Note: Descriptions are shown in the official language in which they were submitted.
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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
1
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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
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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
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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
R4
(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
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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
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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
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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
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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
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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
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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
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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
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R3
R R2 R~ R2 R1
R4
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
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"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
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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
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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.
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"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
16
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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~
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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.
18
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R9 R9
\ 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
19
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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
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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
21
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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
0 0
o>
/ _N, ~ ,N. /
'N°~ 'N°S N
H CH3
\ 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
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unsaturated carbocyclic ring containing 1 to 3
heteroatom(s), which is fused with a benzene ring" includes
the following groups and the like.
S / I 0 /
\ \ \ \
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-
23
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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-
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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
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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
R3
RQ R2
+ ~ +
R3 R2 R5
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.
26
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R3 R3
R4 R2 R4 R2CH0
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.
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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
R R2 R1
O O Ra
4
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
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R3
R2 R1 1
R4
+ 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)
29
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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
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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.
31
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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 .
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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
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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 .
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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-
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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-
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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) ,
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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
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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 ) .
39
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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+) .
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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) .
41
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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
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(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
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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 ) ,
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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+) .
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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),
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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-
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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 ) .
48
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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.
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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.
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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-
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[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-
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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
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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 ) .
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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
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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
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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
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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.
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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
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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),
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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+) .
G1
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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 .
2 3-
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).
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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
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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)
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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) ,
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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-
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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)
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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 ) ,
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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
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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) ,
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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) ,
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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).
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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-
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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 .
90-
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,
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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.
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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
76
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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-
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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~
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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
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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-
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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+) .
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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+) .
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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-
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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,
84
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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-
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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
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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+) .
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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-
88
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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
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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,
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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
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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) ,
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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
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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,
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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
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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,
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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),
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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.
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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.
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'' ~ ~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
H3C- CH3
Example 13 Example 14 Example 15 Example 16
~K i ~N, \ O
O O ,N
N N H C CH3 NC
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
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i ~N,
0
~N
NC
.a '
H C I N ~N~NH HOC.
HCF3COOH H3C.
Example 21 Example 22 CH3 Example 23 Example 24
H
H
0 0 0
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~
CH CH3 0
Example 33 Example 34 Example 35 Example 36
OH
Example 37 Example 38 ~......r._ __ Example 40
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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
N 3
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
0
Example 57 Example 58 Example 59 Example 60
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\ 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
H H HN H HC1
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
H3C CH3
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
H3C CH3 H3C 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
3HC1
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.
2HC1 3HC1 0 0
Example 77 Example 78 Example 79 Example 80
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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
H3C
Example 93 Example 94 Example 95
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/ ,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
96 99
/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
2 HCI
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
2 HC1
Example Example 113 Example 114 Example
112 115
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\ \ \ 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 HCI 2 HN
HCI
HN
Example Example Example ~ Example
120 121 122 123
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
2 HCI /N H /N N
HN H i
Example Example Example Example
124 125 126 127
\ \
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
HN H2 HN H /N /N H
HCI 2 HCI H
Example Example Example Example
128 129 130 131
\ \ \
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
132 133 134 135
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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
139
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
143
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
147
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
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;~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
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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-
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Arg-Arg-Pro-Ser(P)-Tyr-Arg.
Table 1
Example No. ICSO (nmol/L)
2 10
3 2.5
8 3.7
11 14
23 4.1
58 1.8
63 3 . 0
146 0.61
148 3.2
155 ~.2
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
110
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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~
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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.
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