 12.26 (1 H, brs).

Example 37

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

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

MP:> 270 ^o C.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.56 (2H, m), 1.83-1.87 (2H, m), 2.46-2.50 (3H, m), 2.71-2.74 (1H, m), 3.00-3.04 (1H, m), 5.45 (1H, s), 7.32 (1H, s), 7.56-7.58 (2H, m), 7.81 (1H, d, J = 7.3 Hz), 9.74 (1H) , brs), 12.26 (1 H, brs).

Example 38

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 270 ^o C.

MS (EI): 423 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.65-1.71 (2H, m), 2.02-2.08 (3H, m), 2.29 (3H, s), 2.48-2.52 (1H, m) , 1.66-1.69 (1H, m), 2.95-2.98 (2H, m), 5.50 (1H, s), 7.34 (1H, s), 7.55-7.57 (2H, m), 7.83 (1H, d, J = 7.3 Hz), 9.83 (1 H, brs), 12.32 (1 H, brs).

Example 39

4- (2-bromo-3-cyanophenyl) -6- (1- t -Butoxycarbonylpiperidin-3-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 238 ^o C.

Calcd for C ₂₄ H ₂₅ BrN ₆ O ₂ : C, 56.56; H, 4.95; N, 16.50.

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

MS (EI): 509 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.37 and 1.39 (9H, s), 1.68-2.06 (4H, m), 2.65-2.75 (2H, m), 3.30-3.32 (1H, m), 3.94-3.97 (2H, m), 5.47 and 5.49 (1H, s), 7.34 (1H, s), 7.58-7.61 (2H, m), 7.82-7.86 (1H, m), 9.89 (1H, brs), 12.31 (1 H, brs).

Example 40

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-3-yl) -2 H -Pyrazolo [3,4- b ] Pyridine trifluoroacetate

In the same manner as in Example 21, 4- (2-bromo-3-cyanophenyl) -6- (1- t -butoxycarbonylpiperidin-3-yl) -5-cyano-4 The title compound was prepared from, 7-dihydro-2 H -pyrazolo [3,4- b ] pyridine.

MP: 225 ^o C.

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

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

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.68-1.98 (4H, m), 2.65-2.68 (1H, m), 3.21-3.33 (4H, m), 5.50 (1H, s) , 7.35 (1H, s), 7.55-7.66 (2H, m), 7.84-7.87 (1H, m), 8.54 (1H, br), 8.96 (1H, br), 9.96 (1H, brs), 12.36 (1H , br).

Example 41

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 174 ^o C.

MS (EI): 423 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.54-1.78 (4H, m), 2.18-2.20 (1H, m), 2.20 (3H, s), 2.55-2.58 (2H, m) , 2.94-2.96 (1H, m), 3.31-3.34 (1H, m), 5.47 (1H, s), 7.33 (1H, s), 7.57-7.58 (2H, m), 7.84 (1H, d, J = 7.3 Hz), 10.06 (1H, brs), 12.29 (1H, brs).

Example 42

4- (2-bromo-3-cyanophenyl) -6- (1- t -Butoxycarbonylpiperidin-2-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 509 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.35 (9H, s), 1.34-1.90 (6H, m), 3.48-3.52 (2H, m), 4.42-4.48 (1H, m) , 5.43 and 5.46 (1H, s), 7.36-7.39 (1H, m), 7.53-7.57 (2H, m), 7.80-7.83 (1H, m), 9.68 and 9.82 (1H, brs), 12.26 (1H, brs).

Example 43

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine trifluoroacetate

In the same manner as in Example 21, 4- (2-bromo-3-cyanophenyl) -6- (1- t -butoxycarbonylpiperidin-2-yl) -5-cyano-4 The title compound was prepared from, 7-dihydro-2 H -pyrazolo [3,4- b ] pyridine.

MP: 232 ^o C.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27-1.98 (5H, m), 2.47-2.51 (2H, m), 3.12-3.18 (1H, m), 4.7-4.10 (1H, m), 4.50-4.57 (1H, m), 7.40-7.63 (3H, m), 7.79-7.82 (2H, m), 8.06 (1H, br), 10.93 (1H, brs), 12.41 (1H, brs) .

Example 44

4- (2-bromo-3-cyanophenyl) -6- (4- t -Butoxycarbonylmorpholin-2-yl) -5-cyano-4,7-dihydro-2 H -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-aminopyrazole.

MP: 219 ^o C.

MS (EI): 511 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.40 (9H, s), 2.97-3.10 (2H, m), 3.47-3.53 (1H, m), 3.77-3.94 (3H, m) , 4.37-4.39 (1H, m), 5.52 and 5.54 (1H, s), 7.34-7.36 (1H, m), 7.58-7.65 (2H, m), 7.94-7.96 (1H, m), 9.87 and 9.92 ( 1 H, brs), 12.33 (1 H, brs).

Example 45

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (morpholin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine trifluoroacetate

In the same manner as in Example 21, 4- (2-bromo-3-cyanophenyl) -6- (4- t -butoxycarbonylmorpholin-2-yl) -5-cyano-4, The title compound was prepared from 7-dihydro-2 H -pyrazolo [3,4- b ] pyridine.

MP: 236 ^o C.

MS (EI): 411 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.02-3.05 (1H, m), 3.24-3.33 (3H, m), 3.80-3.84 (1H, m), 4.08-4.11 (1H, m), 4.82-4.85 (1H, m), 5.55 (1H, s), 7.36 (1H, s), 7.55-7.62 (2H, m), 7.84-7.87 (1H, m), 9.14 (2H, br) , 10.04-10.09 (1H, brs), 12.40 (1H, brs).

Example 46

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 180 ^o C.

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.18-2.20 (1H, m), 2.20 and 2.21 (3H, s), 2.26-2.29 (1H, m), 2.58-2.62 (1H, m), 2.75-2.78 (1H, m), 3.58-3.62 (1H, m), 3.88-3.91 (1H, m), 4.48-4.50 (1H, m), 5.51 (1H, s), 7.35 (1H, s), 7.56-7.61 (2H, m), 7.84-7.86 (1H, m), 9.81 and 9.84 (1H, brs), 12.31 (1H, brs).

Example 47

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,2,3,6-tetrahydropyridin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

From ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1 and the following Example 2 The title compound was prepared.

MP: 226 ^o C.

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.36-2.40 (2H, m), 2.95-2.98 (2H, m), 3.56-3.60 (3H, m), 5.51 (1H, s) , 6.15 (1H, s), 7.34 (1H, s), 7.56-7.60 (2H, m), 7.84 (1H, d, J = 7.3 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 233 ^o C.

MS (EI): 421 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.31 (3H, s), 2.56-2.67 (4H, m), 3.00-3.03 (2H, m), 5.50 (1H, s), 6.10 (1H, s), 7.34 (1H, s), 7.58-7.60 (2H, m), 7.83 (1H, d, J = 7.3 Hz), 9.91 (1H, brs), 12.29 (1H, brs).

Example 49

4- (2-bromo-3-cyanophenyl) -6-(( N - t Butoxycarbonyl N -Methylamino) methyl) -5-cyano-4,7-dihydro-2 H -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 (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39 (9H, s), 2.85 (3H, s), 4.15-4.18 (2H, m), 5.49 (1H, s), 7.37 (1H s), 7.56-7.57 (2H, m), 7.83 (1H, d, J = 7.3 Hz), 9.78-9.93 (1H, br), 12.31 (1H, brs).

Example 50

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6-(( N -Methylamino) methyl) -2 H -Pyrazolo [3,4- b ] Pyridine trifluoroacetate

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

MP: 258 ^o C.

MS (EI): 369 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.10 (3H, s), 4.46-4.66 (2H, m), 5.50 (1H, s), 7.47-7.48 (2H, m), 7.65 (1H, s), 7.80-7.81 (2H, m), 8.09 (1H, br), 10.81 (1H, brs), 12.38 (1H, brs).

Example 51

6- (1-acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 25, the title compound was prepared from acetylchloride, ethyl isonipekotate, 2-bromo-3-cyanobenzaldehyde, and 3-aminopyrazole.

MP:> 280 ^o C.

MS (EI): 451 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.63-1.82 (3H, m), 1.98-2.00 (1H, m), 2.00 (3H, s), 2.49-2.51 (1H, m) , 2.94-3.10 (2H, m), 3.89-3.91 (1H, m), 4.48-4.50 (1H, m), 5.47 (1H, s), 7.34 (1H, s), 7.56-7.58 (2H, m) , 7.84 (1H, d, J = 7.3 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-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 25, the title compound was prepared from benzoylchloride, ethyl isonipekotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP:> 280 ^o C.

MS (FAB): 514 (M ⁺ +1).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.64-2.04 (4H, m), 2.76-2.80 (1H, m), 3.05-3.10 (2H, m), 3.60-3.63 (1H, m), 4.62-4.65 (1H, m), 5.48 (1H, s), 7.34-7.58 (8H, m), 7.84 (1H, d, J = 7.3 Hz), 9.90 (1H, brs), 12.31 (1H) , brs).

Example 53

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine trifluoroacetate

In the same manner as in Example 25, the title compound was prepared from methanesulfonylchloride, ethyl isonipekotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MP:> 280 ^o C.

MS (EI): 487 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.75-2.07 (4H, m), 2.76-2.79 (2H, m), 2.89 (3H, s), 3.66-3.69 (2H, m) , 5.48 (1H, s), 7.34 (1H, s), 7.56-7.58 (2H, m), 7.84 (1H, d, J = 7.3 Hz), 9.84 (1H, brs), 12.30 (1H, brs).

Example 54

6- (1- t -Butoxycarbonylpiperidin-4-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 280 ^o C.

Calcd for C ₂₃ H ₂₆ ClN ₅ O ₂ : C, 62.79; H, 5.96; N, 15.92.

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

MS (EI): 439 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.58-1.67 (2H, m), 1.86-1.91 (2H, m), 2.84-2.90 (3H, m) , 4.06-4.09 (2H, m), 5.35 (1H, s), 7.21-7.33 (4H, m), 7.42 (1H, d, J = 7.3Hz), 9.69 (1H, brs), 12.18 (1H, brs ).

Example 55

4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP: 221 ^o C.

MS (EI): 339 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.92 (2H, m), 2.10-2.16 (2H, m), 2.96-3.00 (3H, m), 3.30-3.40 (2H, m), 5.36 (1H, s), 7.22-7.33 (4H, m), 7.42 (1H, d, J = 7.2 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 270 ^o C.

Calcd for C ₁₉ H ₂₀ ClN ₅ : C, 64.49; H, 5.70; N, 19.79.

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

MS (EI): 353 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.56-1.65 (2H, m), 1.84-1.90 (2H, m), 2.02-2.06 (2H, m), 2.16 (3H, s) , 2.60-2.65 (1H, m), 2.85-2.88 (2H, m), 5.34 (1H, s), 7.21-7.33 (4H, m), 7.41 (1H, d, J = 7.3Hz), 9.63 (1H , brs), 12.17 (1 H, brs).

Example 57

2-acetyl-6- (1-acetylpiperidin-4-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -pyrazolo [3,4- b in pyridine (1.2 mL) To a] pyridine (1.0 g) solution, acetic anhydride (0.42 mL) was added at room temperature and the mixture was stirred for two hours. The mixture was evaporated under reduced pressure, the residue was washed with methanol and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.

MS (EI): 423 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.58-1.70 (2H, m), 1.91-1.96 (1H, m), 1.99-2.00 (1H, m), 2.02 (3H, s) , 2.51 (3H, s), 2.55-2.58 (1H, m), 3.11-3.18 (2H, m), 3.91-3.94 (1H, m), 4.49-4.52 (1H, m), 5.37 (1H, s) 7.32-7. 37 (3H, m), 7.48 (1H, d, J = 7.3 Hz), 7.84 (1H, s), 10.24 (1H, brs).

Example 58

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexan-1-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL), ethylene glycol (10.1 g) and p-toluenesulfonic acid (2.8 g) are added at room temperature, and the mixture is Dean-Stark (Dean-). Stark) was heated under reflux for 5 hours. The reaction mixture is cooled to room temperature, the solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to ethyl 1,4-dioxa-spiro [4,5] decane-6-carboxylate (31 g) was obtained as a colorless oil. n- BuLi (160 mmol) was added to a solution of acetonitrile (7.2 g) in THF (700 mL) at −78 ° C. In addition, ethyl 1,4-dioxa-spiro [4,5] decane-6-carboxylate (31 g) was added and the mixture was stirred for one hour. The mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10: 1)) to give 1-cyano-2- (1,4-dioxa-spiro [ 4,5] -decane-6-yl) ethan-2-one (14.5 g) was obtained as a colorless oil. 2,1,3-benzoxadiazol-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2- (1,4-dioxa- in acetonitrile (10 mL) Spiro [4,5] decane-6-yl) ethan-2-one (1.2 g) solution was heated at reflux overnight. The reaction mixture is cooled to room temperature and the precipitated crystals are collected by filtration to give 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1,4-Dioxa-spiro [4,5] decan-6-yl) -2 H -pyrazolo [3,4- b ] pyridine (1.3 g) was obtained as colorless crystals.

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1,4-dioxa-spiro [4, in methanol (30 mL)) 5] Decan-6-yl) -2 H -pyrazolo [3,4- b ] pyridine (1.0 g) solution was added 4N HCl dioxane solution (6.0 mL) at room temperature and the mixture was placed at 60 ° C. Heated for hours. The mixture was alkalized with sodium bicarbonate and then extracted with chloroform. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (20 mg) as colorless crystals.

MP:> 270 ^o C.

MS (EI): 360 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.74-1.80 (5H, m), 2.60-2.65 (3H, m), 3.31-3.35 (1H, m), 5.98 (1H, s) , 6.92 (1H, d, J = 6.6 Hz), 7.39 (1H, s), 7.47 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.84 (1H, d, J = 9.0 Hz), 9.33 (1H , brs), 12.15 (1 H, brs).

Example 59

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-oxocyclohexan-1-yl) -2 H -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 (400 MHz, DMSO-d ₆ ) δ (ppm): 1.96-2.12 (3H, m), 2.22-2.30 (3H, m), 2.48-2.51 (1H, m), 3.27-3.31 (2H, m), 5.42 (1H, s), 7.26 (1H, s), 7.38-7.46 (1H, m), 7.57-7.61 (1H, m), 7.88-7.95 (1H, m), 9.76 (1H, brs) , 12.16 (1 H, br).

Example 60

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (2-oxocyclopentan-1-yl) -2 H -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 (400 MHz, DMSO-d ₆ ) δ (ppm): 1.60-1.63 (2H, m), 1.86-2.05 (2H, m), 2.31-2.34 (2H, m), 3.43-3.46 (1H, m), 5.47 (1H, s), 7.25 and 7.30 (1H, s), 7.39-7.46 (1H, m), 7.56-7.60 (1H, m), 7.91-7.94 (1H, m), 9.90 (1H, brs), 12.20 (1 H, brs).

Example 61

6-acetylmethyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -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 ^o C.

MS (FAB): 321 (M ⁺ +1).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.22 (3H, s), 3.63-3.66 (2H, m), 5.48 (1H, s), 7.30 (1H, s), 7.47 (1H , d, J = 6.6 Hz, 7.61 (1 H, dd, J = 9.0 Hz and 6.6 Hz), 7.94 (1 H, d, J = 9.0 Hz), 10.00 (1 H, brs), 12.21 (1 H, brs).

Example 62

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro) -6- (2-oxocyclohexan-1-yl) -2 H -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 ^o C.

MS (EI): 422 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.72-1.81 (5H, m), 2.59-2.65 (3H, m), 3.30-3.32 (1H, m), 5.91 (1H, s) , 7.05 (1H, d, J = 7.3 Hz), 7.40-7.43 (2H, m), 7.52 (1H, s), 7.74 (1H, d, J = 7.3 Hz), 9.33 (1H, brs), 12.24 ( 1H, brs).

Example 63

6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -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 ^o C.

MS (EI): 382 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.70 (1H, d, J = 7.3 Hz), 7.83 (1H, d, J = 7.3 Hz), 9.97 (1H, brs), 12.29 (1H, brs).

Example 64

4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (1- t -butoxycarbonylpiperidin-4-yl) -2 H -pyrazolo [3,4 b ] pyridine (2.0 g) was added to 4N-HCl dioxane solution (20 mL) at 0 ° C. and the mixture was stirred for one hour. The solvent was evaporated under reduced pressure, the residue was washed with ethanol and the precipitated crystals were collected by filtration to give the title compound (1.2 g) as yellow crystals.

MS (EI): 339 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.83-1.90 (2H, m), 2.07-2.15 (2H, m), 2.94-2.97 (3H, m), 3.34-3.37 (2H, m), 5.36 (1H, s), 7.22-7.33 (4H, m), 7.42 (1H, d, J = 7.3 Hz), 8.41 (1H, br), 9.17 (1H, br), 9.77 (1H, brs ), 12.27 (1 H, brs).

Example 65

4- (2-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MP:> 270 ^o C.

Calcd for C ₁₈ H ₁₇ N ₇ OHCl: C, 56.09; H, 5.20; N, 24.10.

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

MS (EI): 347 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.82-1.85 (2H, m), 2.14-2.20 (2H, m), 2.93-2.99 (3H, m), 3.34-3.36 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J = 6.6 Hz), 7.58 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 8.44 (1 H, br), 9.21 (1 H, br), 9.87 (1 H, brs), 12.25 (1 H, brs).

Example 66

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MP:> 270 ^o C.

MS (EI): 409 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.92 (2H, m), 2.07-2.10 (2H, m), 2.92-2.98 (5H, m), 5.48 (1H, s) , 7.34 (1H, s), 7.57-7.59 (2H, m), 7.84 (1H, dd, J = 7.3 Hz and 7.2 Hz), 8.30 (1H, br), 9.04 (1H, br), 9.90 (1H, brs), 12.35 (1 H, br).

Example 67

4- (2-Bromo-3-cyanophenyl) -5-cyano-6- (1- t -Butoxycarbonylpyrrolidin-2-yl) -4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 495 (M ⁺ ).

¹ H-NMR (400 MHz, 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 (1 H, s), 7.51-7.91 (4 H, m), 9.83 (1 H, m), 12.26 (1 H, s).

Example 68

4- (2-Bromo-3-cyanophenyl) -5-cyano-6- (pyrrolidin-2-yl) -4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 240 ^o C.

MS (EI): 395 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39-1.55 (1H, m), 1.97 (2H, m), 2.30 (1H, m), 3.32 (2H, m), 4.10-4.28 (1H, m), 5.41 (1H, s), 6.52 (1H, s), 7.34-7.47 (2H, m), 7.70 (1H, dd, J = 8.3 Hz and 9.0 Hz), 11.89 (1 H, brs) .

Example 69

4- (2,1,3-benzoxadiazol-4-yl) -6- (1- t -Butoxycarbonylpyrrolidin-2-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, titled from ethyl 1- t -butoxycarbonylpyrrolidine-2-carboxylate, 2,1,3-benzoxadiazol-4-benzaldehyde and 3-aminopyrazole The compound was prepared.

MS (EI): 433 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.40 (9H, s), 1.78-1.89 (4H, m), 2.11-2.31 (1H, m), 3.72 (1H, m), 4.53 (1H, m), 5.40 (1H, s), 7.26 (1H, s), 7.30-7.40 (1H, m), 7.58 (1H, dd, J = 6.4 Hz and 9.6 Hz), 7.91 (1H, d, J = 9.6 Hz), 9.86 (1 H, s), 12.16 (1 H, s).

Example 70

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (pyrrolidin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 240 ^o C.

MS (EI): 333 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41-1.46 (1H, m), 1.97-2.14 (4H, m), 3.72 (1H, m), 4.11-4.32 (1H, m) , 5.52 (1H, s), 7.00 (1H, s), 7.26 (1H, s), 7.30-7.42 (1H, m), 7.58 (1H, dd, J = 6.4 Hz and 9.6 Hz), 7.91 (1H, d, J = 9.3 Hz), 11.87 (1H, s).

Example 71

6- (1- t -Butoxycarbonylpyrrolidin-2-yl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.6 Hz), 9.68 (1H, s), 12.17 (1H, s).

Example 72

6- (1- t -Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 449 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39 (1H, m), 1.97-2.13 (2H, m), 2.00 (2H, m), 2.78-3.15 (2H, m), 3.31 (1H, m), 3.96 (2H, s), 5.03 (1H, d, J = 9.5 Hz), 6.00-6.02 (1H, m), 6.64 (1H, d, J = 2.9 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 390 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.27-1.88 (5H, m), 2.49-2.96 (5H, m), 5.02 (1H, s), 6.00-6.02 (2H, m) , 6.66 (1H, m), 6.76 (2H, m), 7.27 (1H, s), 9.98 (1H, s), 12.14 (1H, s).

Example 74

4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine-6-carboxylic acid phenylamide

In the same manner as in Example 1, the title compound was prepared from N -phenyloxamic acid ethyl ester, 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 = 8.3Hz), 10.4 (1H, s), 10.76 (1H, s), 12.3 (1H, s).

Example 75

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine-6-carboxylic acid phenylamide

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

MS (EI): 383 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 5.59 (1H, s), 7.11-7.15 (1H, dd, J = 7.3 Hz and 7.6 Hz), 7.33-7.36 (3H, m), 7.51 (1H, d, J = 6.6Hz), 7.63-7.68 (3H, m), 7.96 (1H, d, J = 9.0Hz), 10.52 (1H, s), 10.76 (1H, s), 12.3 (1H , s).

Example 76

4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- [4- (naphthalen-1-yl) piperazin-1-yl] methyl-2 H -Pyrazolo [3,4- b ] Pyridine Trihydrochloride

In the same manner as in Example 1, 4- (2-chlorophenyl) -5-cyano-6- ( t -butyldimethyl from ethyl t -butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole Silyloxy) methyl-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine was prepared. 4- (2-Chlorophenyl) -5-cyano-6- ( t -butyldimethylsilyloxy) methyl-4,7-dihydro-2 H -pyrazolo [3,4- in tetrahydrofuran (200 mL) b ] To a solution of pyridine (20 g) was added a THF solution (49.9 mL) of 1.0 M tetrabutylammonium fluoride 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 solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue obtained was crystallized from ethyl acetate to give triphenylphosphine (12.2 g) in methylene chloride (100 mL) under ice cooling to 4- (2-chlorophenyl) -5- in methylene chloride (340 mL). To a solution of cyano-6-hydroxymethyl-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine (12.7 g) and carbon tetrabromide (15.4 g), add the mixture to room temperature Stirred for 13 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethylacetate (1: 1)) to give 4- (2-chlorophenyl) -5-cyano-6- Bromomethyl-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine (3.84 g) was obtained as a pale yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mL) was added 1- (naphthalen-1-yl) piperazine (334 mg) and the mixture was stirred under ice cooling for 30 minutes. In this reaction mixture, a 4- (2-chlorophenyl) -5-cyano-6-bromomethyl-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine (500 mg) solution was ice-cooled. Was added 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 solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate-methanol (1: 1)). The oil obtained 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 (400 MHz, DMSO-d ₆ ) δ (ppm): 3.31-3.70 (8H, m), 4.33 (2H, m), 4.85 (3H, m), 5.54 (1H, s), 7.19 (1H , d, J = 7.3 Hz, 7.29-7.54 (8H, m), 7.67 (1H, d, J = 8.1 Hz), 7.92 (1H, d, J = 7.1 Hz), 8.15 (1H, d, J = 7.3 Hz), 10.35 (1H, s), 11.28 (1H, brs).

Example 77

4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (4-methylhomopiperazin-1-yl) methyl-2 H -Pyrazolo [3,4- b ] Pyridine Dihydrochloride

In the same manner as in Example 76, 4- (2-chlorophenyl) -5-cyano-6-bromomethyl-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine and The title compound was obtained from N -methyl homopiperazine.

MP: 204-206 ° C (decomposition)

MS (EI): 382 (M ⁺ ).

¹ H-NMR (400 MHz, 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-2 H -Pyrazolo [3,4- b ] Pyridine Trihydrochloride

In the same manner as in Example 76, 4- (2-chlorophenyl) -5-cyano-6-bromomethyl-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine and The title compound was obtained from 1-phenylpiperazine.

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 = 8.0 Hz), 7.24-7.39 (6H, m), 7.45 (1H, d, J = 9.9 Hz), 9.50 (1H, brs), 10.37 (1H, s), 11.40 (1H, brs).

Example 79

4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6-phthalimidomethyl-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 250 ℃

MS (EI): 416 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4.66 (2H, d, J = 2.4 Hz), 5.40 (1H, s), 7.24-7.45 (5H, m), 7.82-7.94 (4H m), 10.04 (1 H, s), 12.23 (1 H, s).

Example 80

6-acetyl-4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, 4- (2-chlorophenyl) -5-cyano-4,7-di from methyl 2,2-dimethoxypropionate, 2-chlorobenzaldehyde and 3-aminopyrazole Hydro-6- (1,1-dimethoxyethyl) -2 H -pyrazolo [3,4- b ] pyridine was prepared. 4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (1,1-dimethoxyethyl) -2 H -pyrazolo [3,4- b in dichloromethane (10 mL) To the pyridine (1.0 g) solution trifluoroacetic acid (10 mL) was added under ice cooling and the mixture was stirred for 1 hour under ice cooling. The solvent was evaporated and the residue obtained 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 (400 MHz, DMSO-d ₆ ) δ (ppm): 2.56 (3H, s), 5.49 (1H, s), 7.25-7.36 (4H, m), 7.45 (1H, d, J = 7.8 Hz ), 10.12 (1H, s), 12.50 (1H, brs).

Example 81

6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 230 ° C

MS (EI): 368 (M ⁺ ).

¹ H-NMR (400 MHz, 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-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, the title compound was prepared from 2,1,3-benzoxadiazol-4-aldehyde, 3-aminopyrazolo 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 = 6.6 Hz), 7.61 (1H, dd, J = 6.6 Hz and 8.6 Hz), 7.96 (1H, d, J = 9.2 Hz), 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-2 H -Pyrazolo [3,4- b ] Pyridine

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

MP:> 230 ° C

Calcd for C ₂₄ H ₂₀ ClN ₅ O: C, 67.05; H, 4.69; N, 16.29.

Found: C, 66.86; H, 4.56; N, 16.31.

MS (EI): 429 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.60 (1H, dd, J = 9.5 Hz and 16.4 Hz), 2.81 (1H, dd, J = 10.5 Hz and 16.4 Hz), 3.39 (1H m, 3.47 (1 H, m), 4.42 (2 H, m), 5.36 (1 H, s), 7.23-7.43 (10 H, m), 10.04 (1 H, s), 12.21 (1 H, s).

Example 84

4- (2-Bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2 H -Pyrazolo [3,4- b ] Pyridine

N- BuLi (113 mmol) was added at −40 ° C. to a 2-picolin (10 g) solution in THF (75 mL). In addition, methyl butanoate (15.8 mL) was added, the mixture was stirred for 1 hour, and the mixture was quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give 2- (2-oxopentanyl) pyridine (4.8 g) as a yellow oil. It was. 2-bromo-3-cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2- (2-oxopentanyl) pyridine (1.2 g) and ammonium acetate (0.6 in acetic acid (7 mL) g) The solution was heated at reflux for 11 hours. The reaction mixture is cooled to room temperature, the solvent is evaporated under reduced pressure, the residue is purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) and the residue obtained is ethyl acetate Crystallization from gave colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in chloroform (5 mL) was added phosphorus oxychloride (805 mg) and the obtained crystal (520 mg) solution 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 one hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give an oil. The oil obtained was purified by silica gel column chromatography (eluent: chloroform-methanol (9: 1)) to give a yellow solid (530 mg). To the obtained solid solution in pyridine (10 mL) was added hydrazine (120 mg) and the mixture was stirred with heating for 4 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give 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 solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue obtained was crystallized from ethyl acetate to give the title compound (145 mg) as pale yellow crystals.

MP: 205-208 ° C. (decomposition)

Calcd for C ₂₁ H ₁₈ BrN ₅ : C, 60.01; H, 4.32; N, 16.66.

Found: C, 59.83; H, 4.42; N, 16.26.

MS (EI): 420 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.83 (3H, t, J = 7.6 Hz), 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 = 3.6 Hz), 8.52 (1H, s), 11.84 (1H, s).

Example 85

6- (1- tert -Butoxycarbonylpyrrolidin-3-yl) -4- (2-chloro-phenyl) -5-cyano-4,7-dihydro-2 H -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 in THF (84 mL) under ice cooling, and the mixture was stirred for 1 hour. It was refluxed. Excess borane and boron complexes were decomposed by adding 30 mL of methanol-based hydrogen chloride dropwise and refluxing for 1 hour. After the solvent was removed under reduced pressure, additional 30 mL of methanol-based hydrogen chloride was added and the mixture was further refluxed for 1 hour. After the solvent was removed again in vacuo, the residue was treated with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue obtained was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) and methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 g) was added. Obtained as a pale 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 added. It was refluxed for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol (9: 1)) to give methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) is added dimethylaminopyridine (161 mg) and di- tert -butyldicarbonate (3.4 g) at 0 ° C. and the mixture Was stirred for 13 hours. The mixture was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1)), methyl 1- tert -butoxycarbonyl-3-pyrrolidinecar Cyclate (2.6 g) was obtained as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added n- BuLi (12.4 mmol) at -78 ° C. In addition, methyl 1- tert -butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was 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: hexane-ethyl acetate (2: 1)) to give 1- (1- tert -butoxycarbonylpyrrolidin-3-yl ) -2-cyanoethan-1-one (2.35 g) was obtained as a colorless oil. 2-chlorophenylaldehyde (1.4 g), 3-aminopyrazole (819 mg) and 1- (1- tert -butoxy-carbonylpyrrolidin-3-yl) -2- in acetonitrile (10 mL) The cyanoethan-1-one (2.35 g) solution was heated at reflux for 1.5 h. The reaction mixture was cooled to room temperature and the crystals precipitated by filtration to give the title compound (2.18 g) as colorless crystals.

Calcd for C ₂₂ H ₂₄ ClN ₅ O ₂ : C, 62.04; H, 5.68; N, 16.44.

Found: C, 61.94; H, 5.69; N, 16.45.

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 8.3 Hz), 9.78 (1H, s), 12.20 (1H, s).

Example 86

4- (2-Chlorophenyl) -5-cyano-4,7-dihydro-6- (pyrrolidin-3-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

6- (1- tert -butoxycarbonylpyrrolidin-3-yl) -4- (2-chloro-phenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3, 4- b ] -pyridine (706 mg) was added to 4N-HCl dioxane solution (5 mL) at room temperature and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue was washed with ethanol-ethyl acetate and then the precipitated crystals were collected by filtration to give the title compound (460 mg) as colorless crystals.

MP: 210-215 ℃ (decomposition)

MS (EI): 325 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 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-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 84, the title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, Meldrum acid, 2- (2-oxopentanyl) pyridine and ammonium acetate.

MS (EI): 358 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 7.3 Hz), 1.64 (2H, m), 2.27 (1H, m), 2.35 (1H, m), 5.96 (1H, s), 6.95 (1H, m), 7.11-7.18 (3H, m), 7.40 (1H, m), 7.51 (1H, m), 7.69 (1H, d, J = 9.3Hz), 8.35 (1H, m), 8.54 (1H, s), 11.78 (1H, brs).

Example 88

6- (1- t b-butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (indan-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 445 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.56-1.59 (2H, m), 1.88-1.06 (4H, m), 2.58-2.83 (7H, m) , 4.06 (2H, m), 4.96 (1H, s), 6.90 (1H, m), 7.04-7.07 (2H, m), 7.14 (1H, s), 9.55 (1H, s), 12.08 (1H, s ).

Example 89

6- (1- t -Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (2,3-dihydrobenzo [ b Furan-7-day) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 445 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42 (9H, s), 1.57-1.66 (2H, m), 1.88 (4H, m), 2.73-2.90 (3H, m), 3.17 (2H, m), 4.09 (2H, m), 4.54 (2H, m), 5.01 (1H, s), 6.76 (1H, m), 6.84 (1H, d, J = 7.1 Hz), 7.05 (1H, d, J = 6.6 Hz), 7.22 (1H, s), 9.52 (1H, s), 12.06 (1H, s).

Example 90

6- (1- t -Butoxycarbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (3,4-dihydro-2 H -Benzopyran-8-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, the title compound was prepared from ethyl isonipekotate, 8- (3,4-dihydro-2 H -benzopyran) carboxaldehyde and 3-amino-pyrazole.

MS (EI): 461 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42 (9H, s), 1.58-1.69 (2H, m), 1.80-2.00 (4H, m), 2.73-2.95 (5H, m) , 4.09 (2H, m), 4.22 (2H, m), 5.14 (1H, s), 6.74 (1H, m), 6.84-6.89 (2H, m), 7.21 (1H, s), 9.48 (1H, s ), 12.03 (1H, s).

Example 91

6- (1- t -Butoxycarbonylpiperidin-4-yl) -4- (2-chloro-3-trifluoromethylphenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 461 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.41 (9H, s), 1.62 (2H, m), 1.89 (2H, m), 2.60-2.90 (3H, m), 4.10 (2H , m), 5.54 (1H, s), 7.32 (1H, s), 7.52-7.56 (2H, m), 7.75 (1H, d, J = 9.3Hz), 9.79 (1H, s), 12.25 (1H, s).

Example 92

5-cyano-4,7-dihydro-4- (3,4-dihydro-2 H -Benzopyran-8-yl) -6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

In the same manner as in Example 2, 6- (1- t -butoxy-carbonylpiperidin-4-yl) -5-cyano-4,7-dihydro-4- (3,4-di The title compound was prepared from hydro-2 H -benzopyran-8-yl) -2 H -pyrazolo [3,4- b ] pyridine.

MS (EI): 361 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.83-1.98 (4H, m), 2.14 (2H, m), 2.74 (2H, m), 2.90-3.00 (3H, m), 4.22 (2H, m), 3.40-3.70 (5H, m), 4.16-4.27 (2H, m), 5.15 (1H, s), 6.74 (1H, m), 6.83-6.89 (2H, m), 7.22 (1H) , s), 9.54 (1 H, s).

Example 93

5-cyano-4,7-dihydro-4- (indan-4-yl) -6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 345 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.80-1.99 (4H, m), 2.14 (2H, m), 2.58 (1H, m), 2.82-2.95 (6H, m), 3.30 -3.50 (2H, m), 4.97 (1H, s), 6.90 (1H, m), 7.04-7.09 (2H, m), 7.17 (1H, s), 8.37 (1H, m), 9.10 (1H, m ), 9.62 (1 H, s), 12.18 (1 H, brs).

Example 94

5-cyano-4,7-dihydro-4- (indan-4-yl) -6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.56 (2H, m), 1.84-1.98 (6H, m), 2.15 (2H, m), 2.58 (1H, m), 2.80-3.00 (6H, m), 3.20-3.40 (2H, m), 4.95 (1H, s), 6.90 (1H, m), 7.05-7.07 (2H, m), 7.14 (1H, s), 9.54 (1H, brs ), 12.10 (1 H, brs).

Example 95

5-cyano-4,7-dihydro-4- (3,4-dihydro-2 H -Benzopyran-8-yl) -6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

Carried out in the same manner as in Example 3, 5-Cyano-4,7-dihydro-4- (3,4-dihydro -2 H - benzopyran-8-yl) -6- (piperidin-4 -yl) -2 H - pyrazolo [3,4- b] pyridine the title compound was prepared from the hydrochloride.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.90-2.00 (4H, m), 2.24 (2H, m), 2.73-2.75 (5H, m), 2.94-3.08 (3H, m) , 3.40-3.48 (2H, m), 4.17-4.27 (2H, m), 5.15 (1H, s), 6.74 (1H, m), 6.84-6.89 (2H, m), 7.22 (1H, s), 9.58 (1H, s), 9.80 (1H, m), 12.15 (1H, s).

Example 96

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methanesulfonylpiperidin-2-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 425 (M ⁺ ).

¹ H-NMR (400 MHz, 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) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 361 (M ⁺ ).

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

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

MS (EI): 371 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.46 (3H, s), 5.42 (1H, s), 6.34 (1H, d, J = 7.2 Hz), 6.56 (1H, s), 7.33 (1H, s), 7.52 (1H, d, J = 7.2 Hz), 7.61 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.80 (1H, d, J = 6.6 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

In the same manner as in Examples 1 and 2, 1,2,3,4-tetrahydropyridine-3-carboxylic acid ethyl ester, 2,1,3-benzoxadiazol-4-aldehyde and 3-aminopyra The title compound was prepared from the sol.

MS (EI): 345 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 6.6 Hz), 7.56 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.94 (1H, doublet, 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-tetrahydropyridine- 3-day) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 359 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 6.6 Hz), 7.59 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.92 (1H, d, J = 9.0 Hz), 9.87 (1 H, brs), 12.16 (1 H, brs).

Example 101

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1- (methylamino) ethyl) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 321 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.56 (3H, d, J = 6.8 Hz), 3.07 (3H, s), 4.59-4.68 (3H, m), 5.66 (1H, s ), 7.29 (1H, d, J = 6.6 Hz), 7.44 (1H, s), 7.52 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.87 (1H, d, J = 9.0 Hz), 8.22 ( 1H, br), 8.44 (1H, br), 10.95 (1H, brs).

Example 102

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl )-2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, 1,2-dihydro-1-methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole The title compound was prepared from.

MS (EI): 433 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.46 (3H, s), 5.35 (1H, s), 6.37 (1H, d, J = 7.2 Hz), 6.61 (1H, s), 7.38 (1H, s), 7.60 (1H, dd, J = 7.3 Hz and 7.2 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 15 and 2, the title compound was prepared from 4-aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole.

MS (EI): 436 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz ), 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) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 1 and 2, the title compound from 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole Was prepared.

MS (EI): 407 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.84 (1H, d, J = 7.3 Hz) 7.86 (1H, d, J = 7.3 Hz), 9.32 (2H, br), 10.03 (1H, brs).

Example 105

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4- (dimethylamino) cyclohexyl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 450 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 420 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 9.87 (1H, brs), 12.26 (1H, broad singlet).

Example 107

6- (exo-2-azabicyclo [2,2,2] octan-6-yl) -4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7 -Dihydro-2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 1 and 2, exo-2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3 The title compound was prepared from aminopyrazole.

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.53-1.55 (1H, m), 1.75-1.77 (1H, m), 1.89-2.06 (4H, m), 2.21-2.23 (1H, m), 3.07-3.10 (2H, m), 3.43-3.48 (4H, m), 5.39-5.43 (1H, s), 7.26-7.28 (1H, m), 7.44-7.47 (1H, m), 7.57- 7.61 (1 H, m), 7.93-7.95 (1 H, m), 8.87-9.03 (1 H, br), 9.46-9.52 (1 H, br), 9.73 and 9.80 (1 H, 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- 2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 1 and 2, endo-2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3 The title compound was prepared from aminopyrazole.

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400 MHz, 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 (1 H, br), 9.89 (1 H, br).

Example 109

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- ( Exo -2-methyl-2-azabicyclo [2,2,2] octane-6-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.43-1.44 (1H, m), 1.70-1.90 (5H, m), 2.11-2.13 (1H, m), 2.38-2.46 (4H, m), 3.00-3.02 (1H, m), 3.32-3.36 (2H, m), 5.38 and 5.40 (1H, s), 7.25-7.27 (1H, m), 7.38-7.42 (1H, m), 7.56- 7.61 (1 H, m), 7.90-7.93 (1 H, m), 9.73 (1 H, br), 12.23 (1 H, br).

Example 110

Ethyl 4- (2,1,3-benzoxadiazol-4-yl) -4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine-5-carboxylate 2 hydrobromide

2,1,3-benzoxadiazole-4-aldehyde (3.0 g) in acetic acid (20 mL), Meldrum acid (3.0 g), ethyl 3-keto-3- (1-benzylcarbonylpiperidine-4 -Yl) propionate (6.8 g) and ammonium acetate (1.8 g) solution were stirred under reflux for 12 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give colorless crystals (4.7 g). To a solution of dimethylformamide (2.7 g) in chloroform (10 mL) was added a solution of phosphorus oxychloride (3.4 mL) and colorless crystals (4.7 g) obtained 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 1 hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The oil thus obtained was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to thereby give colorless crystals. To a colorless crystal solution in pyridine (20 mL) was added hydrazine (1.4 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (840 mg) as colorless crystals. To the colorless crystal solution obtained in acetic acid (10 mL) was added HBr-AcOH solution (10 mL) and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure to give colorless crystals. The crystals were purified by recrystallization from EtOH to give the title compound (630 mg) as colorless crystals.

MS (EI): 394 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.77 (3H, t, J = 7.3 Hz), 1.80-2.16 (4H, m), 2.90-2.93 (2H, m), 3.40-3.43 (2H, m), 3.80 (2H, q, J = 7.3 Hz), 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 = 9.0 Hz and 6.6 Hz), 7.79 (1H, d, J = 9.0 Hz), 8.10 (1H, br), 8.74 (1H, br) , 9.38 (1H, broad singlet).

Example 111

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- ( Endo -2-methyl-2-azabicyclo [2,2,2] octan-6-yl) -2H-pyrazolo [3,4- b ] Pyridine

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

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.43-1.47 (2H, m), 1.60-1.64 (2H, m), 1.81-1.82 (1H, m), 1.79-2.06 (2H, m), 2.24-2.26 (1H, m), 2.36 (3H, s), 2.76-2.80 (2H, m), 3.19-3.22 (1H, m), 5.43 (1H, s), 7.25 (1H, s) , 7.42-7.46 (1H, m), 7.57-7.60 (1H, m), 7.90-7.94 (1H, m), 10.79 (1H, brs), 12.16 (1H, brs).

Example 112

Ethyl 4- (2,1,3-benzoxadiazol-4-yl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine-5-carboxylate 2 hydrochloride

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

MS (EI): 408 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.75 (3H, t, J = 7.3 Hz), 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 = 7.3 Hz), 3.93-3.96 (1H, m), 5.68 (1H, s), 7.12 (1H, d, J = 6.6 Hz), 7.22 (1H, s), 7.49 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.77 (1H, d, J = 9.0 Hz), 9.32 (1H, brs), 12.06 (1H, broad singlet).

Example 113

4- (2-Bromophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 383 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.85-1.93 (2H, m), 2.14-2.20 (2H, m), 2.94-2.98 (2H, m), 3.32-3.36 (3H, m), 5.36 (1H, s), 7.16 (1H, dd, J = 7.3 Hz and 7.2 Hz), 7.23-7.27 (2H, m), 7.35 (1H, dd, J = 7.3 Hz and 7.2 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 335 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 6.99 (1H, d, J = 7.3 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.90 (2H, m), 2.16-2.20 (2H, m), 2.94-3.00 (3H, m), 3.32-3.38 (2H, m), 5.44 (1H, s), 7.24-7.36 (3H, m), 7.56 (1H, d, J = 7.3 Hz), 8.52 (1H, br), 9.24 (1H, br), 9.79 (1H, brs ), 12.29 (1H, broad singlet).

Example 116

4- (2-Bromophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 397 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.60 (1 H, d, J = 7.3 Hz), 9.60 (1 H, brs), 12.16 (1 H, brs).

Example 117

5-cyano-4,7-dihydro-4- (2-methoxyphenyl) -6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 349 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 6.98 ( 1H, d, J = 7.3 Hz, 7.05 (1H, d, J = 7.3 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 7.29 (1H, s), 7.35 (1H, dd , J = 7.3 Hz and 7.2 Hz), 7.51 (1H, d, J = 7.3 Hz), 9.65 (1H, brs), 12.18 (1H, brs).

Example 119

5-cyano-4,7-dihydro-4- (2-fluorophenyl) -6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 323 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.85-1.89 (2H, m), 2.12-2.20 (2H, m), 2.90-2.98 (3H, m), 3.33-3.39 (2H, m), 5.20 (1H, s), 7.14-7.28 (5H, m), 8.37 (1H, br), 9.09 (1H, br), 9.66 (1H, brs), 12.23 (1H, brs).

Example 120

5-cyano-4- (2,3-difluorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 341 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.88 (2H, m), 2.14-2.19 (2H, m), 2.95-3.00 (3H, m), 3.33-3.38 (2H, m), 5.26 (1H, s), 7.03 (1H, d, J = 7.3 Hz), 7.18 (1H, dd, J = 7.3 Hz and 7.2 Hz), 7.26-7.31 (2H, m), 8.80 (2H, br), 9.74 (1 H, brs), 12.29 (1 H, brs).

Example 121

5-cyano-4- (2,6-difluorophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 341 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.76-1.84 (2H, m), 2.13-2.18 (2H, m), 2.91-2.95 (3H, m), 3.28-3.30 (2H, m), 5.35 (1H, s), 7.02-7.07 (2H, m), 7.31-7.38 (2H, m), 8.77 (2H, br), 9.68 (1H, brs), 12.22 (1H, brs).

Example 122

5-cyano-4,7-dihydro-4- (2-methylthiophenyl) -6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 351 (M ⁺ ).

¹ H-NMR (400 MHz, 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) -2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.38 (1H, d, J = 7.3 Hz), 7.51 (1H, d, J = 7.3 Hz), 8.41 (1 H, br), 9.16 (1 H, br), 9.73 (1 H, brs), 12.18 (1 H, brs).

Example 124

5-cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (2-trifluoromethylphenyl) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 373 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.83-1.90 (2H, m), 2.18-2.26 (2H, m), 2.92-3.00 (3H, m), 3.38-3.43 (2H, m), 4.16 (2H, br), 5.22 (1H, s), 7.06 (1H, s), 7.42-7.44 (2H, m), 7.63-7.69 (2H, m), 8.57 (1H, br), 9.30 (1 H, br), 9.77 (1 H, br).

Example 125

5-cyano-4,7-dihydro-4- (2-fluorophenyl) -6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 337 (M ⁺ ).

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

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

MS (EI): 355 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.55-1.59 (2H, m), 1.82-1.8 (2H, m), 1.99-2.02 (2H, m), 2.15 (3H, s) , 2.57-2.60 (1H, m), 2.84-2.88 (2H, m), 5.23 (1H, s), 7.00 (1H, dd, J = 7.3 Hz and 7.2 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 355 (M ⁺ ).

¹ H-NMR (400 MHz, 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, broad singlet).

Example 128

5-cyano-4,7-dihydro-4- (2-nitrophenyl) -6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 351 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.84-1.93 (2H, m), 2.17-2.23 (2H, m), 2.94-3.00 (3H, m), 3.35-3.38 (2H, m), 4.42 (2H, br), 5.40 (1H, s), 7.30 (1H, s), 7.46-7.51 (2H, m), 7.71 (1H, dd, J = 7.3 Hz and 7.2 Hz), 7.90 ( 1 H, d, J = 7.3 Hz, 8.61 (1 H, br), 9.36 (1 H, br), 9.87 (1 H, brs).

Example 129

5-cyano-4,7-dihydro-4-phenyl-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 305 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.81-1.89 (2H, m), 2.14-2.20 (2H, m), 2.90-2.96 (3H, m), 3.32-3.35 (2H, m), 4.20 (2H, br), 4.89 (1H, s), 7.17-7.22 (4H, m), 7.28-7.31 (2H, m), 8.58 (1H, br), 9.32 (1H, br), 9.65 (1H, brs).

Example 130

5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (2-methylthiophenyl)- 2H- Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 366 (M ⁺ ).

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

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

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.36 ( 1 H, d, J = 7.3 Hz, 7.48 (1 H, d, J = 7.3 Hz), 9.67 (1 H, brs), 12.12 (1 H, brs).

Example 132

5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (2-trifluoromethylphenyl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 387 (M ⁺ ).

¹ H-NMR (400 MHz, 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 (1 H, brs), 12.23 (1 H, brs).

Example 133

5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (2-nitrophenyl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 365 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.88 (1H, d, J = 7.3 Hz), 9.72 (1H, brs), 12.26 (1H, brs).

Example 134

5-cyano-4,7-dihydro-4-phenyl-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 319 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.54-1.57 (2H, m), 1.81-1.87 (2H, m), 1.97-2.03 (2H, m), 2.15 (3H, s) , 2.58-2.60 (1H, m), 2.84-2.86 (2H, m), 4.87 (1H, s), 7.17-7.20 (4H, m), 7.27-7.32 (2H, m), 9.52 (1H, brs) , 12.13 (1H, broad singlet).

Example 135

5-cyano-4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6-propyl-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 322 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.93 (3H, t, J = 7.3 Hz), 1.63-1.68 (2H, m), 2.34-2.45 (2H, m), 5.16 (1H) , s), 7.02 (1H, d, J = 7.3 Hz), 7.18 (1H, dd, J = 7.3 Hz and 7.2 Hz), 7.28 (1H, d, J = 7.2 Hz), 9.88 (1H, brs), 12.22 (1 H, broad singlet).

Example 136

4- (2,1,3-benzothiadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 363 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.89-1.98 (2H, m), 2.22-2.29 (2H, m), 2.98-3.05 (3H, m), 3.37-3.43 (2H, m), 5.20 (2H, br), 5.72 (1H, s), 7.24 (1H, s), 7.48 (1H, d, J = 6.6 Hz), 7.72 (1H, dd, J = 9.0 Hz and 6.6 Hz) , 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) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 1 and 2, the title compound was prepared from ethyl nifekotate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole.

MS (EI): 385 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 7.19 (1H, dd, J = 7.3 Hz and 7.2 Hz), 7.29 (1H, d, J = 7.3 Hz), 7.33 (1 H, s), 8.65 (1 H, br), 9.43 (1 H, br), 9.86 (1 H, brs).

Example 138

4- (2,1,3-benzothiadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 377 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 6.6 Hz), 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-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 399 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 7.17 (1H, dd, J = 7.3 Hz 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) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

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

MS (EI): 330 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.82 ( 1 H, d, J = 7.3 Hz, 8.61 (1 H, br), 9.41 (1 H, br), 9.93 (1 H, brs).

Example 141

5-cyano-4- (2-cyanophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 344 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz and 7.2 Hz), 7.81 (1H, d, J = 7.3 Hz), 9.77 (1H, brs), 12.26 (1H, brs).

Example 142

5-cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (pyridin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine 3 Hydrochloride

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

MS (EI): 306 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.92 (2H, m), 2.18-2.25 (2H, m), 2.93-3.00 (3H, m), 3.35-3.38 (2H, m), 5.41 (1H, s), 6.50 (3H, br), 7.42 (1H, s), 7.97 (2H, d, J = 6.8 Hz), 8.90 (1H, br), 8.93 (2H, d, J = 6.8 Hz), 9.60 (1 H, br), 10.10 (1 H, brs).

Example 143

5-cyano-4,7-dihydro-6- (piperidin-4-yl) -4- (pyridin-3-yl) -2 H -Pyrazolo [3,4- b ] Pyridine 3 Hydrochloride

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

MS (EI): 306 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.86-1.93 (2H, m), 2.19-2.25 (2H, m), 2.90-2.97 (3H, m), 3.35-3.38 (2H, m), 5.39 (1H, s), 6.50 (3H, br), 7.41 (1H, s), 8.09 (1H, dd, J = 8.2 Hz and 5.4 Hz), 8.49 (1H, d, J = 8.2 Hz) , 8.72 (1H, br), 8.88 (1H, d, J = 5.4 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 320 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 6.8 Hz), 7.31 (1H, s), 8.50 (2H, d , J = 6.8 Hz), 9.67 (1 H, brs), 12.25 (1 H, brs).

Example 145

5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -4- (pyridin-3-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 320 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 8.2 Hz and 5.4 Hz), 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- ( Exo -2-azabicyclo [2,2,2] octane-6-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 1 and 2, exo -2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole The title compound was prepared from.

MS (EI): 435 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 7.55-7.60 (2H, m), 7.84 (1H, d, J = 7.3 Hz), 8.97 (1 H, br), 9.73 (1 H, br), 9.78 (1 H, brs).

Example 147

6- ( Endo -2-azabicyclo [2,2,2] octane-6-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 1 and 2, endo -2-azabicyclo [2,2,2] octane-6-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole The title compound was prepared from.

MS (EI): 435 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.67-1.69 (3H, m), 2.02-2.12 (4H, m), 3.02-3.05 (1H, m), 3.31-3.35 (1H, m), 3.45-3.51 (2H, m), 4.04 (2H, br), 5.50 (1H, s), 7.34 (1H, s), 7.56 (1H, dd, J = 7.3 Hz and 7.2 Hz), 7.82 ( 1 H, d, J = 7.3 Hz, 8.16 (1 H, br), 9.82 (1 H, br), 9.93 (1 H, brs).

Example 148

4- (2-Bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- ( Exo -2-methyl-2-azabicyclo [2,2,2] octane-6-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 3, 6- ( exo -2-azabicyclo [2,2,2] octan-6-yl) -4- (2-bromo-3-cyanophenyl) -5-sia The title compound was prepared from no-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine 2 hydrochloride.

MS (EI): 449 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.42-1.45 (1H, m), 1.72-1.88 (5H, m), 2.06-2.09 (1H, m), 2.46-2.51 (4H, m), 3.04-3.07 (1H, m), 3.45-3.48 (2H, m), 5.48 (1H, s), 7.34 (1H, s), 7.57-7.60 (2H, m), 7.83 (1H, dd, J = 7.3 Hz and 7.2 Hz), 9.83 (1 H, brs), 12.37 (1 H, brs).

Example 149

Ethyl 4- (2,2-difluoro-1,3-benzodioxol-4-yl) -4,7-dihydro-6-propyl-2 H -Pyrazolo [3,4- b ] Pyridine-5-carboxylate

2,2-difluoro-1,3-benzodioxol-4-aldehyde (2.0 g) in acetic acid (20 mL), Meldrum acid (1.6 g), ethyl 3-keto-hexanoate (1.7 g) and The ammonium acetate (0.91 g) solution was stirred at reflux for 12 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give colorless crystals (2.4 g). To a solution of dimethylformamide (1.9 g) in chloroform (10 mL), a solution of phosphorus oxychloride (4.0 g) and obtained colorless crystals (2.4 g) in chloroform (10 mL) is added under ice cooling and the mixture is stirred overnight It was. Under ice cooling, aqueous sodium acetate (27 g) solution was added and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The oil thus obtained was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to thereby give colorless crystals. To the colorless crystal solution obtained in pyridine (20 mL) was added hydrazine (1.0 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (190 mg) as colorless crystals.

MS (EI): 391 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 5.32 (1H, m), 6.86 (1H, d, J = 7.3 Hz), 7.03-7.11 (2H, m), 7.24 (1H, s), 9.61 (1 H, brs), 12.06 (1 H, brs).

Example 150

Ethyl 4- (2-bromo-3-cyanophenyl) -4,7-dihydro-6- (piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine-5-carboxylate 2 hydrobromide

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 (400 MHz, DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 7.3 Hz), 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 = 7.3 Hz), 3.80-4.25 (3H, m), 5.64 (1H, s), 7.35 (1H, s), 7.40-7.47 (2H, m), 7.70 (1H, doublet, J = 7.3 Hz), 8.10 (1H, br), 8.73 (1H, br), 9.37 (1H, brs).

Example 151

Ethyl 4- (2-bromo-3-cyanophenyl) -4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine-5-carboxylate

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

MS (EI): 469 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.85 (3H, t, J = 7.3 Hz), 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 = 7.3 Hz), 3.94-3.96 (1H, m), 5.63 (1H, s), 7.34-7.48 (3H, m), 7.68 (1H, d, J = 7.3 Hz), 9.34 (1H, brs), 12.16 (1H, brs).

Example 152

4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methyl-2- Oxo -Piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 375 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.88-1.91 (1H, m), 2.26-2.33 (2H, m), 2.65-2.70 (1H, m), 2.82 (3H, m) , 3.17-3.20 (1H, m), 3.31-3.36 (2H, m), 5.40 (1H, s), 7.29 (1H, s), 7.44 (1H, d, J = 6.6 Hz), 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-oxo-piperidin-4-yl) -2 H -Pyrazolo [3,4- b ] Pyridine

In the same manner as in Example 1, the title compound was prepared from 1-methyl- 2 - oxo- piperidine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole. It was.

MS (EI): 437 (M ⁺ ).

¹ H-NMR (400 MHz, 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 = 7.3 Hz), 9.90 (1H, brs ), 12.33 (1H, broad singlet).

Example 154

4- (2-chlorophenyl) -4,7-dihydro-5- (5-methyl-1,3,4-oxadiazol-2-yl) -6-propyl-2 H -Pyrazolo [3,4- b ] Pyridine

A solution of 2-chlorobenzaldehyde (21 g), Meldrum acid (21 g), 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) overnight under reflux Heated. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give colorless crystals (16 g). 1N NaOH solution (100 mL) was added and the mixture was stirred with heating for 3 h. The reaction mixture was cooled to room temperature and the solvent acidified. The reaction mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give colorless crystals (9.6 g). Hydrazine (0.22 g) and CDI (0.66 g) were added to the colorless crystals (1.0 g) obtained in DMF (5 mL), the mixture was stirred for 3 hours, and the precipitated crystals were collected by filtration to give colorless crystals. Obtained (0.7 g). Orthoacetic acid triethyl ester (3.7 g) was added to the colorless crystals (1.0 g) obtained in DMF (5 mL), the mixture was heated for 3 hours, and 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) was added phosphorus oxychloride (1.2 g) and a colorless crystal solution in chloroform (6 mL) under ice cooling and the mixture was stirred overnight. Under ice cooling, an aqueous solution of sodium acetate (7.7 g) was added and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The oil obtained was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to give colorless crystals. To the colorless crystal solution (10 mL) obtained in pyridine was added hydrazine (0.15 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (170 mg) as colorless crystals.

MS (EI): 356 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.00 (3H, t, J = 7.3 Hz), 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) -2 H -Pyrazolo [3,4- b ] Pyridine 2 Hydrochloride

In the same manner as in Examples 15 and 2, the title compound was prepared from 2-methylglycine ethyl ester, 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 = 7.3 Hz), 5.53 (1H, s), 7.48-7.53 (2H, m), 7.64 (1H, s), 7.82 (1H, d, J = 7.3 Hz), 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-2 H -Pyrazolo [3,4- b ] Pyridine

A solution of 2-chlorobenzaldehyde (21 g), Meldrum acid (21 g), 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) overnight at reflux Heated. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give colorless crystals (16 g). 1N NaOH solution (100 mL) was added and the mixture was stirred with heating for 3 h. The reaction mixture was cooled to room temperature and the solvent acidified. The reaction mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give colorless crystals (9.6 g). Ammonia solution (3.0 g) and CDI (2.8 g) were added to the colorless crystals (4.2 g) obtained in DMF (20 mL) and the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give an oil. The residue in N, N-dimethylacetamide dimethyl acetal (30 mL) solution 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 1 hour. The reaction mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give colorless crystals (1.3 g). To a solution of dimethylformamide (1.7 g) in chloroform (20 mL) (10 mL), phosphorus oxychloride (3.5 g) and the colorless crystal solution obtained in chloroform were added under reduced pressure and the mixture was stirred overnight. Under ice cooling, an aqueous solution of sodium acetate (23 g) was added and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The oil obtained was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2)) to give colorless crystals. To the colorless crystal solution obtained in pyridine (15 mL) was added hydrazine (0.6 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1)) to give the title compound (500 mg) as colorless crystals.

MS (EI): 356 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.99 (3H, s), 1.62 (3H, t, J = 7.3 Hz), 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- Profile-2 H -Pyrazolo [3,4- b ] Pyridine

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

MS (EI): 364 (M ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.01 (3H, t, J = 7.3 Hz), 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 = 6.6 Hz), 7.32 (1H, s), 7.48 (1H, dd, J = 9.0 Hz and 6.6 Hz), 7.80 (1H, d , J = 9.0 Hz), 9.65 (1 H, brs), 12.07 (1 H, brs).

Example 158

4- (2-Bromo-3-cyanophenyl) -4,7-dihydro-5- (5-methyl-1,3,4-oxadiazol-2-yl) -6-propyl-2 H -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 (400 MHz, DMSO-d ₆ ) δ (ppm): 1.00 (3H, t, J = 7.3 Hz), 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 Hz and 7.2 Hz), 9.63 (1H, brs), 12.14 (1H, brs).

Example 159

6- (1-amino-1-methylethyl) -4- (2-chlorophenyl) -5-cyano-4,7-dihydro-2 H -Pyrazolo [3,4- b ] Pyridine Hydrochloride

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

Formulation Example 1

The compound of Example 1 (0.5 parts), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were mixed as a whole and kneaded well with a binder (2 parts) made from corn starch. The kneaded product was passed through a 16 mesh sieve, then dried in an oven at 50 ° C. and passed through a 24 mesh sieve. After obtaining the powder so kneaded, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were mixed and compressed punched as a whole to obtain a tablet containing 0.5 mg of the active ingredient per tablet.

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 pyrogen. The filtrate was transferred to ampoules under sterile conditions. After sterilization, the ampoules were hermetically sealed to obtain injections containing 1.0 mg of active ingredient.

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

Experimental Example 1 : GSK-3β-inhibitory activity

CREB phosphopeptide (4.6 nmol), rabbit GSK-3β (0.5 unit), ATP (5 nmol), [g- ³² P] ATP (12.3 kBq) and test compound GSK-3β containing 1% dimethyl sulfoxide The reaction was carried out in a buffer solution (25 µl) (20 mmol / L Tris-HCl (pH 7.5), 10 mmol / L magnesium chloride, 5 mmol / L dithiothritol) at 30 ° C. for 20 minutes. The reaction product (10 μl) was absorbed on P81 ion exchange resin, the ion exchange resin was washed with phosphoric acid (100 mmol / L), and cpm was measured on a scintillation counter. As a result, the compound of the present invention exhibited an IC ₅₀ value of 1 to 1000 nmol / L. For example, the IC ₅₀ values of the compounds are shown in Table 1 below.

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

Example number IC ₅₀ (nmol / L) 2 10 3 2.5 8 3.7 11 14 23 4.1 58 1.8 63 3.0 146 0.61 148 3.2 155 2.2 158 0.65

Experimental Example 2 : GSK-3β-Inhibitory Activity in Neurons of Cultured Hippocampus of Rats

Neurons of hippocampus were obtained from the embryos of rats 18 days after conception. After culturing hippocampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 mmol / L) and test compound (GSK-3β inhibitor) and incubated for 3 hours to phosphorylate Tau protein Induced. After incubation, phosphorylation level of Tau protein was measured by EIA method using phosphorylated Tau-cognitive antibody (phosphorylation site by GSK-3β), and the inhibitory effect of GSK-3β inhibitor on neurons was evaluated.

Experimental Example 3 : Effect of Amyloid β-induced Cell Destruction on Neurons of Cultured Hippocampus of Rats

Neurons of hippocampus were obtained from the embryos of rats 18 days after conception. After culturing hippocampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 mmol / L) and test compound (GSK-3β inhibitor) and incubated for 24 hours (intracellular dehydrogenation). Cell destruction), which reduces the activity of the enzyme. After incubation, intracellular dehydrogenase activity was measured and the effect of GSK-3β inhibitors on GSK-3β induced cell destruction was assessed.

Experimental Example 4 : Effect of GSK-3β-inhibition in Cerebral Ischemia Model of Gerbilus Rats

Test compound (GSK-3β inhibitor) was administered to gerbilus rats intraperitoneally and 30 minutes later, all carotid arteries were blocked (for 4 minutes) to induce cerebral ischemia, thereby inducing phosphorylation of Tau protein in the brain. Three hours after the onset of cerebral ischemia, hippocampal elevations were taken from the brains of Gerbilus rats, measured by Western blot using phosphorylated Tau-cognitive antibodies (phosphorylation sites by GSK-3β), GSK-3β-inhibitory effects of GSK-3β inhibitors in the rat brain were evaluated.

The compounds of the present invention exhibit selective and potent inhibitory activity against glycogen synthase kinase-3 β (GSK-3β) and are associated with diabetes mellitus, diabetic complications, degenerative neurological diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, amyloid cerebrovascular vessels). Cerebral ischemia due to the disease, progressive nuclear palsy, subacute septic encephalitis Parkinson's disease, post-encephalitis Parkinson's disease, boxer encephalopathy, Parkinson's dementia complications of old carcinoma, Lewy body dementia, PEEK disease, cortical hyponuclear degeneration, frontal temporal dementia, AIDS Brain disease, Huntington's chorea, manic psychosis, etc.), alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and as a prophylactic and / or treatment of tumors induced by some viruses, or as an adjuvant Useful as

This application is based on patent application 2002-230581 filed in Japan, the contents of which are hereby incorporated by reference.

Claims (17)

Dihydropyrazolopyridine compounds of formula (I), optically active agents thereof or pharmaceutically acceptable salts thereof: [In the meal, R ⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl , Alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl which may have substituent (s), may have substituent (s) Aromatic heterocyclic group, phenylalkyl which may have substituent (s), or the following group: -COOR ⁸ , wherein R ⁸ is hydrogen, alkyl, aryl or substituent (s) which may have substituent (s) Is an aralkyl which may have); R ¹ is hydrogen; R ² is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy , Phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsul Phonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl which may have substituent (s), aromatic heterocyclic group or phenylalkyl; R ³ is (1) alkyl or haloalkyl, (2) cycloalkyl, (3) phenyl which may have substituent (s), (4) aromatic heterocyclic groups, (5) groups derived from benzene rings fused with saturated or unsaturated 5 or 6 membered carbocyclic rings, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatoms, or (7) a group derived from a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatoms, fused with a benzene ring, Wherein the groups of (2) to (7) are one or more substituents, or the following formulas (II) and (III): Wherein R ⁶ and R ⁷ are each a phenyl or aromatic heterocyclic group which may have substituent (s), or R ² and R ³ together form a ring which may contain heteroatoms, wherein The ring may be fused with a benzene ring which may have substituent (s)); R ⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl which may have substituent (s), substituent (s) Aromatic heterocyclic group, cyano, or nitro; R ⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4-7 membered heterocyclic ring which may have substituent (s), having substituent (s) Saturated 3 to 7 membered carbocyclic rings, alkyl substituted by saturated or unsaturated 4 to 7 membered rings containing 1 or 2 nitrogen atoms which may have substituent (s), or The following groups:-(CR ^a R ^b ) _n NR ¹¹ R ¹² (wherein n is an integer from 1 to 4, R ^a is hydrogen or alkyl, R ^b is hydrogen or alkyl, R ¹¹ is hydrogen, alkyl , Alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenyl Alkylcarbonyl, R ¹² is hydrogen or alkyl), Provided that when R ⁰ , R ¹ and R ² are each hydrogen, R ⁴ is methoxycarbonyl and R ⁵ is methyl, then R ³ is phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl Or 4-methoxycarbonylphenyl and when R ⁵ is alkyl, R ⁴ is alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosph Not phonyl, cyano or nitro]. The compound of claim 1, wherein R ⁴ may have alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, substituent (s). Phenyl, an aromatic heterocyclic group which may have substituent (s), cyano or nitro, R ⁵ represents alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4-7 membered heterocyclic ring, substituent (s) which may have substituent (s) A saturated 3 to 7 membered carbocyclic ring, an alkyl having a substituent (s) and substituted with a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atoms, or the following groups: (CH ₂ ) _n NR ¹¹ R ¹² wherein n is an integer from 1 to 4, R ¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, Phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, R ¹² is hydrogen or alkyl), dihydropyrazolopyridine compound, Optically active agents thereof or pharmaceutically acceptable salts thereof. The dihydropyrazolopyridine compound, optically active agent thereof or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ² is hydrogen or alkyl. The phenyl, naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-di according to claim 1 or 2, wherein R ³ may have 1 to 3 substituent (s). A dihydropyrazolopyridine compound, an optically active agent thereof or a pharmaceutically acceptable salt thereof, which is hydro-2H-benzopyran-8-yl. The compound according to claim 1 or 2, wherein R ⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, and alkylsulfinyl having 1 to 4 carbon atoms. Dihydropyrazolopyridine compounds, optically active agents thereof or pharmaceutically acceptable salts thereof. 3. The compound of claim 1, wherein R ⁵ is a group of — (CH ₂ ) _n NR ¹¹ R ¹² wherein n is an integer from 1 to 4 and R ¹¹ is hydrogen, alkyl or alkoxycarbonyl , R ¹² is hydrogen or alkyl), an optically active agent thereof or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein R ⁰ is hydrogen or the following group: -COOR ⁸ , wherein R ⁸ is alkyl, aryl which may have substituent (s) or aralkyl which may have substituent (s). ) Phosphorus, dihydropyrazolopyridine compound, its optically active agent or a pharmaceutically acceptable salt thereof. The dihydropyrazolopyridine compound according to claim 1 or 2, a tautomer thereof, an optically active agent thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (2) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -pyra Zolo [3,4- b ] pyridine, (3) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H -pyrazolo [3,4- b ] pyridine, (11) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2 H -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-tetra Hydropyridin-4-yl) -2 H -pyrazolo [3,4- b ] pyridine, (23) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4- (N, N-dimethylamino) cyclohexyl) -2 H -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-2 H -pyrazolo [3,4- b ] pyridine, (33) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (1-ethylpiperidin-4-yl) -2 H -pyrazolo [3,4- b ] pyridine, (37) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (piperidin-4-yl) -2 H -pyrazolo [3, 4- b ] pyridine, (38) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-4-yl) -2 H - pyrazolo [3,4- b ] pyridine, (41) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methylpiperidin-3-yl) -2 H - pyrazolo [3,4- b ] pyridine, (46) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (4-methylmorpholin-2-yl) -2 H -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) -2 H - pyrazolo [3,4- b] pyridine, (51) 6- (1-acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine, (52) 6- (1-benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine, (53) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (1-methanesulfonyloxy nilpi-4-yl) -2 H - pyrazol Zolo [3,4- b ] pyridine, (59) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-6- (4-oxocyclohexan-1-yl) -2 H -Pyrazolo [3,4- b ] pyridine, (62) 4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-6- (2-oxocyclohexane-1-yl) -2 H -pyrazolo [ 3,4- b ] pyridine, (63) 6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine, (73) 5-cyano-4,7-dihydro-4- (2,3- (methylenedioxy) phenyl) -6- (piperidin-4-yl) -2 H -pyrazolo [3, 4- b ] pyridine, (75) 4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine-6- Carboxylic acid phenylamide, (78) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (4-phenylpiperazin-1-yl) methyl- 2H -pyrazolo [3,4- b ] Pyridine, (81) 6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] pyridine, (82) 6-acetyl-4- (2,1,3-benzoxadiazol-4-yl) -5-cyano-4,7-dihydro-2 H -pyrazolo [3,4- b ] Pyridine, (84) 4- (2-bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2 H -pyrazolo [3,4- b ] Pyridine, (86) 4- (2-chlorophenyl) -5-cyano-4,7-dihydro-6- (pyrrolidin-3-yl) -2 H -pyrazolo [3,4- b ] pyridine, And (87) 4- (2,1,3-benzoxadiazol-4-yl) -5- (pyridin-2-yl) -4,7-dihydro-6-propyl-2 H -pyrazolo [3 , 4- b ] pyridine. A medicament comprising the dihydropyrazolopyridine compound of claim 1 or 2, an optically active agent thereof or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the dihydropyrazolopyridine compound of claim 1 or 2, an optically active agent thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of the dihydropyrazolopyridine compound of claim 1, an optically active agent thereof or a pharmaceutically acceptable salt thereof. The agent according to claim 9, which is used for the prevention and / or treatment of a disease caused by glycogen synthase kinase-3 beta hypersensitivity. 10. A medicament according to claim 9 for use in the prophylaxis and / or treatment of neurodegenerative diseases. The method of claim 13, wherein the disease is Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral infarction due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism ), Postencephalitic Parkinsonism, boxer's encephalopathy, Parkkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration degeneration), frontotemporal dementia, AIDS encephalitis, Huntington's disease and manic depression. 10. A medicament according to claim 9 for use in the prevention and / or treatment of diabetes and diabetic complications. The agent according to claim 9, which is used as an adjuvant. The agent of claim 9 for use in the prevention and / or treatment of alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell myeloma, or virus-induced tumors.