CA2494785A1

CA2494785A1 - Dihydropyrazolopyridine compounds

Info

Publication number: CA2494785A1
Application number: CA002494785A
Authority: CA
Inventors: Toshiyuki Kohara; Kenji Fukunaga; Tokushi Hanano
Original assignee: Mitsubishi Pharma Corporation; Toshiyuki Kohara; Kenji Fukunaga; Tokushi Hanano
Current assignee: Mitsubishi Pharma Corp
Priority date: 2002-08-07
Filing date: 2003-08-01
Publication date: 2004-02-19
Also published as: JP2005534713A; IL166482A0; EP1537106A1; WO2004014910A1; BR0313262A; NO20051153L; EA200500322A1; ZA200501842B; AR040961A1; KR20050069977A; CN1675209A; AU2003250539A1; MXPA05001434A

Abstract

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

Description

DESCRIPTION
DIHYDROPYRAZOLOPYRIDINE COMPOUNDS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta (GSK-3(3)-inhibitory activity, and use thereof.
BACKGROUND ART
It has been reported that glycogen synthase kinase-3 beta (GSK-3(3), a protein kinase, is involved in the causes zo of various diseases as noted in the following.
Type-II diabetes is a disease in which the insulin reactivity of pancreatic (3 cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like z5 are induced. GSK-3(3 acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GSK-3(3-inhibitory activity actually lowers glucose in blood by a GSK-3(3-2o inhibitory activity (Proc. Nat. Acad. Sci., 93, 8455 (1996)). Therefore, medicaments having a GSK-3(3-inhibitory activity are considered to be a pharmaceutical agent '~ effec ive for the improvement of Type II diabetes and -- complications thereof. . -.
25 The developmental mechanism of Alzheimer's dementia has not yet been elucidated. However, it is considered that amyloid aggregation and neurofibril changes are closely related to the cause of the development. GSK-3(3 is involved in both the amyloid aggregation and the .~o neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Pros. Nat. Acad. Sci., 95, 9637 (1998)). (2)' It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons 35 to induce neuronal death (Neurosci. Lett., 128, 195 (1991)).
In addition to the above, (3) the direct involvement of GSK-3(3 in neuronal death through inactivation of pyruvate dehydrogenase by phosphorylation to decrease the production amount of acetylcholine necessary for maintaining cell activity (Pros. Nat. Acad. SCi., 93, 2719 (1996)) has been reported.
In addition, the effectiveness for AIDS
encephalopathia as a neurodegenerative disease other than Alzheimer's dementia has been suggested. Tat, which. is a protein produced by HIV virus that causes AIDS, enhances so GSK-3(3 activity in neurons to induce neuronal death (J.
Neurochem., 73, 578 (1999) ) . From the above, GSK-3(3 inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.
Lithium and valproic acid, which have anti-manic-depressive activity, have a GSK-3(3 inhibitory activity (J.
Neurochem., 72, 1327 (1999)). The relationship between anti-manic-depressive activity and GSK-3(3 inhibitory activity is unclear, but a suppressive activity on glutamiC
20. acid toxicity is considered to be partly responsible for maintaining neuronal activity (ProC. Nat. ACad. SCi., 95, 2642 (1998)). Based on the foregoing, GSK-3(3 inhibitors are considered to be medicaments effective for improving manic-depressive psychosis.
NF-AT, a transcription factor, is dephosphorylated by calcineurin to increase immunological responses (SCience, 275, 1930 (1997)). GSK-3(3 acts for suppressing immunological function by conversely phosphorylating NF-AT.
Therefore, GSK-3(3 inhibitors are considered to be 3o medicaments effective for immunopotentiation.
Incidentally, JP-A-3-272189 (invention drawn to an improved synthesis method of mevalolacton intermediates), JP-A-2-275878 (therapeutic agents for hyperlipoproteinemia and atherosclerosis) and JP-A-1-272584 (therapeutic agents 35 for hyperlipoproteinemia) disclose pyrazolo[3,4-b]pyridine compounds wherein the 6-position is either methyl,

2 isopropyl or cyclopropyl. These publications do not disclose or suggest any action of these compounds on GSK-3(3 or the central nervous system.
The specifications of JP-A-59-65089, JP-A-59-118786, JP-A-60-56979, JP-A-60-197685 and the like disclose 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]-pyridine-5-carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods. The present inventors reproduced the following Zo reaction A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo[1,5-a]pyrimidine derivative represented by the formula (V) could be produced.
Z5 They measured IR, NMR and the melting point of the compound of the formula (V) and found them to be identical with IR, NMR and the melting point described in the specification of this publication. It is therefore concluded that an erroneous structural formula has been disclosed in these 2o publications. In other words, 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate cannot be synthesized according to the methods described in these publications.
A o 0 o2N
I ~ I \
'o ozN \ I . + I 1N_ ~ /'~0 I I N C IV ) I , HaN N ~N
H N H
H
B O O OaN \
I
O~ O
O N I + I ~ ~O N ~ C
H2N N.N I
H N
H
25 The compound of the above formula (IV) can be synthesized according to the method described in J. Chem.
Soc., Perkin Trans. 1, 947 (1996), and this publication discloses methyl 4-(2-chlorophenyl)-6-methyl-4,7-dihydro-

3 1H-pyrazolo[3,4-b]pyridine-5-Carboxylate and the like.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel compounds having a selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3(3), and further, medicaments comprising them and pharmaceutical compositions comprising them.
The present inventors have intensively studied to zo achieve the above object, and have found that 4,7-dihydropyrazolo[3,4-b]pyridine derivatives have a selective and strong inhibitory activity on GSK-3(3, which resulted in the completion of the present invention. That is, the present invention relates to medicaments comprising, as an active ingredient, dihydropyrazolopyridine compounds represented by the following formula (I), which have a GSK-3(3-inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
2o The present invention provides the following.
[1] A dihydropyrazolopyridine compound of the formula (I):
Rs R2 R1 (I) R5 N N Ro H
wherein R° is hydrogen, alkyl, aralkyl, aryl, Cycloalkyl, a5 formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, Carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, so acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocycliC

4 group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: -COORS (wherein Ra is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)):

Ri is hydrogen;

R2 is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, so cyano, vitro, alkylthio, haloalkyl, aminoalkyl,, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, z5 cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl~

~o R3 is (1) alkyl or haloalkyl, (2) cycloalkyl, (3) phenyl optionally having substituent(s), (4) aromatic heterocyclic group, 25 (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or ~ membered carbocyclic ring, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered so carbocyclic ring containing 1 to 3 heteroatom(s), or (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused 35 with a benzene ring, wherein the groups of (2) to (7) may have one or

5 more substituent(s), or a group selected from the groups represented by the following formulas ( II ) and ( III ) Rs R' (II) (III) wherein R6 and R' are each phenyl optionally having substituent(s) or an aromatic heterocycliC group, or R~ and R3 in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a~benzene ring optionally having so substituent ( s ) ;
R4 is alkoxycarbonyl, alkylCarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), ao an aromatic heterocycliC group optionally having substituent(s), Cyano or nitro~ and R5 is alkyl, phenylaminoalkyl, aryl, acylalkyl, aminocarbonyl, arylaminocarbonyl, 3o a saturated or unsaturated 4 to 7 membered heterocyCliC ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring

6 having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CRaRb) "NRllRia wherein n is an integer of 1 to 4, Ra is hydrogen or alkyl, Rb is hydrogen or alkyl, R11 is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, zo alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R1~ is hydrogen or alkyl, provided that when R°, R1 and R'' are each hydrogen, R4 is z5 methoxycarbonyl and R5 is methyl, then R3 should not be phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R5 is alkyl, then R4 is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, 2o dialkylphosphonyl, cyano or nitro, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[2] The dihydropyrazolopyridine compound of the above-mentioned [1], wherein R4 is alkoxycarbonyl, alkylcarbonyl, 25 alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group having substituent(s), cyano or nitro, and 3o R5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted 35 by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a

7 substituent, or a group of the formula: - (CH2) "NR11Ri2 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R12 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[3] The dihydropyrazolopyridine compound of the above-described [1] or [2], wherein R2 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[4] The dihydropyrazolopyridine compound of the above-described [1] or [2], wherein R3 is phenyl optionally having 1 to 3 substituent(s), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
ao [5] The dihydropyrazolopyridine compound of the above-described [1] or [2], wherein R4 is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[6] The dihydropyrazolopyridine compound of the above-described [1] or [2], wherein R5 is a group of the formula:
- (CHI) nNRllRiz wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl or alkoxycarbonyl and R~' is hydrogen or so alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[7] The dihydropyrazolopyridine compound of the above-described [1] or [2], wherein R° is hydrogen or a group of the formula: -COOR$ (wherein R~ is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)), or an optically active form thereof, or a

8 pharmaceutically acceptable salt thereof.
[8] The dihydropyrazolopyridine compound of the above-described [1] or [2], which is selected from the group consisting of s (2) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (3) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (11) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-so methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine, (14) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2H-pyrazolo,[3, 4-.b] -pyridine, (23) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-z5 (N,N-dimethylamino)Cyclohexyl)-2H-pyrazolo[3,4-b]pyridine, (27) 6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine, (33) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-2o ethylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (37) 4-(2-bromo-3-Cyanophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (38) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, 25 (41) 4-(2-bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine, (46) 4-(2-bromo-3-Cyanophenyl)-5-Cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl) -2H-pyrazolo [3, 4-.b]pyridine, (48) 4-(2-bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(1-so methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine, (51) 6-(1-acetylpiperidin-4-yl)-4-(2-bromo-3-Cyanophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (52) 6-(1-benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-35 5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (53) 4-(2-bromo-3-cyanophenyl)-5-CYano-4,7-dihydro-6-(1-

9

10 PCT/JP2003/009787 methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (59) 4-(2,1,3-benzoxacliazol-4-yl)-5-Cyano-4,7-dihydro-6-(4-oxocyClohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine, (62) 4-(2-bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine, (63) 6-acetylmethyl-4-(2-bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (73) 5-Cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, so (75) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2H-pyrazolo[3,4-b]pyridine-6-Carboxylic acid phenylamide, (78) 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(4-phenyl-piperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine, (81) 6-acetyl-4-(2-bromo-3-Cyanophenyl)-5-Cyano-4,7-s5 dihydro-2H-pyrazolo[3,4-b]pyridine, (82) 6-acetyl-4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (84) 4-(2-bromo-3-Cyanophenyl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, 20 (86) 4-(2-chlorophenyl)-5-Cyano-4,7-dihydro-6-(pyrrolidin-3-yl)-2H-pyrazolo[3,4-b]pyridine, and (87) 4-(2,1,3-benzoxadiazol-4-yl)-5-(pyridin-2-yl)-4,7-.
dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, a tautomer thereof, an optically active form thereof, or a 25 pharmaceutically acceptable salt thereof.
[9] A medicament comprising a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof.
30 [10] A pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described [1]
or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
35 [11] A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described [1], an optically active form thereof and a pharmaceutically acceptable salt thereof.
[12] The medicament of the above-described [9], which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.
[13] The medicament of the above-described [9], which is used for prevention and/or treatment of a neurodegenerative disease.
Io [14] The medicament of the above-described [13], wherein the disease is selected from the group consisting of Alzheimer's disease, ischemiC Cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute s5 sclerosing panencephalitiC Parkinsonism, postencephalitiC
Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, Corticobasal degeneration, frontotemporal dementia, AIDS
encephalopathy, Huntington's disease and manic-depressive 2o psychosis.
[15] The medicament of the above-described [9], which is used for prevention and/or treatment of diabetes and diabetic complications.
[16] The medicament of the above-described [9], which is used as an immunopotentiator.
[17] The medicament of the above-described [9], which is used for prevention and/or treatment of alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell lukemia or virus-induced tumors.
DETAILED DESCRIPTION OF THE INVENTION
The formula (I) indicates the presence of tautomers represented by the following formulas (I-a) and (I-b), based on the positions of hydrogen atoms of the pyrazole ring. The present invention encompasses each isomer of formulas (I-a) and (I-b), and a mixture of these isomers.

11 R R2 R~ R2 R1 R
N N-Ro R H Ro R H
CI _a) CI _b) The compounds represented by the formula (I) in the present specification are described in detail in the following.
"Alkyl" means a linear or branched hydrocarbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl r(i.e., amyl), hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tart-butyl, isopentyl, neopentyl, tent-pentyl and the like, so with a preference for alkyl having 1 to 4 carbon atom(s).
The alkyl of R2 is preferably alkyl having 1 to 4 carbon atoms. The alkyl of RS is preferably alkyl having 2 to 8 carbon atoms. The "alkyl having 2 to 8 carbon atoms"
concretely includes ethyl, propyl, butyl, pentyl (i.e., s5 amyl), hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tart-butyl, isopentyl, neopentyl, tart-pentyl and the like. Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.
zo "Acyl" means C~-C14 aryl, and includes "alkylcarbonyl"
having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, at R4 preferably having 2 to 5 carbon atoms, "C7_C1~ arylcarbonyl" such as benzoyl, naphthoyl and the 25 like, and "C7_Ci~ aralkylcarbonyl" such as benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl and the like, and the like. The benzene and naphthalene rings may have 1 to 5 substituent(s) and substitution sites are not particularly limited.

12 "Acylalkyl" is acylalkyl consisting of the above C1-Ca alkyl and the above,C2-Ci4 aryl, and includes, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyrylmethyl, valerylmethyl, pivaloylmethyl, 2-acetylethyl, 2-propionylethyl, 3-acetylpropyl and the like.
"Cycloalkyl" means a cyclic hydrocarbon chain of 3 to 8 carbon atoms. Cycloalkyl concretely includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with a preference for cycloalkyl zo having 3 to 6 carbon atoms. The cycloalkyl may have 1 to 5 substituent(s) and substitution sites are not particularly limited.
"Halogen" represents fluorine, chlorine, bromine or iodine.
s5 "Amino°' is primary amino, secondary or tertiary amino having the above Cl-CB alkyl, and includes, for example, amino, mono- or di-C1-CB alkyl-substituted amino such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino and 2o the like.
"Alkylthio" is a linear or branched alkylthio having 1 to 6 carbon atom(s), and includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio (i.e., amylthio), hexylthio and structural isomers thereof, 25 such as isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-pentylthio and the like, with a preference for alkylthio having 1 to 3 carbon atom ( s ) .
"Phenylthio" means phenylthio optionally having 1 to so 5 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Haloalkyl" is the above C1-Ce alkyl substituted by 1 to 5 halogen(s), and represents fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 35 2,2,3,3,3-pentafluoropropyl and the like.
"Aminoalkyl" is C1-CB alkyl having primary amino, and

13 includes, for example, aminomethyl, 2-aminoethyl, 3-aminopropyl,~4-aminobutyl and the like, with a preference for aminoalkyl containing alkyl having 1 to 4 carbon atom ( s ) .
"Acylamino" is acylamino having the above C~-C14 acyl, and represents, for example, acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino and the like.
so "Alkoxy" is alkoxy having the above C1-C$ alkyl, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy (i.e., amyloxy), hexyloxy and structural isomers thereof, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy and the z5 like, with a preference for alkoxy having 1 to 4 carbon atoms) .
"Cycloalkoxy" is cycloalkoxy having the above C3-Ca cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, w 2o with a preference for cycloalkoxy having cycloalkyl having 3 to 6 carbon atoms.
"Phenoxy" means phenyloxy optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Phenylalkoxy" is phenylalkoxy having the above C1-C$
alkoxy, and includes, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-methyl-1-phenylethoxy, 1-methyl-2-phenylethoxy, 1-phenylpropoxy, 2-pheylpropoxy, 1-methyl-1-3o phenylpropoxy, 1-methyl-2-phenylpropoxy, 1-methyl-3-phenylpropoxy and the like, with a preference for phenylalkoxy containing alkoxy having 1 to 4 carbon atom(s).
The phenylalkoxy optionally has 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly 35 limited.
"Aminoalkoxy" is aminoalkoxy consisting of the above

14 amino and C1-Ca alkoxy, and includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, 4-(dimethylamino)butoxy and the like, with a preference for aminoalkoxy consisting of tertiary amino containing alkyl having 1 to 4 carbon atom(s), and alkoxy having 1 to 4 carbon atom ( s ) .
"Alkoxyalkyl" is alkoxyalkyl consisting of the above Cl-C$ alkoxy and C1-C$ alkyl, and includes, for example, Zo methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atoms) and alkyl having 1 to 4 carbon atom(s).
"Phenoxyalkyl" is phenoxyalkyl consisting of the z5 above phenoxy and C1-C8 alkyl, and includes, for example, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl and the like, with a preference for phenoxyalkyl containing alkyl having 1 to 4 carbon atom(s). The phenoxyalkyl optionally has 1 to 5 substituent(s) on the phenyl and substitution sites 2o are not particularly limited.
"Hydroxyalkyl" is hydroxyalkyl having the above C1-Cg alkyl, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like, with a preference for hydroxyalkyl containing alkyl having 1 to 4 25 carbon atom ( s ) .
"Alkoxycarbonyl" is alkoxycarbonyl having the above C1-Cs alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers so thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tart-butoxycarbonyl, ~isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 s5 carbon atom(s). The alkoxycarbonyl of R~ is preferably alkoxycarbonyl having 2 to 5 carbon atoms.

"Phenoxycarbonyl" is phenoxycarbonyl optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Aminocarbonyl" is aminocarbonyl having the above amino including mono- or di-C1-CB alkyl-substituted amino, and includes, for example, aminocarbonyl (i.e., Carbamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl and the like.
to "Alkylthiocarbonyl" is alkylthiocarbonyl having the above C1-C6 alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, seC-25 butylthiocarbonyl, tert-butylthiocarbonyl and the like, with a preference for alkylthiocarbonyl, in which the alkyl moiety has 1 to 3 carbon atoms.
"Carboxyalkyl" is Carboxyalkyl having the above C1-C8 alkyl, and includes, for example, Carboxymethyl, 2o Carboxyethyl, Carboxypropyl and the like, with a preference for Carboxyalkyl containing alkyl having 1 to 4 carbon atoms) .
"CyCloalkoxyalkyl" is CyCloalkoxyalkyl consisting of the above C3-C8 Cycloalkoxy and C1-C$ alkyl, and includes, 25 for example, Cyclopropoxymethyl, Cyclopropoxyethyl, CyClobutoxymethyl, CyClopentyloxymethyl, Cyclohexyloxymethyl and the like, with a preference for Cycloalkoxyalkyl consisting of cyCloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atom(s). The so Cycloalkoxyalkyl optionally has 1 to 3 substituent(s) on the cycloalkyl and substitution sites are not particularly limited.
"Alkylsulfinyl" is alkylsulfinyl having the above C1-C$ alkyl, and includes, for example, methylsulfinyl, s5 ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 5 carbon atom(s). The alkylsulfinyl of R9 is preferably alkylsulfinyl having 1 to 4 carbon atoms.
"Phenylsulfinyl" means phenylsulfinyl optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Alkylsulfonyl" is alkylsulfonyl having the above C1-C$ alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl zo having 1 to 5 carbon atom(s). The alkylsulfonyl of R4 is preferably alkylsulfonyl having 1 to 4 carbon atoms.
"Phenylsulfonyl" means phenylsulfonyl optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.
z5 "Mercaptoalkyl" is mercaptoalkyl having the above C1-C$ alkyl, and includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with. a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s).
20 "Alkylthioalkyl" is alkylthioalkyl consisting of the above C1-C6 alkylthio and C1-C$ alkyl, and includes, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for 25 alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atoms) and alkyl having 1 to 4 carbon atom(s).
"Aryl" is aryl having 6 to 14 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and t-he like. They may have 1 to 5 3o substituent(s) and substitution sites are not particularly limited.
"Aralkyl" is aralkyl wherein the above C1-Cs alkyl is substituted by the above C6-C14 aryl, and includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-35 naphthylmethyl and the like. These may have 1 to 5 substituent(s) on the aryl moiety and substitution sites 1~

are not particularly limited.
"Acyloxyacetyl" is acyloxyacetyl having the above C2-C1q aryl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.
"Acyloxyalkyl" is acyloxyalkyl having the above C~-C14 aryl and C1-Cg alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2-.~o butyryloxyethyl, 2-benzoyloxyethyl and the like.
The substituent of the "phenyl optionally having substituent(s)" is exemplified by those mentioned for the "substituent" below, wherein the number of the substituent is generally 1 to 5, preferably 1 to 3. Phenyl having 1 or s5 2 substituent(s) is particularly preferable and substitution sites are not particularly limited.
"Aromatic heterocyclic group" is, for example, a 5-or 6-membered aromatic heterocyclic group containing l to 3 heteroatom(s) selected from the group consisting of 2o nitrogen atom, oxygen atom and sulfur atom, and includes, for example, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, ,isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, etc.), and the like. The aromatic heterocyclic group may have 1 to 6 substituent(s) and substitution sites are not particularly limited.
"Saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s)"
so includes the following groups and the like.

\ 01 N 1 N_1 C
NCO NJ NJ NJ N N N
Rs R9 R9 Rs Rs R9 R9 ~/~O
~/~O ~~
N9 Ns Ns R9 R9 R R R
NCO NJ
R9 Rs wherein R9 is each independently hydrogen, alkyl, aryl, aralkyl, Cycloalkyl, formyl, haloalkyl, aminoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, Carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, alkylsulfinyl, alkylsulfonyl, 1o phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyaCetyl, acyloxyalkyl, aryl optionally having substituent(s), aromatic heterocyClic group optionally having substituent(s), or phenylalkyl optionally having substituent(s).
"Saturated 3 to 7 membered carboCycliC ring having substituent(s)" includes the following groups and the like.
O
,/~~o /~
R1o Rio Rio Rio wherein Rl° is alkyl, aryl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent(s), aromatic heterocycliC group optionally having substituent(s), or Zo phenylalkyl optionally having substituent(s), and R1°~ is hydrogen, alkyl, aryl, aralkyl, Cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, s5 Carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), or phenylalkyl optionally having substituent(s).
The substituent of the "aromatic heterocyclic group optionally having substituent(s)" is exemplified by those mentioned for the "substituent" below, wherein the number 25 of the substituent is generally 1 to 6 and substitution sites are not particularly limited.
"Phenylalkyl" is phenylalkyl consisting of phenyl and the above C1-CB alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, so 1-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom ( s ) .
The kind and the number of the substituent of the "phenylalkyl optionally having substituent(s)" are the same as those for the above-mentioned "aromatic heterocycliC
group" and substitution sites are not particularly limited.
"Dialkylphosphinyl" is dialkylphosphinyl having the above C1-Ce alkyl, and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl and the like, with a preference for dialkylphosphinyl containing alkyl having 1 to 4 carbon atom(s).
"Dialkylphosphonyl" is dialkylphosphonyl having the above C~-C8 alkyl, and includes, for example, zo dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).
In the present specification, "substituent" includes alkyl, acyl, Cycloalkyl, phenyl, aromatic heterocyCliC
ss group, phenylalkyl, hydroxy, Carboxy, thiol, halogen, amino, formyl, Carbamoyl, Cyano, vitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, Cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, 2o alkylthiocarbonyl and the like.
"Ring optionally containing heteroatom(s)" is a 5 or 6 membered CarbocyCliC ring optionally containing 1 to 3 heteroatom(s) selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, with particular 25 preference given to a ring containing sulfur atom. The ring may be substituted by one or more of the above substituents or oxo groups. The substitution site is not particularly limited. This ring is formed by R2 and R3 in the formula (I) together with the attached carbon atom. By 3o forming this ring, a spiro ring is formed in the compound of the formula (I). The above ring can be fused with a benzene ring optionally having substituent(s) and substitution sites are not particularly limited. Such a ring includes, for example, 2,3-dihydrobenzo[b]thiophene, 35 2,3-dihydrobenzo[b]thiophen-1-oxide and the like.
"A group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocycliC ring"
represents a group derived from naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indan and the like. Of these, naphthyl such as naphthalen-1-yl and the like, and indanyl such as indan-4-yl and the like are preferable. The group may have 1 to 4 substituent(s) and substitution sites are not particularly limited.
"A group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered Carbocyclic ring so containing 1 to 3 heteroatom(s)" includes the following groups and the like.
\ ~\ ~ ~' ~ ~\
-o -o -S -o I\ o> I\ o \ \
-o o>
/ _N, ~ ,N. /
'N°~ 'N°S N

\ N \ N / ~N
~O
CH3 ~ / CH3 ~. w C CH3 'C CH3 Of these, 2,1,3-benzoxadiazole, dihydrobenzo[b]furan, methylenedioxyphenyl and 3,4-dihydro-2H-benzopyrane are preferable, and 2,1,3-benzoxadiazol-4-yl, 2,3-dihydrobenzo-[b]furan-7-yl, 2,3-(methylenedioxy)phenyl and 3,4-dihydro-2H-benzopyran-8-yl are particularly preferable. The group may have 1 to 3 substituent(s) and substitution sites are not particularly limited.
"A group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring" includes the following groups and the like.

\ \ \ \
The group may have 1 to 5 substituent(s) and substitution sites are not particularly limited.
"Alkylcarbonylalkyl" is, for example, C1-C4 alkyl-carbonyl-C1-C4 alkyl, and includes, for example, methylcarbonylmethyl, ethylcarbonylmethyl, to propylcarbonylmethyl, butylcarbonylmethyl and the like.
"Arylaminocarbonyl°' is C6-Clo aryl-aminocarbonyl, and includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl and the like. The arylaminocarbonyl optionally has 1 to 3 substituent(s) on the aryl and s5 substitution sites are not particularly limited.
"Aralkylaminocarbonyl" is C7-C14 aralkyl-aminocarbonyl, and includes, for example, benzylaminocarbonyl and the like.
The aralkylaminocarbonyl optionally has 1 to 3 substituent(s) on the aryl and substitution sites are not ao particularly limited.
"Alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or ~ nitrogen atom(s), which optionally has a substituent" means C1-C$ alkyl substituted by "a saturated or unsaturated 4 to 7 membered ring 25 containing 1 or 2 nitrogen atoms)", such as pyrrole, pyrroline, pyrazole, pyridine, piperidine, piperazine, homopiperadine or morpholine and the like, which optionally has a substituent such as' C1-C4 alkyl, C6-C1o aryl such as phenyl, naphthyl and the like, and includes, for example, so (4-phenylpiperazin-1-yl)methyl, ~-(4-phenylpiperazin-1-yl)ethyl, 3-(4-phenylpiperazin-1-yl)propyl, (4-(naphthalen-1-yl)piperazin-1-yl)methyl, 2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl, (4-methylhomopiperazin-1-yl)methyl and the like.
"Phenylaminoalkyl" is phenylamino-C1-C4 alkyl, and includes, for example, phenylaminomethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl and the like. The phenylaminoalkyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Phenylalkylcarbonyl" is phenyl-C1-C4 alkyl-carbonyl, zo and includes, for example, benzylCarbonyl, 2-phenylethylCarbonyl, 3-phenylpropylCarbonyl, 4-phenylbutylcarbonyl and the like. The phenylalkylCarbonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
.25 "Alkyl" in the R11 is C1-CQ alkyl, and includes, for examples, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tart-butyl and the like.
"Alkylsulfonyl" in the R11 is C1-C4 alkyl-sulfonyl, and includes, for example, methylsulfonyl, ethylsulfonyl, 2o propylsulfonyl and the like.
"Phenylsulfonyl" in the R11 is phenylsulfonyl optionally having 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Phenylalkylsulfonyl" in the R11 is phenyl-C1-C4 alkyl-sulfonyl, and includes, for example, benzylsulfonyl, 2-phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl and the like. The phenyla.lkylsulfonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
30 "Alkylsulfinyl" in the R11 1s C1-C4 alkyl-sulfinyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.
"Phenylsulfinyl" in the R11 is phenylsulfinyl optionally having 1 to 3 substituent(s) on the phenyl and s5 substitution sites are not particularly limited.
"Phenylalkylsulfinyl°' in the R11 is phenyl-C1-CQ alkyl-sulfinyl, and includes, for example, benzylsulfinyl, 2-phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4-phenylbutylsulfinyl and the like. The phenylalkylsulfinyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Alkoxycarbonyl" in the R11 is C1-C4 alkoxy-carbonyl, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
"Phenylalkoxycarbonyl" in the R11 is phenyl-C1-C4 Zo alkoxy-carbonyl, and includes, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl and the like.
The phenylalkoxycarbonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not Z5 particularly limited.
"AlkylCarbonyl" in the R11 is C1-C4 alkyl-carbonyl and includes, for example, acetyl, propionyl, butylcarbonyl and the like.
"Phenylcarbonyl" in the R11 is phenylcarbonyl 20 optionally having 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Phenylalkylcarbonyl" in the R~1 is phenyl-C1-C4 alkyl-carbonyl, and includes, for example, benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl and the like. The phenylalkylcarbonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.
"Phenoxycarbonyl" in the R1~ means phenoxycarbonyl optionally having 1 to 3 substituent(s) on the phenyl and so substitution sites are not particularly limited.
"Alkyl" in the R1' is C1-C9 alkyl, and includes, for examples, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl and the like.
The compounds represented by the formula (I) of the 35 present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention. Such acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, malefic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, so benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like. When an asymmetric carbon atom exists, optical isomers and racemates thereof can be present, and all of these are encompassed in the present invention.
Of the compounds (I) of the present invention, a z5 compound wherein R° is hydrogen can be synthesized as shown in the following according to the method described in J.
Chem. Soc., Perkin Trans. 1, 947 (1996) and the like.
First Production Method + ~ +

I ) (Uil) (VIII) (IX) 2o wherein R2, R~, R4 and R5 are as defined above.
Meldrum's acid of the formula (VI) and a carbonyl derivative of the formula (VII) are reacted with a carbonyl derivative of the formula (VIII) in the presence of ammonium acetate to give an amide derivative of the formula 25 (IX). The reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction. As the solvent, formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used. The reaction is carried out at any temperature, for example, so from 0°C to 200°C, preferably from 60°C to 100°C.

I -' I
R5 N~O R5 N CI
H H
wherein R', R3, R4 and R5 are as defined above.
The obtained amide derivative of the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of the formula (X).
The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, zo dimethylformamide, dimethyl sulfoxide and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 0°C to 60°C.
R3 Ra R2 R2 R~
R4 CHO Ra _- ~ ~~ (I) Rs H CI R5 H N H
(X) s5 wherein R1, R2, R3, R4 and R5 are as defined above.
The compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine. The reaction is carried out in the presence of a solvent inert to the ao 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, 25 from 0°C to 200°C, preferably from 60°C to 100°C.

The carbonyl derivative of the formula (VII), which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J.
Med. Chem., 31, 3 (1996) and Tetrahedron Zett., 24, 5023 (1983). The carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993) .
Second Production Method Ra O O Ra N N + R3 ~ R2 + Rs .~ R
H2N H Rs N N H
H
(XI) (VII) (VIII) (I) io wherein R1, R2, R3, R4 and R5 are as defined above.
The compounds (I) of the present invention can be produced by reacting aminopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII). The reaction is carried .25 out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used. The reaction is carried out at any ~o temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
Of the compounds (I) of the present invention, a compound wherein R° is a substituent other than hydrogen can be synthesized as follows.
25 Third Production Method + R°-X
s ~ N H Ro R N
H
(I) (XI) (XII) wherein R°, R1, R~, R3, R9 and R5 are as defined above, and X
represents halogen, provided that R° is not hydrogen.
The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with halide of the formula (XII) in the presence of a base. Suitable base includes, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like. The reaction is so carried out in the presence of a solvent inert to the reaction. As the solvent, one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like.
The reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
Fourth Production Method R3 Rs R2 R~ R2 R1 R4 Ra I \ Ro-~\ o I (~ v~N
N +
s ~~H R s ~~Ro R H R H
(XI) (X111) (I) wherein R°, Rl, R2, R3, R4 and R5 are as defined above, 2o provided that R° is not hydrogen.
The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) such as acetic anhydride in the presence of a base.
Suitable base includes, for example, triethylamine, pyridine, 4-dimethylaminopyridine and the like. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like. The reaction is carried out at any temperature, so for example, from -10°C to 200°C, preferably from 0°C
to 100°C.
Those skilled in the art should understand that the above production methods can be modified corresponding to the desired compounds.
s5 The compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation and purification is carried out by a conventional chemical process such. as extraction, concentration, evaporation, crystallization, filtration, 2o recrystallization, various kinds of chromatography and the like. When the purified product thus obtained is a racemate, a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column 25 packed with optically active carrier. The present invention also encompasses optically active compounds.
The compounds of the present invention obtained by the above methods have a weak inhibitory activity on kinases other than GSK-3(3 such as CaM kinase II, MAP kinase, Casein so kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3(3. Therefore, the compounds of the present invention have a GSK-3(3-selective inhibitory activity and can be medicaments with. small,side-effect for diabetes, diabetic complications, neurodegenerative 35 diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuClear paralysis, subacute sclerosing panenCephalitiC Parkinsonism, postencephalitiC Parkinsonism, boxer's encephalopathy, Parkinsonism dementia Complex of Guam, Lewy body disease, Pick's disease, Corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, maniC-depressive psychosis and the like), alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors. In addition, Zo the compounds of the present invention are useful as immunopotentiators.
Formulations comprising the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives conventionally used for formulation. The carrier and excipient for formulation may be a solid or liquid, and include, for example, lactose, magnesium stearate, starch such as corn starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene 2o glycol and other conventionally used substances.
Administration may be oral administration of tablet, pill, capsule, granule, powder, solution and the like, or parenteral administration by injection (intravenous injection, intramuscular injection and the like), suppository, transdermal agent and the like. While the dose is appropriately determined on each case in consideration of symptom, age and sex of the administration subject, and the like, it is generally 1 - 1,000 mg, preferably 50 - 200 mg per day for an adult person, which 3o is orally administered once to several times a day, or 1.-500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day.

Examples The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples.
Example 1 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-piperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine so To a solution of ethyl isonipecotate (10.0 g) in THF
(200 mL) was added triethylamine, (7.8 g), 4-dimethylamino-pyridine (0.8 g) and di-tert-butyldicarbonate (15.3 g) at 0°C and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was .25 evaporated under reduced pressure to give ethyl N-Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. To a solution of acetonitrile (3.2 g) in THF (300 mL) was added n-BuLi (44 mmol) at -78°C and stirred for three hours.
Further, ethyl N-Boc-piperidine-4-carboxylate (16.3 g) was 2o added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with. ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl 25 acetate (5:1)) to give 1-(N-Boc-piperidin-4-yl)-2-cyanoethan-1-one (11.6 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2-(N-Boc-piperidin-4-yl)-1-cyanoethan-2-one (1.7 g) in acetonitrile (10 mL) was heated under reflux ~o overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.
MP:226°C.
35 Anal . Calcd. For : C~3H25N703: C, 61 . 73; H, 5 . 63; N, 21 . 97 .
Found : C, 61 . 4 5; H, 5 . 8 2 ; N, 21 . 61 .

MS (EI) :447 (M+) .
~H-NMR ( 400MHz, DMSO-d6 ) b (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(lH,s), 7.26(lH,s), 7.41(lH,d,J=6.6Hz), 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9.81(lH,brs), 12.24(lH,brs).
Example 2 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl ) -2H-pyrazolo [ 3, 4-b] pyridine so 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-piperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine (1.7 g) was added to trifluoroacetic acid (20 mL) at 0°C and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure. After z5 alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.83 g) as yellow 2o crystals.
MP : 216°C .
MS (EI) : 348 (M+) .
1H-NMR ( 400MHz, DMSO-d6) b (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) , 25 7 . 27 ( 1H, s ) , 7 . 43 ( 1H, d, J=6 . 6Hz ) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 8 6 ( 1H, brs ) , 12 . 2 4 ( 1H, brs ) .
Example 3 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine ~o To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (0.7 g) in MeOH (200 mL) was added 37o formaldehyde (0.18 g), sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) at room temperature and the mixture was stirred s5 overnight. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals.
MP:>270°C.
MS (EI) :361 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 57-1 . 60 (2H,m) , 1 . 82-1. 8 8 ( 2H, m) , 2 . 01-2 . 0 6 ( 2H, m) , 2 .15 ( 3H, s ) , 2 . 58-2 . 61 ( 1H, m) , 2.85-2.88(2H,m), 5.40(lH,s), 7.26(lH,s), 7.40(lH,d,J=6.6Hz), so 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 91 ( 1H, d, J=9 . OHz ) , 9 . 7 6 ( 1H, brs ) , 12 . 17 ( 1H, brs ) .
Example 4 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-piperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-s5 pyridine The title compound was prepared from ethyl nipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MP:229°C.
2o Anal . Calcd. For : C23H?5N~O3: C, 61. 73; H, 5 . 63; N, 21 . 97 .
Found:C,61.56;H,5.66;N,21.67.
MS (EI) :447 (M+) .
1H-NMR(400MHz,DMSO-d6)8(ppm) : 1.32-1.40(2H, m), 1.39(9H,s), 1.69-1.78(2H,m), 2.69-2.7~(2H,m), 3.16-3.19(lH,m), 3.92-25 3.95(2H,m), 5.42(lH,s), 7.28(lH,s), 7.42(lH,d,J=6.~Hz), 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9.87(lH,brs), 12.21(lH,brs).
Example 5 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-so (piperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-Ja]pyridine in the same manner as in Example 2.
35 MP:202°C.
Anal . Calcd. For : C1aH17N70: C, 62 . 24; H, 4 . 93; N, 28 . 23 .

Found:C,61.97;H,5.13;N,27.89.
MS (EI) :347 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1. 42-1 . 45 (lH,m) , 1 .72-1 . 88 (3H,m) , 2. 66-2.84 (5H,m) , 2.94-3.02 (lH,m) , 5.38 (1H, s) , 7 . 2 6 ( 1H, s ) , 7 . 39 ( 1H, d, J=6 . 6Hz ) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 91 ( 1H, d, J=9 . OHz ) , 10 . 39 ( 1H, brs ) , 12 . 17 ( 1H, brs ) .
Example 6 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-~-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine Zo The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
MP:228°C.
MS (EI) :361 (M+) .
a5 1H-NMR (400MHz, DMSO-d6) b (ppm) : 1.53-1 .76 (4H,m) , 2.21 (3H, s) , 2.47-2.55 (4H,m) , 2.93-2.96 (lH,m) , 5.38 (1H, s) , 7.27 (1H, s) , 7 . 40 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 10 .16 ( 1H, brs ) , 12 . 2 0 ( 1H, brs ) .
Example 7 20 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-piperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from ethyl pipecolinate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the 25 same manner as in Example 1.
MS (EI) :447 (M+) .
1H-NMR(400MHz,DMSO-d~)b(ppm): 1.27 and 1.32(9H,s), 1.42-1.97(6H,m), 3.30-3.33(lH,m), 3.53-3.61(lH,m), 4.47-4.50 (lH,m), 5.37 and 5.39(lH,s), 7.2~ and 7.29(lH,s), 7.38-~0 7 . 44 ( 1H, m) , 7 . 54-7 . 60 ( 1H, m) , 7 . 90-7 . 93 ( 1H, m) , 9 . 63 and 9 . 7 3 ( 1H, brs ) , 12 .16 ( 1H, brs ) .
Example 8 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-2-yl)-2H-pyrazolo[3,4-b]pyridine 35 The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MS (EI) :347 (M+) .
1H-NMR (400MHz, DMSO-d~) b (ppm) : 1 .27-1 . 88 ( 6H,m) , 3. 12-3.16(lH,m), 4.12-4.15(lH,m), 4.48-4.58(lH,m), 5.64 and 5.66(lH,s), 7.22-7.28(lH,m), 7.45-7.52(2H,m), 7.87-7.90 (lH,m) , 8.26 (lH,br) , 10.92 and 10.94 (lH,brs) , 12.35 (lH,brs) .
Example 9 zo 4-(2,1,3-Benzoxadiazol-4-yl)-6-(4-t-butoxycarbonyl-morpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from ethyl morpholine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-amino-Z5 pyrazole in the same manner as in Example 1.
MS (EI) :449 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.36 and 1.40(9H,s), 2.95-3.06(2H,m), 3.50-3.52(lH,m), 3.75-3.95(3H,m), 4.34-4.40 (lH,m), 5.44 and 5.48(lH,s), 7.26 and 7.30(lH,s), 7.42-20 7.45(lH,m), 7.57-7.62(lH,m), 7.93-7.96(lH,m), 9.84 and 9 . 92 ( 1H, brs ) , 12 . 23 ( 1H, brs ) .
Example 10 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-~-(morpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine 25 The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-~-(4-t-butoxycarbonylmorph.olin-2-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MS (EI) :349 (M+) .
~0 1H-NMR(400MHz, DMSO-d6) b (ppm) : 2.64-2.95 (4H,m) , 3.53 (lH,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 (lH,m) , 7.56-7 . 61 ( 1H, m) , 7 . 91-7 . 94 ( 1H, m) , 9 . 74 and 9 . 7 ~ ( 1H, brs ) , 12 . 19 ( 1H, brs ) .
35 Example 11 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
MP : 14 3°C .
MS (EI) :363 (M+) .
1H-NMR (400MHz, DMSO-d6) S (ppm) : 2.21 (3H, s) , 2 . 19-2. 30 (2H,m) , 2.60-2.69(2H,m), 3.60-3.62(lH,m), 3.88-3.92(lH,m), 4.48-4.50(lH,m), 5.44(lH,s), 7.28(lH,s), 7.39(lH,d,J=6.6Hz), zo 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9.80(lH,brs), 12.20(lH,brs).
Example 12 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo-s5 [3,4-b]pyridine The title compound was prepared from ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
2o MP:222°C.
MS (EI ) : 445 (M+) .
1H-NMR (400MHz, DMSO-d6) b (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(lH,s), 6.06-6.09 (lH,m), 7.28(lH,s), 7.45(lH,d,J=6.6Hz), 7.60(lH,dd,J=9.OHz 25 and 6 . 6Hz ) , 7 . 93 ( 1H, d, J=9 . OHz ) , 9 . 94 ( 1H, brs ) , 12 . 19 ( 1H, brs ) .
Example 13 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-so diazol-4-yl)-6-(1-t-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine in the same manner as in Example 2.
MP:180°C.
MS (EI ) : 345 (M+) .
s5 1H-NMR (400MHz, DMSO-d~) b (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 (lH,m) , 7 . 30 ( 1H, s ) , 7 . 43 ( 1H, d, J=6 . 6Hz ) , 7 . 60 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 8 7 ( 1H, brs ) , 12 .18 ( 1H, brs ) .
Example 14 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-Cyano-4,7-dihydro-6-(1,2,3,6-tetrahydro-pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner so as in Example 3.
MP:218°C.
MS (EI ) : 359 (M+) .
1H-NMFt (400MHz, DMSO-d6) S (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(lH,s), 6.04-6.05 25 ( 1H, m) , 7 . 27 ( 1H, s ) , 7 . 43 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 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-2H-pyrazolo[3,4-.b]-2o pyridine To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di-tart-butyldicarbonate (30 g) at 0°C and the mixture was stirred at 40°C for four 25 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. To a solution of ethyl N-BoC-3-aminopropionate (5.0 g) in THF
(50 mL) was added t-BuOK (2.8 g) and methyl iodide (4.9 g) 3o at 0°C and the mixture was stirred at room temperature for an 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. Subsequently, the title compound was prepared from ethyl 3-(N-BoC-N-methylamino)propionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MP:240°C.
Anal . Calcd. For: C~1H~3N703: C, 59. 85; H, 5. 50;N, 23 . 26 .
Found:C,59.69;H,5.45;N,23.22.
MS (EI) :421 (M+) .
1H-NMR ( 4 0 OMHz, DMSO-d6 ) b (ppm) : 1 . 2 6 and 2 . 32 ( 9H, s ) , 2 . 62-2 . 63 (2H,m) , 2.81 (3H, s) , 3.48-3.55 (2H,m) , 5.40 (1H, s) , 7 .27 ( 1H, s ) , 7 . 40 ( 1H, d, J=6 . 6Hz ) , 7 . 57 ( 1H, dd, J=9 . OHz and 6 .
6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 10 . 07 ( 1H, brs ) , 12 .15 ( 1H, brs ) .
so Example 16 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(2-(N-methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(2-(N-t-butoxycarbonyl-N-methylamino)ethyl)-s5 5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MP: 174°C.
MS (EI ) : 321 (M+) .
1H-NMR (400MHz, DMSO-d6) ~ (ppm) : 2 .29 (3H, s) , 2 . 50-2 . 78 (4H,m) , ~0 3 .31 (3H,br) , 5.39 (1H, s) , 7 .24 (1H, s) , 7.43 (1H, d, J=6. 6Hz) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 91 ( lH,.d, J=9 . OHz ) .
Example 17 4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-(N-t-butoxycarbonyl-amino)ethyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 25 The title compound was prepared from ethyl 3-amino-propionate hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MP: 231°C.
Anal . Calcd. For: C2oH2iN70s : C, 58 . 96; H, 5 . 20; N, 24 . 06 .
3o Found:C,58.81;H,5.19;N,23.82.
MS (EI) :407 (M+) .
1H-NMR (400MHz, DMSO-d6) ~ (ppm) : 1. 33 (9H, s) , 2 . 55-2 . 60 (2H,m) , 3.23-3.33 (2H,m) , 5.41 (1H, s) , 6. 81 (lH,brs) , 7 .25 (1H, s) , 7 . 44 ( 1H, d, J=6 . 6Hz ) , 7 . 57 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 35 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 94 ( 1H, brs ) , 12 .14 ( 1H, brs ) .

Example 18 6-(2-Aminoethvl)-4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(2-(N-t-butoxycarbonylamino)ethyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MS (EI ) : 307 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 2 . 50-2 . 54 (2H,m) , 2 . 88 zo (2H, t, J=7.3Hz) , 3.35 (4H,br) , 5.40 (1H, s) , 7.25 (1H, s) , 7 . 44 ( 1H, d, J=6 . 6Hz ) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) .
Example 19 4-(2,1,3-Benzoxadiazol-4--yl)-5-Cyano-4,7-dihydro-6-(2-(N,N-dimethylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-Cyano-4,7-dihydro-6-(2-(N-methylamino)-ethyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
2o MP : 215°C .
MS (EI ) : 335 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 2.19 (6H, s) , 2.45-2. 62 (4H,m) , 5.41(lH,s), 7.27(lH,s), 7.43(lH,d,J=6.6Hz), 7 . 5 8 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 10 . 04 ( 1H, brs ) , 12 .16 ( 1H, brs ) .
Example 20 4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-t-butoxycarbonyl-N-methylamino)methyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-Ja]-pyridine so The title compound was prepared from glycine ethyl ester hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-amino-pyrazole in the same manner as in Example 15.
MP:207°C.
Anal . CalCd. For: C2oH21N703: C, 58 . 96; H, 5 . 20; N, 24 . 06 .
s5 Found:C,58.80;H,5.12;N,24.38.
MS (EI) :407 (M+) .

1H-NMR(400MHz,DMSO-d6)b(ppm): 1.33 and 1.39(9H,s), 2.81(3H,s), 4.13-4.20(2H, m), 5.42(lH,s), 7.29(lH,s), 7 . 43 ( 1H, d, J=6 . 6Hz ) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 94 ( 1H, d, J=9 . OHz ) , 9 . 33 ( 1H, brs ) , 12 .15 ( 1H, brs ) .
Example 21 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-((N-methylamino)methyl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate 4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-t-butoxycarbonyl-N-so methylamino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-.b]-pyridine (0.6 g) was added to trifluoroacetic acid (10 mL) at 0°C and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure and the residue was crystallized by ethanol, and the precipitated crystals were collected by filtration to give the title compound (0.1 g) as yellow crystals.
MP:174°C.
MS (EI ) : 307 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 3 . 10 (3H, s) , 4.51-4. 68 (2H,m) , 7 . 24 ( 1H, d, J=6 . 6Hz ) , 7 . 45 ( 1H, s ) , 7 . 52 ( 1H, dd, J=9 . OHz and 6.6Hz), 7.89(lH,d,J=9.OHz), 8.08-8.20(2H,br), 10.81(lH,brs), 12.41 (lH,brs) .
Example 22 4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- (N-methylamino)cyclohexyl)-2H-pyrazolo[3,4-.b]pyridine The title compound was prepared from ethyl 4-aminocyclo-hexanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 15, and Example 2 followed.
3o MS (EI ) : 375 (M+) .
1H-NMR(400MHz,DMSO-d~)b(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 . 8 5 ( 1H, m) , 5 . 3 9 ( 1H, s ) , 7 . 2 8 ( 1H, s ) , 7 . 41 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 8 . 54 ( 1H, br )., 9 . 7 9 ( 1H, brs ) , 35 12.22 (lH,brs) .

Example 23 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N,N-dimethylamino)CyClohexyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N-methylamino)-cyClohexyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
MP:241°C.
MS (EI) :389 (M+) .
.~0 1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 15-2 . 02 (9H,m) , 2.15 and 2.21(6H,s), 2.62-2.76(lH,m), 5.38 and 5.43(lH,s), 7.26(lH,s), 7.38-7.44(lH,m), 7.56-7.62(lH,m), 7.90-7.96 (lH,m) , 9.74 (lH,brs) , 12.18 (lH,brs) .
Example 24 z5 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-phenylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine To a solution of ethyl isonipecotate (8.9 g) in CH2C12 (500 mL) was added triphenyl bismus (25 g) and Copper(II)acetate (10.3 g) at room temperature, the mixture 2o was stirred overnight. After filteration, the mixture was extracted with CH2C12. 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 ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as 2.s colorless crystals. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-BuLi (41 mmol) at -78°C.
Further, ethyl 1-phenylpiperidine-4-Carboxylate (8.~ g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was 3o 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) as colorless crystals. A solution 35 of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1-(1-phenylpiperidin-4-yl)-2-Cyanoethan-1-one (0.5 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.
MS (FAB) :424 (M++1) .
iH-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 73-1 . 76 (2H,m) , 2. 14-2.18 (2H,m) , 2 . 62-2. 66 (2H,m) , 2. 81-2. 84 (lH,m) , 3. 80-3 . 8 4 ( 2H, m) , 5 . 41 ( 1H, s ) , 6 . 7 5 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , zo 6 . 94-6 . 96 ( 2H, m) , 7 .18-7 . 27 ( 3H, m) , 7 . 42 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 81 ( 1H, brs ) , 12 . 17 ( 1H, brs ) .
Example 25 6-(1-Acetylpiperidin-4-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-z5 cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0°C and the mixture was stirred for an hour. The mixture was extracted with 2o ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at -78°C.
Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was as added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl so acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux 35 overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
MP:248°C.
MS (FAB) :340 (M++1) .
iH-NMR(400MHz,DMSO-d~)S(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(lH,m), 4.48-4.51(lH,m), 5.40(lH,s), 7.27(lH,s), 7.42(lH,d,J=6.6Hz), 7.59(lH,dd,J=9.OHz and 6.6Hz), 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 81 ( 1H, brs ) , 12 . 18 ( 1H, brs ) .
zo Example 26 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-benzoylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from benzoylchloride, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-Z5 aminopyrazole in the same manner' as in Example 25.
MP:228°C.
MS ( FAB ) : 4 5 2 ( M++ 1 ) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 59-1 . 76 (2H,m) , 2 . 04-2. 08 (2H,m) , 2.76-2.80 (lH,m) , 3.01-3.09 (2H,m) , 3.58-3. 60 (lH,m) , 20 4. 60-4. 63 (lH,m) , 5.41 (1H, s) , 7.28 (1H, s) , 7.43-7.46 (6H,m) , 7 . 56-7 . 59 ( 1H, m) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 90 ( 1H, brs ) , 12 . 21 ( 1H, brs ) .
Example 27 6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2,1,3-25 benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from acetyl chloride, ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same 3o manner as in Example 25.
MP:237°C.
MS (EI) :387 (M+) .
iH-NMR (400MHz, DMSO-d6) b (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) , 35 6 .10 ( 1H, s ) , 7 . 2 9 ( 1H, s ) , 7 . 45 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 93 ( 1H, d, J=9 . OHz ) , 9 . 94 ( 1H, brs ) , 12 .17 ( 1H, brs ) .
Example 28 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-(ethoxycarbonyl)piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl chloroformate, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 25.
MS (EI ) : 419 (M+) .
~H-NMR(400MHz,DMSO-d6)b(ppm): 1.19(3H,t,J=7.3Hz), 1.61-zo 1 . 63 (2H,m) , 1 . 90-1 . 94 (2H,m) , 2.84-2 . 88 (3H,m) , 4.02-4.07 (4H,m) , 5.40 (1H, s) , 7.26 (1H, s) , 7 .41 (1H, d, J=6. 6Hz) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9.80 (lH,brs) , 12.17 (lH,brs) .
Example 29 s5 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from methanesulfonyl-chloride, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in 2o Example 25.
MP:243°C.
MS (EI) :425 (M+) .
1H-NMR(400MHz,DMSO-d6)b(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) , 25 5.41(lH,s), 7.27(lH,s), 7.42(lH,d,J=6.6Hz), 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 93 ( 1H, d, J=9 . OHz ) , 9.84 (lH,brs) , 12.20 (lH,brs) .
Example 30 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-(N,N-30 -dimethylaminocarbonyl)piperidin-4-yl)-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from 1-Chloro-N,N-dimethylformamide, ethyl isonipecotate, 2,1,3-benzoxa-diazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 25.
MS (EI ) : 418 (M+) .

1H-NMR (400MHz, DMSO-d~) 8 (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(lH,m), 3.64-3 . 67 ( 2H, m) , 5 . 4 0 ( 1H, s ) , 7 . 27 ( 1H, s ) , 7 . 41 ( 1H, d, J=6 .
6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9.86 (lH,brs) , 12.18 (lH,brs) .
Example 31 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-guanylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine To a solution of 4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-zo 4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.5 g) in MeOH (30 mL) was added diisopropylethylamine (4.2 g), and 1H-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. The precipitated crystals were collected by zs filtration to give the title compound (1.0 g) as yellow crystals.
MP: >270°C.
MS (EI) : 389 (M~) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.53-1.56(2H,m), 1.86-1.91 20 (2H,m) , 2.47-2.50 (2H,m) , 2.71-2.77 (lH,m) , 3.00-3.03 (2H,m) , 3.32-3.36(3H,br), 5.39(lH,s), 7.26(lH,s), 7 . 39 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 91 ( 1H, d, J=9 . OHz ) , 9 . 7 9 ( 1H, brs ) , 12 . 21 ( 1H, brs ) .
Example 32 25 6-(1-Acetylpiperidin-3-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from acetyl chloride, ethyl nipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 25.
so MP : 219°C .
Anal . CalCd. For : C~oHiaN702 : C, 61. 69; H, 4 . 92; N, 25 .18 .
Found:C,61.36;H,4.90;N,25.12.
MS (EI) : 389 (M+) .
1H-NMR ( 400MHz, DMSO-d6) S (ppm) : 1 . 25-1. 49 ( lH,m) , 1 . 74-1. 78 35 ( 2H, m) , 2 . 00 ( 3H, s ) , 2 . 01-2 . 04 ( 1H, m) , 2 . 4 9-2 . 98 ( 3H, m) , 3 . 7 8-3.81(lH,m), 4.37-4.40(lH,m), 5.29 and 5.42(lH,s), 7.28(lH,s), 7.41-7.48(lH,m), 7.58-7.62(lH,m), 7.92-7.95(lH,m), 9.90 (lH,brs), 12.21(lH,brs).
Example 33 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-ethylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine and acetaldehyde in the same manner as in Example 3.
so MP:231°C.
MS (EI) :375 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 0.99(3H,t,J=7.3Hz), 1.60-1. 63 (2H,m) , 1.85-1.88 (2H,m) , 2.00-2.04 (2H,m) , 2.31-2.34(2H,m), 2.64-2.66(lH,m), 2.97-3.00(2H,m), 5.39(lH,s), s5 7 . 2 6 ( 1H, s ) , 7 . 40 ( 1H, d, J=6 . 6Hz ) , 7 . 58 ( 1H, dd, J=9 .
OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9 . 7 5 ( 1H, brs ) , 12 . 18 ( 1H, brs ) .
Example 34 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-propylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2o The title compound was prepared from 4-(2,1,3-Benzoxa-diazol-4-y1)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine and propionaldehyde in the same manner as in Example 3.
MP:246°C.
25 Anal . Calcd. For : C~lH~sN70: C, 64 . 7 6; H, 5 . 95; N, 25 . 18 .
Found:C,64.23;H,5.87;N,24.86.
MS (EI) :389 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 0.84(3H,t,J=7.3Hz), 1.40-1.45 (2H,m) , 1 .59-1 . 62 (2H,m) , 1 . 82-1. 86 (2H,m) , 2. 00-2. 05 (2H,m) , 30 2 . 21 ( 2H, t, J=7 . 3Hz ) , 2 . 62-2 . 65 ( 1H, m) , 2 . 94-2 . 97 ( 2H, m) , 5 . 3 9 ( 1H, s ) , 7 . 2 6 ( 1H, s ) , 7 . 4 0 ( 1H, d, J=6 . 6Hz ) , 7 . 5 8 ( 1H, dd, J=9 . OHz and ~ . 6Hz ) , 7 . 91 ( 1H, d, J=9 . OHz ) , 9 . 7 7 ( 1H, brs ) , 12 . 18 ( 1H, brs ) .
Example 35 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-iso-35 propylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine and acetone in the same manner as in Example 3.
MP:260°C.
MS (EI) :389 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.22(6H,d,J=7.3Hz), 1.82-3.42 (lOH,m), 5.40(lH,s), 7.27(lH,s), 7.42(lH,d,J=6.6Hz), 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 9.66(lH,brs), 12.22(lH,brs).
so Example 36 4-(2-Bromo-3-cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same z5 manner as in Example 1.
MP: >270°C.
Anal . Calcd. For: C24Ha5BrN602: C, 56. 59; H, 4 . 95;N, 16. 50 .
Found:C,56.47;H,4.87;N,16.52.
MS (EI) : 509 (M+) .
20 1H-NMR (400MHz, DMSO-d6) b (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(lH,s), 7.33(lH,s), 7.56-7.60(2H,m), 7.84(lH,d,J=7.3Hz), 9.81(lH,brs), 12.26(lH,brs).
Example 37 25 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in 3o Example 2.
MP: >270°C.
MS (EI) :409 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 53-1. 56 (2H,m) , 1 . 83 1.87 (2H,m) , 2.46-2.50 (3H,m) , 2.71-2.74 (lH,m) , 3. 00 35 3. 04 (lH,m) , 5.45 (1H, s) , 7 .32 (1H, s) , 7.56-7 .58 (2H,m) , 7 . 81 ( 1H, d, J=7 . 3Hz ) , 9 . 7 4 ( 1H, brs ) , 12 . 2 6 ( 1H, brs ) .

Example 38 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-bromo-3-cyano phenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b]pyridine in the same manner as in Example 3.
MP : >270°C .
MS (EI) :423 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.65-1.71(2H,m), 2.02-2.08 so (3H,m) , 2.29 (3H, s) , 2.48-2.52 (lH,m) , 1 . 66-1 . 69 (lH,m) , 2. 95-2.98(2H,m), 5.50(lH,s), 7.34(lH,s), 7.55-7.57(2H,m), 7. 83 (1H, d, J=7.3Hz) , 9.83 (lH,brs) , 12.32 (lH,brs) .
Example 39 4-(2-Bromo-3-Cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-3-z5 yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl nipeCOtate, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MP:238°C.
20 Anal . Calcd. For : C2qH25BrN6O2 : C, 56 . 56; H, 4 . 95; N, 16 . 50 .
Found:C,56.49;H,4.85;N,16.50.
MS (EI) :509 (M~) .
1H-NMR(400MHz,DMSO-d6)S(ppm): 1.37 and 1.39(9H,s), 1.68-2.06(4H,m), 2.65-2.75(2H,m), 3.30-3.32(lH,m), 3.94-3.97 2s (2H,m) , 5.47 and 5. 49 (1H, s) , 7.34 (1H, s) , 7.58-7 . 61 (2H,m) , 7 . 82-7 . 8 6 ( 1H, m) , 9 . 8 9 ( 1H, brs ) , 12 . 31 ( 1H, brs ) .
Example 40 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate so The title compound was prepared from 4-(2-bromo-3-Cyano-phenyl)-6-(1-t-butoxycarbonylpiperidin-3-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 21.
MP: 225°C.
35 Anal.Calcd.For:C19H17BrN~CF3C00H:C, 48.20;H, 3.47;N, 16.06.
Found:C,47.98;H,3.52;N,15.97.

MS (EI) :409 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1 . 68-1 . 98 (4H,m) , 2 . 65-2 . 68 (lH,m), 3.21-3.33(4H,m), 5.50(lH,s), 7.35(lH,s), 7.55-7.66 (2H,m), 7.84-7.87(lH,m), 8.54(lH,br), 8.96(lH,br), 9.96(lH,brs), 12.36(lH,br).
Example 41 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine w The title compound was prepared from 4-(2-bromo-3-Cyano-Zo phenyl)-5-Cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo-[3,4-b]pyridine trifluoroacetate in the same manner as in Example 3.
MP: 174°C.
MS (EI ) : 423 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 54-1.78 (4H,m) , 2 . 18-2.20 (lH,m), 2.20(3H,s), 2.55-2.58(2H,m), 2.94-2.96(lH,m), 3.31-3 . 34 ( 1H, m) , 5 . 47 ( 1H, s ) , 7 . 33 ( 1H, s ) , 7 . 57-7 . 58 ( 2H, m) , 7.84(lH,d,J=7.3Hz), 10.06(lH,brs), 12.29(lH,brs).
Example 42 zo 4-(2-Bromo-3-Cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title Compound was prepared from ethyl pipecolinate, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI ) : 509 (M+) .
1H-NMR(400MHz,DMSO-d~)b(ppm) : 1.35(9H,s), 1.34-1.90(6H, m), 3.48-3.52(2H,m), 4.42-4.48(lH,m), 5.43 and 5.46(lH,s), 7.36-7.39(lH,m), 7.53-7.57(2H,m), 7.80-7.83(lH,m), 9.68 and 9.82(lH,brs), 12.26(lH,brs).
3o Example 43 4-(2-Bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-2-yl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-s5 dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 21.

MP : 2 32°C .
MS (EI) : 409 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 .27-1 . 98 (5H,m) , 2 . 47-2 . 51 (2H,m), 3.12-3.18(lH,m), 4.7-4.10(lH,m), 4.50-4.57(lH,m), 7.40-7.63(3H,m), 7.79-7.82(2H,m), 8.06(lH,br), 10.93(lH,brs), 12.41(lH,brs).
Example 44 4-(2-Bromo-3-Cyanophenyl)-6-(4-t-butoxycarbonylmorpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine zo The title compound was prepared from ethyl morpholine-2-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazole in the same manner as in Example 1.
MP:219°C.
MS (EI ) : 511 (M+) .
z5 1H-NMR(400MHz,DMSO-d~)b(ppm) : 1.40(9H,s), 2.97-3.10(2H, m), 3.47-3.53(lH,m), 3.77-3.94(3H,m), 4.37-4.39(lH,m), 5.52 and 5.54(lH,s), 7.34-7.36(lH,m), 7.58-7.65(2H,m), 7.94-7.96(lH,m), 9.87 and 9.92(lH,brs), 12.33(lH,brs).
Example 45 20 4-(2-Bromo-3-Cyanophenyl)-5-Cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine trifluoroaCetate The title compound was prepared from 4-(2-bromo-3-cyano-phenyl,)-6-(4-t-butoxycarbonylmorpholin-2-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in 25 Example 21.
MP:236°C.
MS (EI ) : 411 (M+) .
1H-NMR(400MHz,DMSO-d~)b(ppm): 3.02-3.05(lH,m), 3.24-3.33 (3H,m), 3.80-3.84(lH,m), 4.08-4.11(lH,m), 4.82-4.85(lH,m), 30 5.55 (1H, s) , 7.36 (1H, s) , 7.55-7. 62 (2H,m) , 7.84-7. 87 (lH,m) , 9.14(2H,br), 10.04-10.09(lH,brs), 12.40(lH,brs).
Example 46 4-(2-Bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine 35 The title compound was prepared from 4-(2-bromo-3-Cyano-phenyl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo-[3,4-b]pyridine trifluoroacetate in the same manner as in Example 3.
MP : 18 0°C .
MS (EI) :425 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 2 . 18-2.20 (lH,m) , 2 .20 and 2.21 (3H,s), 2.26-2.29(lH,m), 2.58-2.62(lH,m), 2.75-2.78(lH,m), 3.58-3.62(lH,m), 3.88-3.91(lH,m), 4.48-4.50 (lH,m) , 5.51 (1H, s) , 7.35 (1H, s) , 7.56-7. 61 (2H,m) , 7. 84-7.86(lH,m), 9.81 and 9.84(lH,brs), 12.31(lH,brs).
.to Example 47 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2-bromo-3-cyano-s5 benzaldehyde and 3-aminopyrazole in the same manner as in Example 1; and Example 2 followed.
MP : 22 6°C .
MS (EI) :407 (M+) .
~H-NMR (400MHz, DMSO-d~) 8 (ppm) : 2 . 36-2 . 40 (2H,m) , 2 . 95-2. 98 20 (2H,m) , 3.56-3. 60 (3H,m) , 5. 51 (1H, s) , 6. 15 (1H, s) , 7 .34 (1H, s) , 7.56-7. 60 (2H,m) , 7.84 (1H, d, J=7.3Hz) , 9. 93 (lH,brs) , 12 . 32 ( 1H, brs ) .
Example 48 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-25 , 1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl) -2H-pyrazolo [3, 4-.b] pyridine in the same manner as in Example 3.
so MP:233°C.
MS (EI ) : 421 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 2.31 (3H, s) , 2.56-2. 67 (4H,m) , 3.00-3.03 (2H,m) , 5.50 (1H, s) , 6.10 (1H, s) , 7.34 (1H, s) , 7.58 7 . 60 (2H,m) , 7 . 83 (1H, d, J=7.3Hz) , 9. 91 (lH,brs) , 12.29 (lH,brs) .
35 Example 49 4-(2-Bromo-3-cyanophenyl)-6-((N-t-butoxycarbonyl-N-methyl-amino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from glycine ethyl ester hydrochloride, 2-bromo-3-Cyanobenzaldehyde and 3-amino-pyrazole in the same manner as in Example 15.
MS (EI) :469 (M+) .
1H-NMR(400MHz,DMSO-d6)b(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 (lH,d, J=7.3Hz) , 9.78-9.93 (lH,br) , 12.31 (lH,brs) .
.1o Example 50 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-((N-methyl-amino)methyl)-2H-pyrazolo[3,4-b]pyridine trifluoracetate The title compound was prepared from 4-(2-bromo-3-Cyano-phenyl)-6-((N-t-butoxycarbonyl-N-methylamino)methyl)-5-s5 Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 21.
MP:258°C.
MS (EI) :369 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 3.10(3H,s), 4.46-4.66(2H, m), ao 5.50 (1H, s) , 7 .47-7.48 (2H,m) , 7. 65 (1H, s) , 7. 80-7. 81 (2H,m) , 8.09(lH,br), 10.81(lH,brs), 12.38(lH,brs).
Example 51 6-(1-ACetylpiperidin-4-yl)-4-(2-bromo-3-Cyanophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 25 The title compound was prepared from acetyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 25.
MP : >2 8 0°C .
MS (EI) :451 (M~) .
so ~H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1 . 63-1 . 82 (3H,m) , 1. 98-2 . 00 (lH,m), 2.00(3H,s), 2.49-2.51(lH,m), 2.94-3.10(2H,m), 3.89-3.91 (lH,m) , 4.48-4.50 (lH,m) , 5.47 (1H, s) , 7.34 (1H, s) , 7.56-7.58 (2H,m) , 7.84 (lH,d,J=7.3Hz) , 9.81 (lH,brs) , 12.27 (lH,brs) .
Example 52 s5 6-(1-Benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from benzoyl chloride, ethyl isonipecotate, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 25.
MP:>280°C.
MS (FAB) :514 (M++1) .
1H-NMR(400MHz,DMSO-d~)S(ppm): 1.64-2.04(4H, m), 2.76-2.80 (lH,m), 3.05-3.10(2H,m), 3.60-3.63(lH,m), 4.62-4.65(lH,m), 5.48 (1H, s) , 7.34-7.58 (8H,m) , 7. 84 (1H, d, J=7.3Hz) , 9 . 90 ( 1H, brs ) , 12 . 31 ( 1H, brs ) .
1o Example 53 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-la]pyridine The title compound was prepared from methanesulfonyl chloride, ethyl isonipecotate, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 25.
MP:>280°C.
MS (EI) :487 (M+) .
1H-NMR (400MHz, DMSO-d6) b (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(lH,d,J=7.3Hz), 9.84(lH,brs), 12.30(lH,brs).
Example 54 6-(1-t-Butoxycarbonylpiperidin-4-yl)-4-(2-chlorophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl isonipecotate, 2-Chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MP:>280°C.
Anal . CalCd. For : C23H~6C1N50~ : C, 62 . 79; H, 5 . 9 6; N, 15 . 92 .
3o Found:C,62.81;H,5.87;N,16.01.
MS (EI) : 439 (M+) .
1H-NMR (400MHz, DMSO-d~) b (ppm) : 1 .41 (9H, s) , 1 .58-1 . 67 (2H,m) , 1.86-1.91(2H,m), 2.84-2.90(3H,m), 4.06-4.09(2H,m), 5 . 35 ( 1H, s ) , 7 . 21-7 . 33 ( 4H, m) , 7 . 42 ( 1H, d, J=7 . 3Hz ) , 9 . 69 ( 1H, brs ) , 12 .18 ( 1H, brs ) .

Example 55 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 6-(1-t-butoxy-Carbonylpiperidin-4-yl)-4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MP:221°C.
MS (EI) :339 (M+) .
zo 1H-NMR (400MHz, DMSO-d6) 8 (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(lH,d,J=7.2Hz), 8.56(lH,br), 9.76(lH,brs), 12.26 (lH,brs) .
Example 56 z5 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-(1-methyl-piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]
pyridine trifluoroacetate in the same manner as in Example 20 3.
MP: >270°C.
Anal . CalCd. For: Cl9HvoC1N5: C, 64 . 49; H, 5 . 70; N, 19. 79.
Found:C, 64.71;H, 5. 68;N, 19.59.
MS (EI ) : 353 (M+) .
25 1H-NMR (400MHz, DMSO-d6) b (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(lH,m), 2.85-2 . 8 8 ( 2H, m) , 5 . 34 ( 1H, s ) , 7 . 21-7 . 33 ( 4H, m) , 7 . 41 ( 1H, d, J=7 . 3Hz ) , 9.63(lH,brs), 12.17(lH,brs).
Example 57 so 2-Acetyl-6-(1-acetylpiperidin-4-yl)-4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine To a solution of 4-(2-chlorophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in pyridine (1.2 mL) was added acetic anhydride (0.42 mL) at room temperature and the mixture was stirred for two hours.
The mixture was evaporated under reduced pressure and the residue was washed with methanol and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.
MS (EI) :423 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 .58-1. 70 (2H,m) , 1 . 91-1 . 96 (lH,m) , 1.99-2. 00 (lH,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 . 4 9-4 . 52 ( 1H, m) , 5.37(lH,s), 7.32-7.37(3H, m), 7.48(lH,d,J=7.3Hz), 7.84(lH,s), 10.24 (lH,brs) .
.~o Example 58 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and z5 p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column ao chromatography (eluent: hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at -78°C.
Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 25 g) was added and the mixture was stirred for an hour.
After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl so acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A
solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was 35 heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]-decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.
To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo-[3,4-b]pyridine (1.0 g) in methanol (30 mL) was added 4N
HC1 dioxane solution (6.0 mL) at room temperature and the mixture was heated at 60°C for two hours. After so alkalification with sodium bicarbonate, the mixture was 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 : >2 7 0°C .
MS (EI) :360 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 74-1.,80 (5H,m) , 2 . 60-2 . 65 ( 3H, m) , 3 . 31-3 . 3 5 ( 1H, m) , 5 . 98 ( 1H, s ) , 6 . 92 ( 1H, d, J=~ .
6Hz ) , 7.39(lH,s), 7.47(lH,dd,J=9.OHz and 6.~Hz), 7 . 84 ( 1H, d, J=9 . OHz ) , 9 . 33 ( 1H, brs ) , 12 .15 ( 1H, brs ) .
Example 59 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 4-cyclohexanonecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 58.
MS (FAB) :361 (M++1) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.96-2.12(3H,m), 2.22-2.30 (3H,m) , 2.48-2 .51 (lH,m) , 3.27-3.31 (2H,m) , 5.42 (1H, s) , 7.26(lH,s), 7.38-7.46(lH,m), 7.57-7.61(lH,m), 7.88-7.95 (lH,m) , 9.76 (lH,brs) , 12.16 (lH,br) .
Example 60 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-oxocyclopentan-1-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 2-cyclopentanonecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 58.
MS (FAB) :347 (M++1) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.60-1.63(2H,m), 1.86-2.05 (2H,m), 2.31-2.34(2H,m), 3.43-3.46(lH,m), 5.47(lH,s), 7.25 s and 7.30(lH,s), 7.39-7.46(lH,m), 7.56-7.60(lH,m), 7.91-7.94 (lH,m) , 9.90 (lH,brs) , 12.20 (lH,brs) .
Example 61 6-ACetylmethyl-4-(2,1,3-benzoxadiazol-4-y1)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine to The title compound was prepared from ethyl acetoacetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 58.
MP:200°C.
MS (FAB) :321 (M++1)..
s5 1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 2 .22 (3H, s) , 3. 63-3. 66 (2H,m) , 5.48(lH,s), 7.30(lH,s), 7.47(lH,d,J=6.6Hz), ,7 . 61 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 94 ( 1H, d, J=9 . OHz ) , 10.00(lH,brs), 12.21(lH,brs).
Example 62 20 4-(2-Bromo-3-Cyanophenyl)-5-Cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 2-CyClohexanonecarboxylate, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 58.
25 MP:273°C.
MS (EI) :422 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 72-1 . 81 (5H,m) , 2 . 59-2. 65 ( 3H, m) , 3 . 30-3 . 32 ( 1H, m) , 5 . 91 ( 1H, s ) , 7 . 05 ( 1H, d, J=7 .
3Hz ) , 7.40-7.43 (2H,m) , 7.52 (1H, s) , 7.74 (lH,d, J=7.3Hz) , 30 9 . 33 ( 1H, brs ) , 12 . 24 ( 1H, brs ) .
Example 63 6-Acetylmethyl-4-(2-bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl acetoacetate, 35 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 58.

MP:230°C.
MS (EI) :382 (M+) .
~H-NMR (400MHz, DMSO-d6) b (ppm) : 2.23 (3H, s) , 3. 60-3. 67 (2H,m) , 5.50 (1H, s) , 7.39 (1H, s) , 7. 60 (1H, dd, J=7.3Hz and 7.2Hz) , 7.70(lH,d,J=7.3Hz), 7.83(lH,d,J=7.3Hz), 9.97(lH,brs), 12.29 (lH,brs) .
Example 64 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride Zo 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(1-t-butoxy-carbonylpiperidin-4-yl)-2H-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 an hour. The solvent was evaporated under reduced pressure and the residue was Z5 washed by ethanol, and the precipitated crystals were collected by filtration to give the title compound (1.2 g) as yellow crystals.
MS (EI) :339 (M~) .
1H-NMR(400MHz,DMSO-d6)8(ppm): 1.83-1.90(2H,m), 2.07-20 2 . 15 ( 2H, m) , 2 . 94-2 . 97 ( 3H, m) , 3 . 34-3 . 37 ( 2H, m) , 5 . 3 6 ( 1H, s ) , 7 . 22-7 . 33 ( 4H, m) , 7 . 42 ( 1H, d, J=7 . 3Hz ) , 8 . 41 ( 1H, br ) , 9.17 (lH,br) , 9.77 (lH,brs) , 12.27 (lH,brs) .
Example 65 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-25 (piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 64.
3o MP: >270°C.
Anal . Calcd. For: C18H17N70HC1: C, 56 . 09; H, 5 . 20; N, 24 . 10 .
Found:C,55.80;H,5.00;N,23.80.
MS (EI ) : 347 (M+) .
1H-NMR(400MHz,DMSO-d6)8(ppm) : 1.82-1.85(2H, m), 2.14-2.20 35 (2H,m) , 2.93-2. 99 (3H,m) , 3.34-3.36 (2H,m) , 5.40 (1H, s) , 7 . 27 ( 1H, s ) , 7 . 43 ( 1H, d, J=6 . 6Hz ) , 7 . 58 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 92 ( 1H, d, J=9 . OHz ) , 8 . 4 4 ( 1H, br ) , 9 . 21 ( 1H, br ) , 9.87 (lH,brs) , 12.25 (lH,brs) .
Example 66 4-(2-Bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from 4-(2-bromo-3-Cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 64.
zo MP:>270°C.
MS (EI) :409 (M+) .
1H-NMR (400MHz, DMSO-d6) S (ppm) : 1 . 84-1 . 92 (2H,m) , 2 . 07-2 .10 (2H,m), 2.92-2.98(5H,m), 5.48(lH,s), 7.34(lH,s), 7.57-7.59 (2H,m) , 7 . 84 (1H, dd, J=7. 3Hz and 7.2Hz) , 8.30 (lH,br) , 9.04 (lH,br) , 9.90 (lH,brs) , 12.35 (lH,br) .
Example 67 4-(2-Bromo-3-cyanophenyl)-5-Cyano-6-(1-t-butoxycarbonyl pyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 1-t-butoxy-2o Carbonylpyrrolidine-2-carboxylate, 2-bromo-3-Cyano-benzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI) :495 (M+) .
1H-NMR(400MHz,DMSO-d~)&(ppm): 1.47(9H,s), 1.82-1.97(4H, m), 2 . 31 ( 1H, m) , 3 . 50 ( 1H, m) , 4 . 53 ( 1H, m) , 5 . 47 ( 1H, s ) , 7 .
51-7 . 91 (4H,m) , 9.83 (lH,m) , 12.26 (1H, s) .
Example 68 4-(2-Bromo-3-Cyanophenyl)-5-Cyano-6-(pyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine so The title compound was prepared from 4-(2-bromo-3-Cyano-phenyl)-5-Cyano-6-(1-t-butoxycarbonylpyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MP: >240°C.
s5 MS (EI ) : 395 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm): 1.39-1.55(lH, m), 1.97(2H,m), 2.30 (lH,m) , 3.32 (2H,m) , 4.10-4.28 (lH,m) , 5.41 (1H, s) , 6 . 52 ( 1H, s ) , 7 . 34-7 . 47 ( 2H, m) , 7 . 7 0 ( 1H, dd, J=8 . 3Hz and 9 . OHz ) , 11.89 (lH,brs) .
Example 69 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine The title compound was prepared from ethyl 1-t-butoxycarbonylpyrrolidine-2-carboxylate, 2,1,3-benzoxa-Zo diazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI) :433 (M+) .
iH-NMR (400MHz, DMSO-d6) b (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 ) , z5 7.26(lH,s), 7.30-7.40(lH,m), 7.58(lH,dd,J=6.4Hz and 9.6Hz), 7.91(lH,d,J=9.6Hz), 9.86(lH,s), 12.16(lH,s).
Example 70 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(pyrrolidin-2-yl)-2H-pyrazolo[3,4-b]pyridine 2o The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpyrrolidin-2-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MP: >240°C.
25 MS (EI) :333 (M+) .
1H-NMR(400MHz,DMSO-d~)b(ppm): 1.41-1.46(lH,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(lH,s), 7.30-7.42(lH,m), 7.58(lH,dd,J=6.4Hz and 9.6Hz), 7.91(lH,d,J=9.3Hz), 11.87(lH,s).
3o Example 71 6-(1-t-Butoxycarbonylpyrrolidin-2-yl)-4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 1-t-butoxy-carbonylpyrrolidine-2-carboxylate, 2-Chlorobenzaldehyde and 35 3-aminopyrazole in the same manner as in Example 1.
MS (EI ) : 425 (M+) .

1H-NMR(400MHz,DMSO-d6)8(ppm): 1.36(9H,s), 1.86(4H,m), 2 . 32 ( 1H, m) , 3 . 54 ( 1H, m) , 4 . 57 ( 1H, m) , 5 . 3 8 ( 1H, s ) , 7 .

7.27(4H,m), 7.42(lH,d,J=7.6Hz), 9.68(lH,s), 12.17(lH,s).
Example 72 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-Cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl 1-t-butoxy-carbonylpiperidine-4-carboxylate, 2,3-(methylenedioxy)-benzaldehyde and 3-aminopyrazole in the same manner as in so Example 1.
MS (EI) :449 (M+) .
1H-NMR(400MHz,DMSO-d6)b(ppm) : 1.39(lH,m), 1.97-2.13(2H, m), 2.00(2H,m), 2.78-3.15(2H,m), 3.31(lH,m),3.96(2H,s), 5 . 03 ( 1H, d, J=9 . 5Hz ) , 6 . 00-6 . 02 ( 1H, m) , 6 . 64 ( 1H, d, J=2 .
9Hz ) , s5 6.78(lH,d,J=l.7Hz), 7.29(lH,s), 9.46(lH,s), 12.18(lH,s).
Example 73 5-Cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-6-(piperidin-4-yl ) -2H-pyrazolo [ 3, 4-b] pyridine The title compound was prepared from 6-(1-t-butoxy-2o carbonylpiperidin-4-yl)-5-Cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MS (EI) :390 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 27-1 . 88 (5H,m) , 2 . 49-2 . 96 25 (5H,m) , 5.02 (1H, s) , x.00-6. 02 (2H,m) , 6. 66 (lH,m) , 6.76 (2H,m), 7.27(lH,s), 9.98(lH,s), 12.14(lH,s).
Example 74 4-(2-Chlorophneyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine-6-carboxylic acid phenylamide 3o The title compound was prepared from N-phenyloxamiC acid ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI) :375 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 5. 50 (1H, s) , 35 7.13(lH,dd,J=7.lHz and 7.~Hz), 7.25-7.46(7H,m), 7.66(2H,dd,J=8.3Hz), 10.4(lH,s), 10.76(lH,s), 12.3(lH,s).

Example 75 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-6-carboxylic acid phenylamide The title compound was prepared from N-phenyloxamiC acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI) :383 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 5. 59 (1H, s) , 7 .11-7 . 15 (lH,dd,J=7.3Hz and 7.6Hz), 7.33-7.36(3H,m), zo 7 . 51 ( 1H, d, J=6 . 6Hz ) , 7 . 63-7 . 68 ( 3H, m) , 7 . 96 ( 1H, d, J=9 . OHz ) , 10.52 (1H, s) , 10.76 (1H, s) , 12.3 (1H, s) .
Example 76 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-[4-(naphthalen-1-yl)piperazin-1-yl]methyl-2H-pyrazolo[3,4-b]pyridine z5 trihydrochloride 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyl-oxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner ao as in Example 1. To a solution of 4-(2-chlorophenyl)-5-Cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (20 g) in tetrahydrofuran (200 mL) was added a THF solution (49.9 mL) of 1.0 M tetrabutyl-ammonium fluoride and the mixture was stirred at room 2.s temperature for 1 hour. To the reaction mixture was added ethyl acetate (800 mL), and the resulting mixture was washed with a .saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized 3o from ethyl acetate to give 4-(2-Chlorophenyl)-5-Cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) as a white solid. To a solution of 4-(2-Chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine (12.7 g) and carbon tetrabromide (15.4 g) in methylene chloride (340 mL) was added triphenylphosphine (12.2 g) in methylene Chloride (100 mL) under ice-cooling and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (3.84 g) as a pale-yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mZ) was added 1-(naphthalen-1-yl)piperazine (334 mg) and the mixture was stirred under ice-cooling for 30 so minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (500 mg) under ice-cooling and the mixture was stirred under ice-cooling for 6 hours. To the reaction mixture was added water and the mixture was s5 extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol (1:1)). The 20 obtained oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals.
MP:203-205°C (decomposition) MS (EI) :481 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 3.31-3.70 (8H,m) , 4.33 (2H,m) , 25 4 . 8 5 ( 3H, m) , 5 . 54 ( 1H, s ) , 7 . 19 ( 1H, d, J=7 . 3Hz ) , 7 . 2 9-7 . 54 ( 8H, m) , 7 . 67 ( 1H, d, J=8 .1Hz ) , 7 . 92 ( 1H, d, J=7 .1Hz ) , 8 . 15 ( 1H, d, J=7 . 3Hz ) , 10.35 (1H, s) , 11.28 (lH,brs) .
Example 77 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(4-methyl-3o homopiperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine dihydrochloride The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and N-methylhomopiperazine in the same manner as 35 In Example 76.
MP:204-206°C (decomposition) MS (EI) : 382 (M+) .
iH-I~IMR (400MHz, DMSO-d6) S (ppm) : 2.22 (2H,m) , 2.78 (3H, s) , 3.24-4.11(l2H,m), 5.48(lH,s), 7.14-7.35(4H,m), 7 . 45 ( 1H, d, J=8 . OHz ) , 10 . 17 ( 1H, brs ) , 11 . 51 ( 1H, brs ) .
Example 78 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-(4-phenyl-piperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine trihydrochloride The title compound was prepared from 4-(2-chlorophenyl)-so 5-Cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and 1-phenylpiperazine in the same manner as in Example 76.
MP:217-220°C (decomposition) MS (EI) :430 (M+) .
z5 1H-NMR (400MHz, DMSO-d6) b (ppm) : 3.20-4. 00 (9H,m) , 4.27 (2H,m) , 5 . 51 ( 1H, s ) , 6 . 8 6 ( 1H, t, J=7 .1Hz ) , 7 . 01 ( 2H, d, J=8 . OHz ) , 7 . 2 4-7.39(6H,m), 7.45(lH,d,J=9.9Hz), 9.50(lH,brs), 10.37(lH,s), 11.40 (lH,brs) .
Example 79 20 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-phthalimidomethyl-2H-pyrazolo[3,4-b]pyridine To a solution of 4-(2-Chlorophenyl)-5-Cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.8 g) in DMF (10 mL) was added potassium phthalimide (445 mg) 25 under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate.
The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium so sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane (2:1)) to give the~title compound (285 mg) as white crystals.
MP:>250°C
s5 MS (EI ) : 416 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 4 . 66 (2H, d, J=2 . 4Hz) , 5.40(lH,s), 7.24-7.45(5H,m), 7.82-7.94(4H,m), 10.04(lH,s), .12.23(lH,s) .
Example 80 6-Acetyl-4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-(1,1-dimethoxyethyl)-2H-pyrazolo[3,4-b]pyridine was prepared from methyl 2,2-dimethoxypropionate, 2-Chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. To zo a solution of 4-(2-Chlorophenyl)-5-Cyano-4,7-dihydro-6-(1,1-dimethoxyethyl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in dichloromethane (10 mL) was added a trifluoroacetiC acid (10 mL) under ice-Cooling and the mixture was stirred under ice-cooling for 1 hour. The solvent was evaporated and the s5 obtained residue was crystallized from ethyl acetate to give the title compound (370 mg) as white crystals.
MP: 225-228°C (decomposition) MS (EI) :298 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 2 . 56 (3H, s) , 5.49 (1H, s) , ~0 7.25-7.36 (4H,m) , 7.45 (1H, d, J=7. 8Hz) , 10. 12 (1H, s) , 12.50(lH,brs).
Example 81 6-Acetyl-4-(2-bromo-3-cyanoph.enyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 25 The title Compound was prepared from 2-bromo-3-Cyano-benzaldehyde, 3-aminopyrazole and methyl 2,2-dimethoxy-propionate in the same manner as in Example 1.
MP: >230°C
MS (EI) :368 (M+) .
30 1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 2.42 (3H, s) , 5.54 (1H, s) , 7 . 32 ( 1H, brs ) , 7 . 50-7 . 59 ( 2H, m) , 7 . 8 0 ( 1H, dd, J=1. 7Hz and 7.3Hz) , 10.19 (1H, s) , 12.39 (lH,brs) .
Example 82 6-Acetyl-4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title Compound was prepared from 2,1,3-benzoxa-diazole-4-aldehyde, 3-aminopyrazole and methyl 2,2-dimethoxypropionate in the same manner as in Example 1.
MP: 230°C (decomposition) MS (EI) :306 (M+) .
1H-NMR (400MHz, DMSO-d~) 8 (ppm) : 2.55 (3H, s) , 5.54 (1H, s) , 7 . 33 ( 1H, s ) , 7 . 4 9 ( 1H, d, J=6 . 6Hz ) , 7 . 61 ( 1H, dd, J=6 . 6Hz and 8.6Hz), 7.96(lH,d,J=9.2Hz), 10.27(lH,s), 12.36(lH,brs).
Example 83 6-(1-Benzyl-2-oxopyrrolidin-4-yl)-4-(2-Chlorophenyl)-5-so Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 2-Chloro-benzaldehyde, 3-aminopyrazole and methyl 1-benzyl-2-oxopyrrolidine-4-carboxylate in the same manner as in Example 1.

15 MP: >230°C
Anal . CalCd. for: C~4H2pC1N5O: C, 67 . 05; H, 4 . 69;N, 16. 29 .
Found: C, 66. 86;H, 4.56;N, 16.31.
MS (EI ) : 429 (M+) .
1H-NMR ( 400MHz, DMSO-d6) b (ppm) : 2 . 60 ( 1H, dd, J=9 . 5Hz and 20 16.4Hz), 2.81(lH,dd,J=10.5Hz and 16.4Hz), 3.39(lH,m), 3.47 (lH,m) , 4.42 (2H,m) , 5.36 (1H, s) , 7.23-7.43 (lOH,m) , 10.04(lH,s), 12.21(lH,s) .
Example 84 4-(2-Bromo-3-Cyanophenyl)-5-(pyridin-2-yl)-4,7-dihydro-6-25 propyl-2H-pyrazolo[3,4-b]pyridine To a solution of 2-picoline (10 g) in THF (75 mL) was added n-BuLi (113 mmol) at -40°C. Further, methyl butanoate (15.8 mL) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The ~o 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. A solution of 2-bromo-3-s5 Cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2-(2-oxopentanyl ) pyridine ( 1 . 2 g) and ammonium acetate ( 0 . 6 g) in acetic acid (7 mL) was heated under reflux for 11 hours.
The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in Chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the so obtained crystals (520 mg) under ice-Cooling, and the mixture was stirred overnight. Under iCe-Cooling, an aqueous sodium acetate (3.4 g) solution was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under 25 reduced pressure to give oil. The obtained oil was purified by silica gel column Chromatography (eluent:
chloroform-methanol (9:1)) to give a yellow solid (530 mg).
To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred with 2o heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give oil. To the obtained oil was added water and the mixture was extracted with ethyl acetate. The extract was washed a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as a pale-yellow Crystal.
MP: 205-208°C (decomposition) so Anal . Calcd. for : CZ1HIBBrN5: C, 60 . 01; H, 4 . 32; N, 16 . 66 .
Found:C,59.83;H,4.42;N,16.26.
MS (EI) :420 (M+) .
iH-NMR (400MHz, DMSO-d6) b (ppm) : 0. 83 (3H, t, J=7 . 6Hz) , 1. 62 (2H,m) , 2.24 (lH,m) , 2.33 (lH,m) , 5. 93 (1H, s) , 6. 98 (1H, dd, 35 J=4 . 9Hz and 7 . 3Hz ) , 7 . 0 5 ( 1H, d, J=7 . 8Hz ) , 7 . 2 8 ( 1H, m) , 7 . 39 ( 1H, m) , 7 . 51-7 . 60 ( 3H, m) , 8 . 36 ( 1H, d, J=3 . 6Hz ) , 8 .
52 ( 1H, s ) , 11 . 84 (1H, s) .
Example 85 6-(1-tart-Butoxycarbonylpyrrolidin-3-yl)-4-(2-Chloro-phenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine To a solution of methyl 1-benzyl-2-oxopyrrolidine-4-Carboxylate (10.9 g) in THF (50 mL) was added 1.0 M borane in THF (84 mL) under ice-cooling and the mixture was refluxed for 1 hour. Decomposition of excess borane and boron complexes was effected by the dropwise addition of 30 so mL of methanolic hydrogen chloride followed by refluxing for 1 hour. After removal of the solvents under reduced pressure another 30 mL of methanoliC hydrogen chloride was added, and the mixture was refluxed an additional 1 hour.
The solvents were again removed in Uacuo and the residue s5 was treated with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column Chromatography (eluent:
hexane-ethyl acetate (1:1)) to give methyl 1-benzyl-3-2o pyrrolidinecarboxylate (4.8 g) as a pale yellow oil. A
suspension of methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 mg), 5o palladium on carbon (300 mg) and ammonium formate (2.8 g) in methanol (50 mL)-water (5 mL) was refluxed for 2 hours. The reaction mixture was filtered through Celite 25 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 3o dichloromethane (20 mL) was added dimethylaminopyridine (161 mg) and di-tart-butyldicarbonate (3.4 g) at 0°C and the mixture was stirred for 13 hours. The mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:
35 hexane-ethyl acetate (2:1)) to give methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added n-BuLi (12.4 mmol) at -78°C. Further, methyl 1-tart-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2:1)) to give 1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-2-cyanoethan-1-one (2.35 g) io as a colorless oil. A solution of 2-chlorophenylaldehyde (1.4 g), 3-aminopyrazole (819 mg) and 1-(1-tart-butoxy-carbonylpyrrolidin-3-yl)-2-cyanoethan-1-one (2.35 g) in acetonitrile (10 mL) was heated under reflux for 1.5 hours.
The reaction mixture was cooled to room temperature, and s5 the precipitated crystals were collected by filtration to give the title compound (2.18 g) as colorless crystals.
Anal . Calcd. For : C~2H~4C1N50~ : C, 62 . 04; H, 5 . 68; N, 16. 44 .
Found:C,61.94;H,5.69;N,16.45.
MS (EI) :425 (M+) .
20 1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 14 (9H, s) , 2 . 07 (lH,m) , 2.32 (lH,m) , 3.29-3.58 (5H,m) , 5.37 (1H, s) , 7.22-7.34 (4H,m) , 7 . 42 ( 1H, d, J=8 . 3Hz ) , 9 . 7 8 ( 1H, s ) , 12 . 2 0 ( 1H, s ) .
Example 86 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(pyrrolidin-3-yl)-as 2H-pyrazolo [ 3, 4-b] pyridine 6-(1-tart-Butoxycarbonylpyrrolidin-3-yl)-4-(2-chloro-phenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (706 mg) was added to 4N-HCl dioxane solution (5 mL) at room temperature and the mixture was stirred for 2 hours. The 3o solvent was evaporated under reduced pressure and the residue was washed by ethanol-ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (460 mg) as colorless crystals.
MP: 210-215°C (decomposition) 35 MS (EI) :325 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 2.24 (2H,m) , 3. 15 (lH,m) , 3.26-3.55(3H,m), 3.64(lH,m), 5.34(lH,s), 5.40(lH,brs), 7.23-7.32 (4H,m) , 7.43 (1H, d, J=7.3Hz) , 9.38 (lH,brs) , 9 . 51 ( 1H, brs ) , 9 . 97 ( 1H, s ) .
Example 87 4-(2,1,3-Benzoxadiazol-4-yl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, Meldrum's acid, 2-(2-oxopentanyl)pyridine and ammonium acetate in the same so manner as in Example 84.
MS (EI) :358 (M~) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 0. 84 (3H, t, J=7 . 3Hz) , 1. 64 (2H,m) , 2.27 (lH,m) , 2.35 (lH,m) , 5.96 (1H, s) , 6.95 (lH,m) , 7 .11-7 .18 ( 3H, m) , 7 . 4 0 ( 1H, m) , 7 . 51 ( 1H, m) , 7 . 69 ( 1H, d, J=9 . 3Hz ) , z5 8.35 (lH,m) , 8.54 (1H, s) , 11.78 (lH,brs) .
Example 88 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(indan-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl isonipecotate, 20 4-indancarboxaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI ) : 445 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (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) , 25 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-y1)-2H-pyrazolo[3,4-b]pyridine so The title compound was prepared from ethyl isonipecotate, 7-(2,3-dihydrobenzo[b]furan)Carboxaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI) :445 (M+) .
iH-NMR (400MHz, DMSO-d6) b (ppm) : 1 .42 (9H, s) , 1.57-1 . 66 (2H,m) , 35 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 (lH,m) , 6. 84 (1H, d, J=7.lHz) , 7.05(lH,d,J=6.6Hz), 7.22(lH,s), 9.52(lH,s), 12.06(lH,s).
Example 90 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-Cyano-4,7-dihydro-4 ( 3, 4-dihydro-2H-benzopyran-8-yl ) -2H-pyrazolo [ 3, 4-b] pyridine The title compound was prepared from ethyl isonipecotate, 8-(3,4-dihydro-2H-benzopyrane)carboxaldehyde and 3-amino-pyrazole in the same manner as in Example 1.
MS (EI) :461 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1. 42 (9H, s) , 1 .58-1 . 69 (2H,m) , so 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 (lH,m) , 6. 84-6.89 (2H,m) , 7.21 (1H, s) , 9.48~1H,s), 12.03(lH,s).
Example 91 6-(1-t-Butoxycarbonylpiperidin-4-yl)-4-(2-Chloro-3-trifluoromethylphenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from ethyl isonipecotate, 2-Chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
2o MS (EI) :461 (M+) .
1H-NMR (400MHz, DMSO-d6) ~ (ppm) : 1. 41 (9H, s) , 1 . 62 (2H,m) , 1 .89 (2H,m) , 2. 60-2. 90 (3H,m) , 4.10 (2H,m) , 5.54 (1H, s) , 7.32 (1H, s) , 7.52-7.56 (2H,m) , 7.75 (1H, d, J=9.3Hz) , 9. 79 (1H, s) , 12.25 (1H, s) .
Example 92 5-Cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from 6-(1-t-butoxy-Carbonylpiperidin-4-yl)-5-Cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MS (EI) :361 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (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) , 4.1~-4.27 (2H,m) , 5.15 (1H, s) , 6.74 (lH,m) , 6.83-6.89 (2H,m) , 7.22(lH,s), 9.54(lH,s).

Example 93 5-Cyano-4,7-dihydro-4-(indan-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from 6-(1-t-butoxy-s Carbonylpiperidin-4-yl)-5-Cyano-4,7-dihydro-4-(indan-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 2.
MS (EI) :345 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1. 80-1 . 99 (4H,m) , 2 . 14 (2H,m) , 20 2.58 (lH,m) , 2.82-2.95 (6H,m) , 3.30-3.50 (2H,m) , 4.97 (1H, s) , 6.90(lH,m), 7.04-7.09(2H,m), 7.17(lH,s), 8.37(lH,m), 9 .10 ( 1H, m) , 9 . 62 ( 1H, s ) , 12 .18 ( 1H, brs ) .
Example 94 5-Cyano-4,7-dihydro-4-(indan-4-yl)-6-(1-methylpiperidin-4-15 yl ) -2H-pyrazolo [ 3, 4-b] pyridine The title compound was prepared from 5-Cyano-4,7-dihydro-4-(indan-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 3.
iH-NMR (400MHz, DMSO-d6) b (ppm) : 1.56 (2H,m) , 1 . 84-1 . 98 ( 6H,m) , 20 2.15 (2H,m) , 2.58 (lH,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(lH,brs), 12.10(lH,brs).
Example 95 5-Cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-25 (1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from 5-Cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same 3o manner as in Example 3.
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1.90-2 . 00 (4H,m) , 2 . 24 (2H,m) , 2.73-2.75(SH,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 (lH,m) , 6. 84-6. 89 (2H,m) , 7.22 (1H, s) , 9.58 (1H, s) , 9.80 (lH,m) , 12.15 (1H, s) .
35 Example 96 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-2-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from methanesulfonyl chloride, ethyl pipecolinate, 2,1,3-benzoxadiazole-4 aldehyde and 3-aminopyrazole in the same manner as in Example 25.
MS (EI) : 425 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (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 .

zo 7.93 (1H, m) , 9.80 and 9.82 (1H, brs) , 12.16 (1H, brs) .
Example 97 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride s5 The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-4,7-di.hydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 64.
MS (EI) : 361 (M~) .
20 1H-NMR (400MHz, DMSO-d6) b (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(1Hy s), 7 . 28 ( 1H, s ) , 7 . 44 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 93 ( 1H, d, J=9 . OHz ) , 9 . 92 ( 1H, brs ) , 12 . 2 6 ( 1H, brs ) .
25 Example 98 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 1,2-dihydro-1-3o methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI ) : 371 (M+) .
~H-NMR (400MHz, DMSO-d6) b (ppm) : 3. 46 (3H, s) , 5.42 (1H, s) , 35 6.34 (1H, d, J=7.2Hz) , 6.56 (1H, s) , 7.33 (1H, s) , 7.52 (1H, d, J=7 . 2Hz ) , 7 . 61 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 8 0 ( 1H, d, J=6.6Hz), 7.95(1H, d, J=9.OHz), 10.33(1H, brs), 12.29(1H, brs ) .
Example 99 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-( 1, 2, 5, 6-tetrahydropyridin-3-yl ) -2H-pyrazolo [ 3, 4-.,b] pyridine hydrochloride The title compound was prepared from 1,2,3,4-tetrahydropyridine-3-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same so manner as in Examples 1 and 2.
MS (EI ) : 345 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 2 . 42-2 . 44 (2H, m) , 3. 11-3.14 (2H, m) , 3. 84-3.87 (2H, m) , 4.39 (1H, br) , 5.46 (1H, s) , 6.36(1H, s), 7.30(1H, s), 7.49(1H, d, J=6.6Hz), 7.56(1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 94 ( 1H, d, J=9 . OHz ) , 9 . 39 ( 2H, br) , 10.06 (1H, brs) .
Example 100 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-2o b] pyridine The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
MS (EI) : 359 (M+) .
1H-NMR (400MHz, DMSO-d6) b (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 . 2 6 ( 1H, s ) , 7 . 43 ( 1H, d, J=6 . 6Hz ) , 7 . 59 ( 1H, dd, J=9 . OHz and 6.6Hz), 7.92(1H, d, J=9.OHz), 9.87(1H, brs), 12.16(1H, brs).
so Example 101 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-(methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from 2-methylglycine ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.

MS (EI) : 321 (M+) 1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 56 (3H, d, J=6. 8Hz) , 3. 07 (3H, s) , 4.59-4. 68 (3H, m) , 5. 66 (1H, s) , 7.29 (1H, d, J=6 . 6Hz ) , 7 . 4 4 ( 1H, s ) , 7 . 52 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7.87(1H, d,~J=9.OHz), 8.22(1H, br), 8.44(1H, br), 10.95(1H, brs) .
Example 102 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl)-2H-pyrazolo[3,4-2o b] pyridine The title compound was prepared from 1,2-dihydro-1-methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
15 MS (EI ) : 433 (M+) .
zH-NMR (400MHz, DMSO-d6) 8 (ppm) : 3. 46 (3H, s) , 5.35 (1H, s) , 6.37 (1H, d, J=7.2Hz) , 6. 61 (1H, s) , 7.38 (1H, s) , 7.60 (1H, dd, J=7.3Hz and 7.2Hz), 7.72-7.86(3H, m), 10.31(1H, brs), 12 . 37 ( 1H, brs ) .
2o Example 103 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-(methylamino)cyclohexyl)-2H-pyrazolo[3,4-.b]pyridine 2 hydrochloride The title compound was prepared from 4-25 aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
MS (EI) : 436 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1 . 39 (2H, m) , 1 . 80-1 .90 (4H, so m), 2.15-2.16(2H, m), 2.84-2.86(1H, m), 3.14-3.16(1H, m), 4.20(2H, br), 5.46(1H, s), 7.33(1H, s), 7.56-7.57(2H, m), 7.82 (1H, d, J=7.3Hz) , 8. 98 (2H, br) , 9. 80 (1H, brs) .
Example 104 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2,5,6-s5 tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from 1,2,5,6-tetrahydropyridine-3-Carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 407 (M+) .
1H-NMR (400MHz, DMSO-d~) 8 (ppm) : 2 . 43-2 . 44 (2H, m) , 3.13-3. 15 (2H, m) , 3.70-3.72 (2H, br) , 3.86-3. 88 (2H, m) , 5.54 (1H, s), 6.41(1H, s), 7.36(1H, s), 7.58(1H, dd, J=7.3Hz and 7 . 2Hz ) , 7 . 8 4 ( 1H, d, J=7 . 3Hz ) , 7 . 8 6 ( 1H, d, J=7 . 3Hz ) , 9 .
32 ( 2H, zo br), 10.03(1H, brs).
Example 105 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(4-(dimethylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-bromo-3-s5 Cyanophenyl)-5-cyano-4,7-dihydro-~-(4-(methylamino)cyclohexyl)-2H-pyrazolo[3,4-.b]pyridine in the same manner as in Example 3.
MS (EI) : 450 (M+) .
iH-NMR (400MHz, DMSO-d~) 8 (ppm) : 1 .26-1 .29 (2H, m) , 1 .76-20 1.93(6H, m), 2.27(6H, s), 2.34-2.36(1H, m), 2.63-2.66(1H, m) , 5 . 45 ( 1H, s ) , 7 . 33 ( 1H, s ) , 7 . 56-7 . 60 ( 2H, m) , 7 . 82 ( 1H, d, J=7.3Hz) , 9.74 (1H, brs) , 12.27 (1H, s) .
Example 106 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-25 1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
so MS (EI) : 420 (M+) .
1H-NMR (400MHz, DMSO-d6) ~ (ppm) : 2.21-2 . 22 (2H, m) , 2 .28 (3H, s) , 2.48-2.49 (2H, m) , 3. 08-3.12 (2H, m) , 5.49 (1H, s) , 6.15 (1H, s) , 7.33 (1H, s) , 7.56-7.61 (2H, m) , 7.84 (1H, dd, J=7.3Hz and 7.2Hz), 9.87(1H, brs), 12.26(1H, brs).
35 Example 107 6-(exo-2-AzabicyClo[2,2,2]octan-6-vl)-4-(2,1,3-benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from exo-2-azabicyclo[2,2,2]octane-6-Carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) :373 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (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 so 3. 10 (2H, m) , 3.43-3.48 (4H, m) , 5.39-5.43 (1H, s) , 7 .26 7.28(1H, m), 7.44-7.47(1H, m), 7.57-7.61(1H, m), 7.93-7.95(1H, m), 8.87-9.03(1H, br), 9.46-9.52(1H, br), 9.73 and 9.80(1H, brs).
Example 108 6- ( endo-2-Azabicyclo [2, 2, 2 ] octan-6-yl) -4- (2, 1, 3-benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from endo-2-azabicyclo[2,2,2]octane-~-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) : 373 (M+) .
1H-NMR (400MHz, DMSO-d6)8(ppm): 1.67-1.73(3H, m), 2.03-2.13(4H, m), 3.04-3.06(1H, m), 3.34-3.57(5H, m), 5.49(1H, s),7.30(1H, s), 7.50-7.51(1H, m), 7.58-7.60(1H, m), 7.92-7.94 (1H, m) , 8.07 (1H, br) , 9.79 (1H, br) , 9.89 (1H, br) .
Example 109 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(exo-2-methyl-2-azabicyClo[2,2,2]octan-6-yl)-2H-pyrazolo[3,4-so b] pyridine The title compound was prepared from 6-(exo-2-azabicyclo[2,2,2]octan-6-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
MS (EI) : 387 (M+) .
1H-NMR ( 400MHz, DMSO-d~) b (ppm) : 1 . 43-1. 44 ( 1H, m) , 1 . 70-7~

1.90(5H, m), 2.11-2.13(1H, m), 2.38-2.46(4H, m), 3.00-3.02(1H, m), 3.32-3.36(2H, m), 5.38 and 5.40(1H, s), 7.25-7.27(1H, m), 7.38-7.42(1H, m), 7.56-7.61(1H, m), 7.90-7.93 (1H, m) , 9.73 (1H, br) , 12.23 (1H, br) .
Example 110 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-Carboxylate 2 hydrobromide A solution of 2,1,3-benzoxadiazole-4-aldehyde (3.0 g), so Meldrum's acid (3.0 g), ethyl 3-keto-3-(1-benzylcarbonylpiperidin-4-yl)propionate (~.8 g) and ammonium acetate (1.8 g) in acetic acid (20 mL) was stirred under reflux for 12 hrs. The reaction mixture was cooled to room temperature, and the solvent was evaporated under Z5 reduced pressure to give colorless crystals (4.7 g). To a solution of dimethylformamide (2.7 g) in chloroform (10 mL) were added phosphorus oxychloride (3.4 mL) and a solution of the obtained colorless crystals (4.7 g) in chloroform (10 mL) under ice-cooling, and the mixture was stirred 20 overnight. Under ice-cooling, an aqueous sodium acetate (37.8 g) solution was added and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.4 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to 3o 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 a solution of the obtained colorless 35 Crystals in aCetiC aCld (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 crystal was purified by recrystalization from EtOH to give the title compound (630 mg) as Colorless crystals.
MS (EI) : 394 (M+) .
1H-NMR (400MHz, DMSO-d6)8(ppm): 0.77(3H, t, J=7.3Hz), 1.80-2 . 16 ( 4H, m) , 2 . 90-2 . 93 ( 2H, m) , 3 . 4 0-3 . 4 3 ( 2H, m) , 3 . 8 0 ( 2H, q, J=7.3Hz), 4.12-4.15(1H, m), 4.50(2H, br), 5.67(1H, s), 7 . 17 ( 1H, d, J=6 . 6Hz ) , 7 . 2 6 ( 1H, s ) , 7 . 51 ( 1H, dd, J=9 . OHz and 6.6Hz) , 7.79 (1H, d, J=9.OHz) , 8.10 (lH,br) , 8.74 (1H, br) , 9.38 (1H, brs) .
Example 111 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(endo-2-methyl-2-azabicyclo[2,2,2]octan-6-yl)-2H-pyrazolo[3,4-s5 b] pyridine The title compound was prepared from 6-(endo-2-azabicyclo[2,2,2]octan-6-yl)-4-(2,1,3-benZOxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
ao MS (EI) : 387 (M+) .
1H-NMR (400MHz, DMSO-d6)S(ppm): 1.43-1.47(2H, m), 1.60-1.~4(2H, m), 1.81-1.82(1H, m), 1.79-2.06(2H, m), 2.24-2.26(1H, m), 2.36(3H, s), 2.76-2.80(2H, m), 3.19-3.22(1H, m), 5.43(1H, s), 7.25(1H, s), 7.42-7.46(1H, m), 7.57-7.60(1H, m), 7.90-7.94(1H, m), 10.79(1H, brs), 12.16(1H, brs ) .
Example 112 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-so carboxylate 2 hydrochloride The title compound was prepared from ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-Carboxylate in the same manner as in Example 3.
35 MS (EI ) : 408 (M+) .
1H-NMR (400MHz, DMSO-d~)b(ppm): 0.75(3H, t, J=7.3Hz), 1.55-1.56(1H, m), 1.71-1.73(1H, m), 1.87-2.06(4H, m), 2.17(3H, s) , 2.84-2.87 (2H, m) , 3.78 (2H, q, J=7.3Hz) , 3.93-3. 96 (1H, m) , . 68 ( 1H, s ) , 7 . 12 ( 1H, d, J=6 . 6Hz ) , 7 . 22 ( 1H, s ) , 7 . 4 9 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 77 ( 1H, d, J=9 . OHz ) , 9 . 32 ( 1H, brs ) , 5 12.06 (1H, brs) .
Example 113 4-(2-Bromophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from ethyl nipeCOtate, so 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) : 383 (M+) .
1H-NMR (400MHz, DMSO-d6) b (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, z5 s), 7.16(1H, dd, J=7.3Hz and 7.2Hz), 7.23-7.27(2H, m), 7 . 35 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 7 . 59 ( 1H, d, J=7 . 3Hz ) , 8 . 41 ( 1H, br ) , 9 .14 ( 1H, br ) , 9 . 7 3 ( 1H, brs ) , 12 . 21 ( 1H, brs ) .
Example 114 5-Cyano-4,7-dihydro-4-(2-methoxyph.enyl)-6-(piperidin-4-yl)-20 2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from ethyl nipecotate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) : 335 (M+) .
2s 1H-NMR (400MHz, DMSO-d6)8(ppm): 1.87-1.95(2H, m), 2.14-2.20(2H, m~, 2.94-3.03(3H, m), 3.32-3.36(2H, m), 3.82(3H, s ) , 5 . 21 ( 1H, s ) , 6 . 88 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 6 . 99 ( 1H, d, J=7.3Hz), 7.05(1H, d, J=7.3Hz), 7.15-7.20(2H, m), 8.44 (1H, br) , 9.17 (1H, br) , 9.53 (1H, brs) , 12.11 (1H, brs) .
3o Example 115 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from ethyl nipecotate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same 35 manner as in Examples 1 and 2.
M5 (EI ) : 373 (M+) .

1H-NMR (400MHz, DMSO-d~) 8 (ppm) : 1 . 84-1. 90 (2H, m) , 2.16-2.20(2H, m), 2.94-3.00(3H, m), 3.32-3.38(2H, m), 5.44(1H, s), 7.24-7.36(3H, m), 7.56(1H, d, J=7.3Hz), 8.52(1H, br), 9.24(1H, br), 9.79(1H, brs), 12.29(1H, brs).
Example 116 4-(2-Bromophenyl)-5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2-bromophenyl)-5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-so b]pyridine in the same manner as in Example 3.
MS (EI ) : 397 (M+) .
1H-NMR (400MHz, DMSO-d6) S (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), s5 7 . 3 6 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 7 . 60 ( 1H, d, J=7 . 3Hz ) , 9 . 60 ( 1H, brs ) , 12 . 16 ( 1H, brs ) .
Example 117 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2o The title compound was prepared from 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 3.
MS (EI ) : 349 (M+) .
1H-NMR (400MHz, DMSO-d~)b(ppm): 1.56-1.66(2H, m), 1.86-25 1. 92 ( 2H, m) , 2 . 01-2 . 04 ( 2H, m) , 2 .17 ( 3H, s ) , 2 . 64-2 . 67 ( 1H, m) , 2.86-2.88 (2H, m) , 3.84 (3H, s) , 5.20 (1H, s) , 6.90 (1H, dd, J=7.3Hz and 7.2Hz), 6.98(1H, d, J=7.3Hz), 7.05(1H, d, J=7.3Hz), 7.16-7.19(2H, m), 9.41(1H, brs), 12.01(1H, brs).
Example 118 so 5-Cyano-4-(2,3-diChlorophenyl)-4,7-dihydro-6-(1 methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-cyano-4-(2,3 dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as 35 in Example 3.
MS (EI) : 387 (M+) .

1H-NMR (400MHz, DMSO-d~) b (ppm) : 0. 57-1 . 65 (2H, m) , 1 . 85-1 . 90 (2H, m) , 2. 01-2. 06 (2H, m) , 2. 17 (3H, s) , 2.59-2. 66 (1H, m), 2.86-2.89(2H, m), 5.43(1H, s), 7.23(1H, d, J=7.3Hz), 7.29(1H, s), 7.35(1H, dd, J=7.3Hz and 7.2Hz), 7.51(1H, d, J=7.3Hz), 9.65(1H, brs), 12.18(1H, brs).
Example 119 5-Cyano-4,7-dihydro-4-(2-fluorophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from ethyl nipecotate, so 2-fluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) : 323 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 85-1 . 89 (2H, m) , 2 . 12-2.20(2H, m), 2.90-2.98(3H, m), 3.33-3.39(2H, m), 5.20(1H, s), 7.14-7.28(5H, m), 8.37(1H, br), 9.09(1H, br), 9.66(1H, brs ) , 12 . 23 ( 1H, brs ) .
Example 120 5-Cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride 2o The title compound was prepared from ethyl nipecotate, 2,3-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 341 (M+) .
1H-NMR (400MHz, DMSO-d~)b(ppm): 1.84-1.88(2H, m), 2.14-2.19 (2H, m) , 2.95-3. 00 (3H, m) , 3.33-3.38 (2H, m) , 5.26 (1H, s ) , 7 . 03 ( 1H, d, J=7 . 3Hz ) , 7 .18 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 7.26-7.31 (2H, m) , 8. 80 (2H, br) , 9.74 (1H, brs) , 12.29 (1H, brs ) .
Example 121 ao 5-Cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-y1)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from ethyl nipecotate, 2,6-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 341 (M+) .
~H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1 . 76-1 . 84 (2H, m) , 2. 13-2.18 (2H, m) , 2.91-2.95 (3H, m) , 3.28-3.30 (2H, m) , 5.35 (1H, s) , 7. 02-7. 07 (2H, m) , 7.31-7.38 (2H, m) , 8 .77 (2H, br) , 9 . 68 ( 1H, brs ) , 12 . 22 ( 1H, brs ) .
Example 122 5-Cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from ethyl nipecotate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
so MS (EI ) : 351 (M+) .
1H-NMR (400MHz, DMSO-d6)b(ppm): 1.86-1.93(2H, m), 2.17-2.23(2H, m), 2.50(3H, s), 2.95-3.00(3H, m),3.36-3.40(4H, m), 5.36(1H, s), 7.14-7.33(5H, m), 8.49(1H, br), 9.22(1H, br), 9 . 63 ( 1H, brs ) .
Example 123 5-Cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from ethyl nipecotate, 2,6-dichlorobenzaldehyde and 3-aminopyrazole in the same 2o manner as in Examples 1 and 2.
MS (EI) : 373 (M~) .
1H-NMR (400MHz, DMSO-d6)b(ppm): 1.80-1.84(2H, m), 2.12-2.20 (2H, m) , 2.90-2.98 (3H, m) , 3.30-3.33 (2H, m) , 5. 92 (1H, s), 7.19(1H, s), 7.29(1H, dd, J=7.3Hz and 7.2Hz), 7.38(1H, 25 d, J=7 . 3Hz ) , 7 . 51 ( 1H, d, J=7 . 3Hz ) , 8 . 41 ( 1H, br) , 9 . 16 ( 1H, br), 9.73(1H, brs), 12.18(1H, brs).
Example 124 5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine so 2 hydrochloride The title compound was prepared from ethyl nipecotate, 2-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2:
MS (EI) : 373 (M+) .
s5 1H-NMR (400MHz, DMSO-d6) S (ppm) : 1 . 83-1 . 90 (2H, m) , 2 . 18-2.26(2H, m), 2.92-3.00(3H, m), 3.38-3.43(2H, m), 4.16(2H, br) , 5.22 (1H, s) , 7. 06 (1H, s) , 7. 42-7.44 (2H, m) , 7 . 63-7. 69 (2H, m) , 8.57 (1H, br) , 9.30 (1H, br) , 9.77 (1H, br) .
Example 125 5-Cyano-4,7-dihydro-4-(2-fluorophenyl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-Cyano-4,7-dihydro-4- (2-fluorophenyl) -6- (piperidin-4-yl) -2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 3.
to MS (EI ) : 337 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (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 ) .
s5 Example 126 5-Cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-(1 methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-Cyano-4-(2,3 difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-2o pyrazolo[3,4-°b]pyridine hydrochloride in the same manner as in Example 3.
MS (EI ) : 355 (M+) .
1H-NMR (400MHz, DMSO-d6)8(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) , 25 2.84-2. 88 (2H, m) , 5.23 (1H, s) , 7.00 (1H, dd, J=7.3Hz and 7.2Hz), 7.16(1H, d, J=7.3Hz), 7.27-7.30(2H, m), 9.66(1H, brs ) , 12 . 2 4 ( 1H, brs ) .
Example 127 5-Cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(1-so methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 3.
35 MS (EI ) : 355 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 49-1. 53 (2H, m) , 1 . 82-1. 86 (2H, m) , 1 .96-2.01 (2H, m) , 2 .15 (3H, s) , 2.48-2.51 (1H, m), 2.83-2.86(2H, m), 5.31(1H, s), 7.00-7.05(2H, m), 7.29-7 . 31 ( 2H, m) , 9 . 60 ( 1H, brs ) , 12 .15 ( 1H, brs ) .
Example 128 5-Cyano-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from ethyl nipecotate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
zo MS (EI ) : 351 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 84-1. 93 (2H, m) , 2 . 17-2.23 (2H, m) , 2. 94-3.00 (3H, m) , 3.35-3.38 (2H, m) , 4. 42 (2H, br) , 5.40 (1H, s) , 7.30 (1H, s) , 7.46-7.51 (2H, m) , 7.71 (1H, dd, J=7.3Hz and 7.2Hz), 7.90(1H, d, J=7.3Hz), 8.61(1H, br), s5 9.36 (1H, br) , 9.87 (1H, brs) .
Example 129 5-Cyano-4,7-dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from ethyl nipecotate, 2o benzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 305 (M+) .
1H-NMR (400MHz, DMSO-d6) b (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, 25 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 3o The title compound was prepared from 5-Cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 3.
MS (EI) : 366 (M+) , 35 1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 58-1. 66 (2H, m) , 1 . 83-1 . 8 9 ( 2H, m) , 1 . 97-2 . 02 ( 2H, m) , 2 .15 ( 3H, s ) , 2 . 50 ( 3H, s ) , ~6 2.62-2.65(1H, m), 2.84-2.87(2H, m), 5.32(1H, s), 7.12-7 . 3 0 ( 5H, m) , 9 . 57 ( 1H, brs ) , 12 . 18 ( 1H, brs ) .
Example 131 5-Cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-Cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 3.
so MS (EI) : 387 (M+) .
1H-NMR (400MHz, DMSO-dG)b(ppm): 1.52-1.56(2H, m), 1.83-1.87(2H, m), 1.99-2.06(2H, m), 2.15(3H, s), 2.52-2.55(1H, s), 2.83-2.87(2H, m), 5.90(1H, s), 7.17(1H, s), 7.28(1H, dd, J=7.3Hz and 7.2Hz), 7.36(1H, d, J=7.3Hz), 7.48(1H, d, s5 J=7.3Hz), 9.67(1H, brs), 12.12(1H, brs).
Example 132 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-Cyano-4,7-ao dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 3.
MS (EI ) : 387 (M+) .
1H-NMR (400MHz, DMSO-d6)S(ppm): 1.57-1.62(2H, m), 1.83 25 1.86(2H, m), 1.97-2.03(2H, m), 2.16(3H, s), 2.60-2.63(1H, m), 2.84-2.87(2H, m), 5.18(1H, s), 7.05(1H, s), 7.40 7 . 42 ( 2H, m) , 7 . 62-7 . 68 (2H, m) , 9 . 69 ( 1H, brs ) , 12 . 23 ( 1H, brs).
Example 133 30 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-cyano-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner 35 as in Example 3.
MS (EI ) : 365 (M+) .

1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 58-1 . 67 (2H, m) , 1 .86-1.90(2H, m), 1.99-2.06(2H, m), 2.16(3H, s), 2.58-2.61(1H, m), 2.86-2.90(2H, m), 5.36(1H, s), 7.26(1H, s), 7.42-7.48(2H, m), 7.69(1H, dd, J=7.3Hz and 7.2Hz), 7.88(1H, d, J=7.3Hz), 9.72(1H, brs), 12.26(1H, brs).
Example 134 5-Cyano-4,7-dihydro-4-phenyl-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-Cyano-4,7-so dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 3.
MS (EI ) : 319 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 54-1 .57 (2H, m) , 1.81-1.87 (2H, m) , 1 . 97-2: 03 (2H, m) , 2. 15 (3H, s) , 2.58-2 . 60 (1H, m) , 2.84-2.86(2H, m), 4.87(1H, s), 7.17-7.20(4H, m), 7.27 7 . 32 ( 2H, m) , 9 . 52 ( 1H, brs ) , 12 .13 ( 1H, brs ) .
Example 135 5-Cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo [ 3, 4-b] pyridine The title compound was prepared from ethyl butanoate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI ) : 322 (M+) .
~H-NMR (400MHz, DMSO-d6) b (ppm) : 0. 93 (3H, t, J=7.3Hz) , 1 . 63-1. 68 ( 2H, m) , 2 . 34-2 . 45 ( 2H, m) , 5 . 16 ( 1H, s ) , 7 . 02 ( 1H, d, J=7.3Hz), 7.18(1H, dd, J=7.3Hz and 7.2Hz), 7.28(1H, d, J=7 . 2Hz ) , 9 . 8 8 ( 1H, brs ) , 12 . 22 ( 1H, brs ) .
Example 136 ~0 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from ethyl nipecotate, 2,1,3-benzothiadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) : 363 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 89-1 .98 (2H, m) , 2.22-2.29(2H, m), 2.98-3.05(3H, m), 3.37-3.43(2H, m), 5.20(2H, br), 5.72(1H, s), 7.24(1H, s), 7.48(1H, d, J=6.6Hz), 7 . 72 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 99 ( 1H, d, J=9 . 0Hz ) , 8. 68 (1H, br) , 9.43 (1H, br) , 9.86 (1H, brs) .
Example 137 5-Cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from ethyl nipecotate, zo 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples_1 and 2.
MS (EI) : 385 (M~) .
1H-NMR (400MHz, DMSO-d~)S(ppm): 1.82-1.85(2H, m), 2.16-2.22(2H, m), 2.95-3.00(3H, m), 3.34-3.39(2H, m), 5.17(1H, s ) , 5 . 65 ( 2H, br) , 7 . 05 ( 1H, d, J=7 . 3Hz ) , 7 . 19 ( 1H, dd, J=7.3Hz and 7.2Hz), 7.29(1H, d, J=7.3Hz), 7.33(1H, s), 8.65(1H, br), 9.43(1H, br), 9.86(1H, brs).
Example 138 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-2o methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 4-(2,1,3-benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 3.
25 MS (EI) : 377 (M+) .
1H-NMR (400MHz, DMSO-d6)b(ppm): 1.64-1.73(2H, m), 1.91-1.97(2H, m), 2.05-2.09(2H, m), 2.419(3H, s), 2.70-2.72(1H, m) , 2. 90-2. 93 (2H, m) , 5.71 (1H, s) , 7 .22 (1H, s) , 7.45 (1H, d, J=6 . 6Hz ) , 7 . 72 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 98 ( 1H, d, so J=9.OHz),9.71(1H, brs), 12.13(1H, brs).
Example 139 5-Cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-cyano-4-(2,2-35 difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 3.
MS (EI ) : 399 (M+) .
1H-NMR (400MHz, DMSO-d6) S (ppm) : 1. 5-1 .58 (2H, m) , 1 . 86-1.90(2H, m), 1.99-2.03(2H, m), 2.16(3H, s), 2.59-2.62(1H, m), 2.85-2.89(2H, m), 5.15(1H, s), 7.03(1H, d, J=7.3Hz), 7.17(1H, dd, J=7.3Hz and 7.2Hz), 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)-so 2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from ethyl nipecotate, 2-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 330 (M+) .
1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1 . 8~-1 . 90 (2H, m) , 2.18-2 . 22 ( 2H, m) , 2 . 92-2 . 98 ( 3H, m) , 3 . 34-3 . 37 ( 2H , m) , 5 .10 ( 2H, br), 5.25(1H, s), 7.27(1H, s), 7.43-7.47(2H, m), 7.68(1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 7 . 82 ( 1H, d, J=7 . 3Hz ) , 8 . 61 ( 1H, br ) , 9 . 41 ( 1H, br) , 9 . 93 ( 1H, brs ) .
2o Example 141 5-Cyano-4-(2-cyanophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-cyano-4-(2-cyanophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 3.
MS (EI) : 344 (M~) .
1H-NMR (400MHz, DMSO-d~) b (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, 3o m), 2.84-2.88(2H, m), 5.23(1H, s), 7.25(1H, s), 7.39-7 . 4 ~ ( 2H, m) , 7 . 6 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 7 . 81 ( 1H, d, J=7.3Hz) , 9.77 (1H, brs) , 12.26 (1H, brs) .
Example 142 5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine 3 hydrochloride The title compound was prepared from ethyl nipecotate, pyridine-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI) : 306 (M+) .
1H-NMR (400MHz, DMSO-d~)b(ppm): 1.86-1.92(2H, m), 2.18-2.25 (2H, m) , 2.93-3. 00 (3H, m) , 3. 35-3.38 (2H, m) , 5. 41 (1H, s) , 6.50 (3H, br) , 7.42 (1H, s) , 7. 97 (2H, d, J=6. 8Hz) , 8.90 (1H, br) , 8.93 (2H, d, J=6.8Hz) , 9. 60 (1H, br) , 10.10 (1H, brs ) .
Example 143 Io 5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine 3 hydrochloride The title compound was prepared from ethyl nipeCOtate, pyridine-3-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
s5 MS (EI) : 306 (M+) .
1H-NMR (400MHz, DMSO-d6)b(ppm): 1.86-1.93(2H, m), 2.19-2.25 (2H, m) , 2.90-2 .97 (3H, m) , 3.35-3.38 (2H, m) , 5.39 (1H, s), 6.50(3H, br), 7.41(1H, s), 8.09(1H, dd, J=8.2Hz and 5.4Hz) , 8.49 (1H, d, J=8.2Hz) , 8.72 (1H, br) , 8. 88 (1H, d, 2o J=5 . 4Hz ) , 8 . 92 ( 1H, s ) , 9 . 57 ( 1H, br ) , 10 . 02 ( 1H, brs ) .
Example 144 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(pyridin-4-yl ) -2H-pyrazolo [ 3, 4-b] pyridine The title compound was prepared from 5-Cyano-4,7-25 dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine 3 hydrochloride in the same manner as in Example 3.
MS (EI) : 320 (M+) .
~H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 56-1. 64 (2H, m) , 1. 86-30 1. 90 ( 2H, m) , 1 . 99-2 . 03 ( 2H, m) , 2 . 17 ( 3H, s ) , 2 . 61-2 . 64 ( 1H, m) , 2. 86-2.89 (2H, m) , 4.96 (1H, s) , 7.23 (2H, d, J=6.8Hz) , 7 . 31 ( 1H, s ) , 8 . 50 ( 2H, d, J=6 . 8Hz ) , 9 . 67 ( 1H, brs ) , 12 . 25 ( 1H, brs ) .
Example 145 35 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 5-Cyano-4,7-dihydro-6- (piperidin-4-yl ) -4- (pyridin-3-yl ) -2H-pyrazolo[3,4-b]pyridine 3 hydrochloride in the same manner as in Example 3.
MS (EI) : 320 (M+) .
1H-NMR (400MHz, DMSO-d6)8(ppm): 1.57-1.60(2H, m), 1.84-1.89(2H, m), 1.99-2.05(2H, m), 2.17(3H, s), 2.58-2.61(1H, m) , 2. 85-2. 8 (2H, m) , 4. 98 (1H, s) , 7.29 (1H, s) , 7 .35 (1H, dd, J=8.2Hz and 5.4Hz), 7.55(1H, d, J=8.2Hz), 8.42-8.45(2H, m), zo 9 . 64 ( 1H, brs ) , 12 . 23 ( 1H, brs ) .
Example 146 6-(exo-2-Azabicyclo[2,2,2]octan-6-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from exo-2-azabicyclo[2,2,2]octane-6-carboxylic acid ethyl ester, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 435 (M+) .
1H-NMR (400MHz, DMSO-d~) b (ppm) : 1 . 52-1 .54 (1H, m) , 1 . 74-2.18(6H, m), 3.06-3.09(2H, m), 3.50-3.52(2H, m), 3.87(2H, br) , 5 . 51 ( 1H, s ) , 7 . 33 ( 1H, d, J=7 . 3Hz ) , 7 . 55-7 . 60 ( 2H, m) , 7.84 (1H, d, J=7.3Hz) , 8.97 (1H, br) , 9.73 (1H, br) , 9.78 (1H, brs ) .
Example 147 6-(endo-2-AzabicyClo[2,2,2]octan-6-yl)-4-(2-bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from endo-2-~o azabicyclo[2,2,2]octane-6-carboxylic acid ethyl ester, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (EI ) : 435 (M+) .
1H-NMR (400MHz, DMSO-d6)b(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) , 9~

7 . 56 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 7 . 82 ( 1H, d, J=7 . 3Hz ) , 8 .16 ( 1H, br) , 9 . 82 ( 1H, br) , 9 . 93 ( 1H, brs ) .
Example 148 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(exo-2-methyl-2-azabicyClo[2,2,2]octan-6-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 6-(exo-2-azabicyClo[2,2,2]octan-6-yl)-4-(2-bromo-3-Cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 1o hydrochloride in the same manner as in Example 3.
MS (EI) : 449 (M+) .
1H-NMR (400MHz, DMSO-d6) S (ppm) : 1 .42-1 .45 (1H, m) , 1 .72-1.88(5H, m), 2.06-2.09(1H, m), 2.46-2.51(4H, m), 3.04-3.07 (1H, m) , 3.45-3.48 (2H, m) , 5.48 (1H, s) , 7.34 (1H, s) , 7 . 57-7 . 60 (2H, m) , 7 . 83 ( 1H, dd, J=7 . 3Hz and 7 . 2Hz ) , 9 . 83 ( 1H, brs), 12.37(1H, brs).
Example 149 Ethyl 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-Carboxylate 2o A solution of 2,2-difluoro-1,3-benzodioxol-4-aldehyde (2.0 g), Meldrum's acid (1.6 g), ethyl 3-keto-hexanoate (1.7 g) and ammonium acetate (0.91 g) in acetic acid (20 mL) were stirred under reflux for 12 hrs. 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) were added phosphorus oxychloride (4.0 g) and a solution of the obtained colorless crystals (2.4 g) in chloroforom (10 mL) under ice-cooling, and the 3o mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (27 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:
hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.0 g), and the mixture was stirred with heating for 3 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+) .
so 1H-NMR (400MHz, DMSO-d6) b (ppm) : 0. 90-0. 97 ( 6H, m) , 1 . 58-1 . 64 ( 2H, m) , 2 . 60-2 . 64 ( 1H, m) , 2 . 8 3-2 . 8 6 ( 1H, m) , 3 . 83 ( 2H, q, J=7.3Hz), 5.32(1H, m), 6.86(1H, d, J=7.3Hz), 7.03-7.11(2H, m), 7.24(1H, s), 9.61(1H, brs), 12.06(1H, brs).
Example 150 Ethyl 4-(2-bromo-3-Cyanophenyl)-4,7-dihydro-6-(piperidin-4 yl)-2H-pyrazolo[3,4-b]pyridine-5-Carboxylate 2 hydrobromide The title compound was prepared from 2-bromo-3 Cyanobenzaldehyde in the same manner as in Example 110.
MS (EI) : 455 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 0. 84 (3H, t, J=7. 3Hz) , 1 . 78-1.81(1H, m), 1.98-2.14(3H, m), 2.87-2.90(2H, m), 3.40-3.42 (2H, m) , 3.78 (2H, q, J=7.3Hz) , 3. 80-4.25 (3H, m) , 5.64(1H, s), 7.35(1H, s), 7.40-7.47(2H, m), 7.70(1H, d, J=7.3Hz), 8.10(1H, br), 8.73(1H, br), 9.37(1H, brs).
Example 151 Ethyl 4-(2-bromo-3-Cyanophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-Carboxylate The title compound was prepared from ethyl 4-(2-bromo-3-3o Cyanophenyl ) -4, 7-dihydro-6- (piperidin-4-yl ) -2H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 hydrobromide in the same manner as in Example 3.
MS (EI) : 469 (M+) .
1H-NMR (400MHz, DMSO-d~) 8 (ppm) : 0. 85 (3H, t, J=7.3Hz) , 1 .53-1.55(1H, m), 1.70-1.72(1H, m), 1.87-2.06(4H, m), 2.16(3H, s) , 2. 84-2. 88 (2H, m) , 3.78 (2H, q, J=7.3Hz) , 3. 94-3.96 (1H, m), 5.63(1H, s), 7.34-7.48(3H, m), 7.68(1H, d, J=7.3Hz), 9.34(1H, brs), 12.16(1H, brs).
Example 152 4-(2,1,3-Benzoxadiazol-4-yl)-5-Cyano-4,7-dihydro-6-(1-methyl-2-oxo-piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 1-methyl-2-oxo-piperidine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1.
to MS (EI ) : 375 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 88-1.91 (1H, m) , 2.26-2.33(2H, m), 2.65-2.70(1H, m), 2.82(3H, m), 3.17-3.20(1H, m) , 3.31-3.36 (2H, m) , 5.40 (1H, s) , 7.29 (1H, s) , 7.44 (1H, d, J=6.6Hz), 7.58(1H, dd, J=9.OHz and 6.6Hz), 7.92(1H, d, J=9 . OHz ) , 9 . 8 8 ( 1H, brs ) , 12 . 22 ( 1H, brs ) .
Example 153 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(1-methyl-2-oxo-piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine The title Compound was prepared from 1-methyl-2-oxo-2o piperidine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (EI ) : 437 (M+) .
lH-NMR (400MHz, DMSO-d6)b(ppm): 1.88-1.92(1H, m), 2.25-2.36(2H, m), 2.69-2.74(1H, m), 2.84(3H, s), 3.18-3.36(3H, m) , 5.50 (1H, s) , 7.37 (1H, s) , 7.59-7. 62 (2H, m) , 7.85 (1H, d, J=7 . 3Hz ) , 9 . 90 ( 1H, brs ) , 12 . 33 ( 1H, brs ) .
Example 154 4-(2-Chlorophenyl)-4,7-dihydro-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine A solution of 2-Chlorobenzaldehyde (21 g), Meldrum's acid (21 g), 3-keto-hexanoiC acid 2-Cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (16 g). A

1N NaOH solution (100mL) was added, and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was acidified.
The reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give Colorless crystals (9.6 g). Hydrazine (0.22 g) and CDI
(0.66 g) were added to the obtained colorless crystals (1.0 g) in DMF (5 mL), and the mixture was stirred for 3 hours.
And the precipitated crystals were collected by filtration so to give colorless crystals (0.7 g). OrthoacetiC acid triethyl ester (3.7 g) was added to the obtained colorless crystals (1.0 g) in DMF (5 mL), and the mixture was heated for 3 hours. And the precipitated crystals were collected by filtration to give colorless crystals (0.6 g). To a s5 solution of dimethylformamide (0.55 g) in chloroform (3 mL) were added phosphorus oxychloride (1.2 g) and a solution of the obtained colorless crystals in chloroform (6 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (7.7 g) solution was zo added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give 25 colorless crystals. To a solution of the obtained colorless crystals in pyridine (10 mL) 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 30 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+) .
1H-NMR (400MHz, DMSO-d~) 8 (ppm) : 1 . 00 (3H, t, J=7.3Hz) , 1 . 67-1.74(2H, m), 2.31(3H, s), 2.70-2.83(2H, m), 5.71(1H, s), 7.07-7.12(3H, m), 7.33-7.40(2H, m), 9.49(1H, brs), 12.04(1H, brs ) .
Example 155 4-(2-Bromo-3-cyanophenyl)-5-Cyano-4,7-dihydro-6-(1-(methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride The title compound was prepared from 2-methylglycine ethyl ester, 2-bromo-3-Cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
MS (EI ) : 384 (M+) .
Io 1H-NMR (400MHz, DMSO-d6) 8 (ppm) : 1 . 49 (3H, d, J=7 .3Hz) , 3.09(3H, s), 4.00(2H, br), 4.60(1H, q, J=7.3Hz), 5.53(1H, s), 7.48-7.53(2H, m), 7.64(1H, s), 7.82(1H, d, J=7.3Hz), 8.00-8.29(2H, br), 10.97(1H, brs).
Example 156 4-(2-Chlorophenyl)-4,7-dihydro-5-(5-methyl-1,2,4-oxadiazol-3-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine A solution of 2-Chlorobenzaldehyde (21 g), Meldrum's acid (21 g), 3-keto-hexanoiC acid 2-Cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was 2o heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give Colorless Crystals (16 g). A
1N NaOH solution (100 mL) was added, and the mixture was stirred with heating for 3 hours. The reaction mixture was 25 Cooled to room temperature, and the solvent was acidified.
The reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give Colorless Crystals (9.6 g). An Ammonia solution (3.0 g) and CDI (2.8 g) were added to the obtained Colorless so crystals (4.2 g) 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 35 heated for 2 hours, and the solvent was evaporated under reduced pressure. Hydroxyammonium (1.4 g), 1N NaOH (20 mL), dioxane (20 mL) and acetic acid (28 mL) were added to the residue, and the mixture was heated for one hour. The reaction mixture was extracted with ethyl acetate, and the solvent was 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 colorless crystals (1.3 g). To a solution of dimethylformamide (1.7 g) in chloroform (10 mL) were added phosphorus oxychloride (3.5 g) and a solution of the so obtained colorless crystals in chloroforom (20 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (23 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the s5 solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (15 mL) was added hydrazine (0.6 g), 2o 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 25 the title Compound (500 mg) as Colorless crystals.
MS (EI ) : 356 (M+) .
1H-NMR (400MHz, DMSO-d6)b(ppm) : 0.99 (3H, s) , 1.62 (3H, t, J=7.3Hz), 1.66-1.73(2H, m), 2.13(3H, s), 2.35-2.38(2H, m), 2.84-3.05(2H, m), 5.73(1H, s), 7.06-7.17(3H, m), 9.90(1H, 3o brs ) , 12 .11 ( 1H, brs ) .
Example 157 4-(2,1,3-Benzoxadiazol-4-yl)-4,7-dihydro-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 2,1,3-35 benzoxadiazole-4-aldehyde in the same manner as in Example 154.

MS (EI) : 364 (M+) .
1H-NMR (400MHz, DMSO-d6) b (ppm) : 1 . 01 (3H, t, J=7.3Hz) , 1 . 69-1.76 (2H, m) , 2.31 (3H, s) , 2.72-2 . 86 (2H, m) , 5.82 (1H, s) , 7 . 18 ( 1H, d, J=6 . 6Hz ) , 7 . 32 ( 1H, s ) , 7 . 4 8 ( 1H, dd, J=9 . OHz and 6 . 6Hz ) , 7 . 8 0 ( 1H, d, J=9 . OHz ) , 9 . 65 ( 1H, brs ) , 12 . 07 ( 1H, brs ) .
Example 158 4-(2-Bromo-3-Cyanophenyl)-4,7-dihydro-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine The title compound was prepared from 2-bromo-3-Zo Cyanobenzaldehyde in the same manner as in Example 154.
MS (EI ) : 425 (M+) .
1H-NMR (400MH~z, DMSO-d~) b (ppm) : 1 . 00 (3H, t, J=7.3Hz) , 1 . 66-1.73 (2H, m) , 2.33 (3H, s) , 2.74-2.78 (2H, m) , 5.78 (1H, s) , 7.40-7.47(3H, m), 7.69(1H, dd, J=7.3Hz and 7.2Hz), 9.63(1H, brs), 12.14(1H, brs).
Example 159 6-(1-Amino-1-methylethyl)-4-(2-chlorophenyl)-5-Cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine hydrochloride The title compound was prepared from 2,2-dimethylglycine 2o ethyl ester, 2-Chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.

'' ~ ~O~ 'O
Example 1 Example 2 Example 3 ~ ~3J ~H3 Example 4 HaC.
1~CH3 Example 5 Example B ~H3 Example 7 Example 8 H3C'~
v Example 9 Example 10 Example 11 Example 12 ~Ko / ,~o / ~~lo ~N~ W ~N ~ ~N \ ~ O
N
NC I ~ NH NC I ~ NH _, 3 ~ NC I ~ NH NC I
' ~p ~ NH
HN I H \N N I H N H3C C113 N ~ 'N' H3C'H H N

Example 13 Example 14 Example 15 Example 16 ~K i ~N, \ O
O O ,N

NC NC 3 ~ CH
H3kCH~ ~ ~ NH ~ ~_ NH H3~ O N 3 ~ N NH
H3~ O H H \N HZN H N
Example 17 Example 18 Example 20 i ~N, ~N
NC
.a ' H C I N ~N~NH HOC.
HCF3COOH H3C.
Example 21 Example 22 CH3 Example 23 Example 24 H
H

Example 25 Example 2B Example 27 Example 28 i ~K i ~K i ~K
o ~ O ~ , O ~ ,ryo ~N ~N N ~ ~N
NC ' NC ~ NC ' I ~NH I NH I ~ ~NH 4II NC I _~ NH
~S.N H N H C.NH3 N ~ N HZN N ~ N H3C~N H~N
Ha~~ ~o ~ o Example 29 Example 30 Example 31 Example 32 H3',YNJ ~~ n3V ar rv~

Example 33 Example 34 Example 35 Example 36 OH
Example 37 Example 38 ~......r._ __ Example 40 CN
CN
_Br I
NC ~ Br I ~~ ~NH NC _ N N I ~ vNH
N~O H N H3C
H3C~CH NH CF~COOH
CH3 a Example 41 Example 42 Example 43 Example 44 CN
Br NC
~~NH
H3C.
H C~N
Example 45 Example 46 Example 47 Example 48 CN ~ CN
Br I ~ Br H C CHs NC
H3~~~~CH3 I N N,NH 'N C I \ NH

O H H3C H CFgCOOH O
Example 49 Example 50 Example 51 Example 52 H3~ o I
CI
NC _ I N~~N
NJ H

NH

H

Example 53 Example 54 Example 55 Example 5B
,N, ~~O
O ~ ~N
~N
NC _ NC I ~_ NH I ~NNH
HJ~N H
H3C~ 0 0 Example 57 Example 58 Example 59 Example 60 \ CN I \ CN I \
\ N I ~ Br ~ Br ~ CI
NC NC Y NC ~ NC
I ~~ ~NH I I_ \NH I ~ ~NH I ~ NH
N N W N N N N

H3C o o H3C o Example 61 Example 62 Example 63 Example 64 CN
'N' ~ I Br i I cN
~N NC
~Br NC I ~ NH NC
I ~NH H N I ~NH
N N N O ~ N
H
HN HCl ~CH3 NH

Example 85 Example 8B Example 67 Example B8 ,N,o / I
N . / ~N, \ CI
NC ~ ~ ~NO NC
I N~NNH NC I ~NNH
H I NH
N~O ~~N N~O
o~CH3 NH 1i o~CH3 Example 69 Example 70 Example 71 Example 72 i I ) ~ I ~ ,N,o i I I \
\ O \ CI \ \N \ ~ CI
NC ~ NC ~ NC ~ I / N NC
I _ NH p I NH a I NH ~N I NH
HN ~~N' I / O H 'N' I / O H \N H ~N

Example 73 Example 74 Example 75 Example 78 \ \ \ \
cl i I ~ cl I ~ cl I ~ cl H3C~ NC ~ \ I NC ONC ~ NC
I ~ NH ~ I NH I N I ~ NH I ~ NH
H N ~N ~ ~N \ ~ N H ~N.

Example 77 Example 78 Example 79 Example 80 io3 CN
CN / ~N, I , ~ o ~ ~ Br Br ~N ~ I
NC ~ NC ~ ~ ~\ ~NH
I NZ ,NH I ~ ,NH N N
~N N N H
O H O H
Example 81 Example 82 Example 83 Example 84 ~ / ,N
I CI ~ I CI / I ~ ~NO
NC NC
I ~~ ~NH I ~ NH N I ~ NH
N
Boc H N HN N
Example 85 Example 86 Example 87 Example 88 Example 89 Example 9o Example 91 Example 92 Example 93 Example 94 Example 95 / ,N, O
~ / ~N / ~N, N ,O O

N w ~ ~N ~ ~N ~ ~N

~ N N~ N~
~

~ _ I I I~ NH NH I ~
NH I NH

N~N ~ HN N~N
N O
w N~N

. s~ ~ H
'' iN HCI iN / H I H
'' HCI

O O

Example Example 97 Example 98 Example /N ~N

~N, \
N I
/

O ~
~N , Br B
O
\

\ N\\ N\\
N

N~\ NH
I

I I ~ NH ~NNH ~N
~ I
NH O

~N N N N
~ i \ H
N ON
N
~

H N H ~H 2 H 2 HCI iN / HCI

Example Example 1o1 Example 102 Example 100 1o3 ~N

~ N ~ ~N
I /
N

/ ~ , I , Br /
I / ~~ Br N

Br ~ N\\ N\\
N NH
\ I

\ N- N NH I ' NH
~ I ~ ' NH ~
~
I

_ w H _ HN '''' N \N ~ N N N
N N
HN

I H ~ H ~ H
2 . 2 HCI HCI

Example Example 1o5 Example 1os Example 1o4 1o7 ,N / ~N / ~N / ,N

O
'N
N

N N p N N
~

~ ~ ~ ~O
~

NH NH _ NH I ~
I I I NH

HN _ \N \N N
NON ~''~ N 'N~ N N
~N

~ H
H H HN H 2 HBr Example Example 109 Example 110 Example 1os 111 CI
/ ,N, ~ ~

o I I I
\N / Br / O~ / CI

W W W

_ ~ I ~ NH H I ~\NH
I \

I NON N H N
NH N N
NON

~N HN H HCI HN H HCI HN HCI
H

Example Example 113 Example 114 Example \ \ \ CI \
I/ Br I/ O~ I/ CI I/ F
~\ ~ _ ~ ~\
I \ ~,IH I ' NH I ~ J~H I ~N~H
~N N N ~N N ~N
/N H /N H /N H HN~ H HCI
Example 116 Example 117 Example 118 Example 119 F \
I

I / F I / I CI
~F ,F / / CI
~
_S

~\ ~\ N~ W

_ _ I ~ I I NH I ~ ~H
NH J~H

NJ~N ~ N N N
N N N H
H

HN H HN H ~ HCI

HCI
HN

Example Example Example ~ Example F

I/ FF I/ I/ F I/
~F ~F _F

~ F N\\ N\\ N\\

I ~H I ~H I NH I ~~
~ 'NH

~N N N N N
~ N N H

HN H i Example Example Example Example \ \

I I
I / I / / CI /
N'~ S CI

~\ U N\\ ~\

_ I 1 NH I I ~~
NH I I I ,NH
\NH ~

a e N/~,N N
N~.N N~~N N

Example Example Example Example \ \ \

I/ FF I/ ~~~ I/ I\ OXF
' F ~ O ~~ / O
F

I _ _ I ~i ~ ~H I WNH ~H

N H N H I ~ NH
N

/N iN /N H N

Example Example Example Example O F / 'N,S I %
OXF

W -N S I / XF ~ N' O F

W W W W

_ _ _ I ~ NH I ~NH I ~'NH I ~~
, ~NH
~ .

N~N N N N N
H

HN~ H 2 HCI ~ ~N N H
HN 2 HCI i Example 136 Example 137 Example 138 Example I N I ~N

I ~ I / _ yN , N

Nw Nw ~w Ny ~ NH ~ NH I 1 NH I ~NH
I

N~N _ I~~N N N
NON H

HN H 2 HCI ,N H HN 3 HCI 3 HCI
HN

Example 140 Example 141 Example 142 Example iN ~N
wN w I w I

I ~ I ~ ~ er ~ er Ns N~ ~ N~

Y I ~~ ~NH
~NH ~\NH NH
I I , N N N H ,.~~ N N H N
~ H N
H

N ~N H 2 HCI 2 HCI

Example 144 Example 145 Example 146 Example N N ~N
I~
I \ OXF O I gr O Br O F ~O ~_ NH ~O I
I NH I ~ NH
N ~N ~O I i NH N H N
H ~ ~N HN~ ' ~N~
Example 148 H 2 HBO sample 151 Example 149 Example 150 iN iN

,N, ~

~N,O I / ~ I
~

Nw Nw _ &
\ I / CI N~~

I ~ NH I ~ NH ~ N i ~ ~ NH
I
I

O N O N O I = NH /N
N N N
_ N
~

J H H
iN J H N H 2 HCI
iN

Example 152 Example 153 Example 154 Example 155 1~7 ;~o ~ CI
~C-N I ~ CI ~ - N N\ ~_ NH
--'~N ~ ~ NH C ~ ~ NH HzN I H~N
H N H N HCI
Example 156 Example 157 Example 158 Example 159 1~g Formulation Example 1 The compound of Example 1 (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were thoroughly mixed and kneaded well with a binder made of corn starch (2 parts). The kneaded product was passed through a 16 mesh sieve, dried in an oven at 50°C
and passed through a 24 mesh sieve. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were thoroughly mixed and so compression-punched to give tablets 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 z5 solution was filtered to remove pyrogen. The filtrate was transferred into an ampoule under sterile conditions.
After sterilization, the ampoule was weld-sealed to give injection containing 1.0 mg of the active ingredient.
The effects of the compounds of the present invention 20 on glycogen synthase kinase-3 beta (GSK-3(3) were evaluated and confirmed as follows.
Experimental Example 1: GSK-3(3-inhibitory activity CREB phosphopeptide (4.6 nmol), rabbit GSK-3(3 (0.5 unit), ATP (5 nmol), [y-32P~ATP (12.3 kBq) and a test 25 compound were reacted in a GSK-3(3 buffer solution (25 ~uL) (20 mmol/L Tris-HC1 (pH 7.5), 10 mmol/L magnesium chloride, 5 mmol/L dithiothreitol) containing 1% dimethyl sulfoxide, at 30°C for 20 minutes. The reaction product (10 ~,L) was adsorbed on a P81 ion-exchange paper, and the paper was 3o washed with phosphoric acid (100 mmol/L) and measured for cpm on a scintillation counter. As a result, the compounds of the present invention showed the ICSO values of 1 to 1000 nmol/L. For example, the ICSO values of the compounds are shown in the following Table 1.
CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser-Arg-Arg-Pro-Ser(P)-Tyr-Arg.
Table 1 Example No. ICSO (nmol/L) 3 2.5 8 3.7 23 4.1 58 1.8 63 3 . 0 146 0.61 148 3.2 155 ~.2 158 0.65 Experimental Example 2: GSK-3(3-inhibitory activity in rat cultured hippocampal neurons Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated Zo with amyloid (3 (25-35) (20 ~u,mol/L) and a test compound (GSK-3(3 inhibitor), and the culture was continued. for 3 hours, whereby phosphorylation of Tau protein was induced.
After the completion of culture, the level of phosphorylation of Tau protein was determined by EIA method Z5 using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3(3), and the inhibitory effect of the GSK-3(3 inhibitor on the neurons was evaluated.
Experimental Example 3: Effect on amyloid (3-induced cytotoxicity in rat cultured hippocampal neurons ~o Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid (3 (25-35) (20 ~,mol/L) and a test compound (GSK-3(3 inhibitor), and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined, and the effect of the GSK-3(3 inhibitor on the amyloid ~3-induced cytotoxicity was.
evaluated.
Experimental Example 4: GSK-3(3-inhibitory effect in gerbil brain ischemia model A test compound (GSK-3(3 inhibitor) was so intraperitoneally administered to gerbils, and 30 minutes later, brain ischemia was created by shutting off (for 4 minutes) all carotid arteries, whereby phosphorylation of Tau protein in the brain was induced. Three hours after the brain ischemia, the hippocampus was obtained from the 25 gerbil brain, and the level of phosphorylation of Tau protein was determined by Western blot using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3(3), based on which the GSK-3(3-inhibitory effect of the GSK-3(3 inhibitor in the gerbil brain was evaluated.
INDUSTRIAL APPLICABILITY
The compounds of the present invention show a selective and strong inhibitory action on glycogen synthase kinase-3 beta (GSK-3(3), and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute so sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS
encephalopathy, Huntington's disease, manic-depressive psychosis and the like), alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, m~

and several virus-induced tumors, or as immunopotentiators.
This application is based on patent application No.
2002-230581 filed in Japan, the contents of which are hereby incorporated by reference.

Claims

1. A dihydropyrazolopyridine compound of the formula (I):
wherein R0 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 optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: -COOR8 (wherein R8 is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s));
R1 is hydrogen;
R2 is hydrogen, alkyl, aralkyl, aryl, 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, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl;
R3 ~is (1) alkyl or haloalkyl, (2) cycloalkyl, (3) phenyl optionally having substituent(s), (4) aromatic heterocyclic group, (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent (s), or a group selected from the groups represented by the following formulas (II) and (III):
wherein R6 and R7 are each phenyl optionally having substituent(s) or an aromatic heterocyclic group, or R2 and R3 in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s);
R4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), cyano or nitro; and R5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CR a R b)n NR11R12 wherein n is an integer of 1 to 4, R a is hydrogen or alkyl, R b is hydrogen or alkyl, R11 is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R12 is hydrogen or alkyl, provided that when R0, R1 and R2 are each hydrogen, R4 is methoxycarbonyl and R5 is methyl, then R3 should not be phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R5 is alkyl, then R4 is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

2. The dihydropyrazolopyridine compound of claim 1, wherein R4 is alkoxycarbonyl, alkyloarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group having substituent(s), cyano or vitro, and R5 is alkyl, phenylaminoalkyl, aryl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CH2) n NR11R12 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R12 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

3. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R2 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

4. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R3 is phenyl optionally having 1 to 3 substituent(s), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

5. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R4 is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

6. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R5 is a group of the formula: -(CH2) nNR11R12 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl or alkoxycarbonyl and R12 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

7. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R0 is hydrogen or a group of the formula: -COOR8 (wherein R8 is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)), or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

8. The dihydropyrazolopyridine compound of claim 1 or 2, which is selected from the group consisting of (2) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (3) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (11) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine, (14) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine, (23) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N,N-dimethylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine, (27) 6-(1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl)-4-(2, 1, 3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine, (33) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-ethylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (37) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (38) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (41) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine, (46) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine, (48) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine, (51) 6-(1-acetylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (52) 6-(1-benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (53) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (59) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine, (62) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine, (63) 6-acetylmethyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (73) 5-cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (75) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-6-carboxylic acid phenylamide, (78) 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(4-phenyl-piperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine, (81) 6-acetyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (82) 6-acetyl-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (84) 4-(2-bromo-3-cyanophenyl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, (86) 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(pyrrolidin-3-yl) -2H-pyrazolo [3,4-b] pyridine, and (87) 4-(2,1,3-benzoxadiazol-4-yl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, a tautomer thereof, an optically active form thereof, or a pharmaceutically acceptable salt thereof.

9. A medicament comprising a dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, or a pharmaceutically acceptable salt thereof.

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

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

12. The medicament of claim 9, which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.

13. The medicament of claim 9, which is used for prevention and/or treatment of a neurodegenerative disease.

14. The medicament of claim 13, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic-depressive psychosis.

15. The medicament of claim 9, which is used for prevention and/or treatment of diabetes and diabetic complications.

16. The medicament of claim 9, which is used as an immunopotentiator.

17. The medicament of claim 9, which is used for prevention and/or treatment of alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell lukemia or virus-induced tumors.