WO2004014910A1 - Dihydropyrazolopyridine compounds - Google Patents

Dihydropyrazolopyridine compounds Download PDF

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Publication number
WO2004014910A1
WO2004014910A1 PCT/JP2003/009787 JP0309787W WO2004014910A1 WO 2004014910 A1 WO2004014910 A1 WO 2004014910A1 JP 0309787 W JP0309787 W JP 0309787W WO 2004014910 A1 WO2004014910 A1 WO 2004014910A1
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Prior art keywords
cyano
dihydro
pyridine
pyrazolo
substituent
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PCT/JP2003/009787
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French (fr)
Inventor
Toshiyuki Kohara
Kenji Fukunaga
Tokushi Hanano
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Mitsubishi Pharma Corporation
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Priority to JP2004527320A priority Critical patent/JP2005534713A/en
Priority to EP03784497A priority patent/EP1537106A1/en
Priority to AU2003250539A priority patent/AU2003250539A1/en
Priority to CA002494785A priority patent/CA2494785A1/en
Priority to EA200500322A priority patent/EA200500322A1/en
Priority to BR0313262-5A priority patent/BR0313262A/en
Priority to MXPA05001434A priority patent/MXPA05001434A/en
Publication of WO2004014910A1 publication Critical patent/WO2004014910A1/en
Priority to IL16648205A priority patent/IL166482A0/en
Priority to NO20051153A priority patent/NO20051153L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta
  • glycogen synthase kinase-3 beta (GSK-3 ⁇ ) , a protein kinase, is involved in the causes of various diseases as noted in the following.
  • Type-II diabetes is a disease in which the insulin reactivity of pancreatic ⁇ cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced.
  • GSK-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 ⁇ -inhibitory activity actually lowers glucose in blood by a GSK-3 ⁇ - inhibitory activity (Proc. Nat. Acad. Sci., 93, 8455
  • medicaments having a GSK-3 ⁇ -inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof.
  • 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 ⁇ is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)).
  • Tat which is a protein produced by HIV virus that causes AIDS, enhances GSK-3 ⁇ activity in neurons to induce neuronal death (J. Neuroche ., 73, 578 (1999)).
  • GSK-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 ⁇ inhibitory activity (J. Neurochem., 72, 1327 (1999)).
  • GSK-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,
  • GSK-3 ⁇ acts for suppressing immunological function by conversely phosphorylating NF-AT.
  • GSK-3 ⁇ inhibitors are considered to be medicaments effective for immunopotentiation.
  • JP-A-3-272189 invention drawn to an improved synthesis method of mevalolacton intermediates
  • JP-A-2-275878 therapeutic agents for hyperlipoproteinemia and atherosclerosis
  • JP-A-1-272584 therapeutic agents for hyperlipoproteinemia
  • 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—J] - pyridine-5-carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods.
  • the present inventors reproduced the following 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.
  • 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- lif-pyrazolo [3, 4-b]pyridine-5-carboxylate and the like.
  • 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 ⁇ ) , and further, medicaments comprising them and pharmaceutical compositions comprising them.
  • GSK-3 ⁇ glycogen synthase kinase-3 beta
  • the present inventors have intensively studied to achieve the above object, and have found that 4,7- dihydropyrazolo [3, 4-i)] pyridine derivatives have a selective and strong inhibitory activity on GSK-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 ⁇ -inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
  • the present invention provides the following.
  • R° is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, for yl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , phenylalkyl optionally having substituent (s) , or a group of the formula: -COOR 8 (wherein R 8 is hydrogen, alkyl, aryl optionally having substituen (s) or a
  • aromatic heterocyclic group (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
  • R 6 and R 7 are each phenyl optionally having substituent (s) or an aromatic heterocyclic group, or R 2 and R 3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent (s) ;
  • R 4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group optionally having substituent (s) , cyano or nitro; and R 5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula:
  • R 4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group having substituent (s) , cyano or nitro
  • R 5 is alkyl, phenyla inoalkyl, acyl, acylalkyl, aminocarbonyl, aryla inocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) , a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1
  • a medicament comprising a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof.
  • 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.
  • a glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described [1], an optically active form thereof and a pharmaceutically acceptable salt thereof.
  • the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Gu
  • 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.
  • Alkyl means a linear or branched hydrocarbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl (i.e., a yl) , hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with a preference for alkyl having 1 to 4 carbon atom(s).
  • the alkyl of R 2 is preferably alkyl having 1 to 4 carbon atoms.
  • the alkyl of R 5 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., amyl) , hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like.
  • Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.
  • "Acyl” means C 2 -C ⁇ acyl, and includes “alkylcarbonyl” having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, at R 4 preferably having 2 to 5 carbon atoms, "C 7 _Ci 2 arylcarbonyl” such as benzoyl, naphthoyl and the like, and "C-Ci2 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.
  • “Acylalkyl” is acylalkyl consisting of the above Ci- C 8 alkyl and the above C2-C 1 4 acyl, and includes, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyryl ethyl, 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 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 .
  • Amino is primary amino, secondary or tertiary amino having the above C ⁇ -C 8 alkyl, and includes, for example, amino, mono- or di-C ⁇ -C 8 alkyl-substituted amino such as methylamino, dimethylamino, ethyla ino, diethylamino, propylamino, dipropylamino, butyla ino, dibutylamino and 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, 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 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Haloalkyl is the above C ⁇ -C 8 alkyl substituted by 1 to 5 halogen (s), and represents fluoromethyl, chloromethyl, difluoro ethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl and the like.
  • Aminoalkyl is C ⁇ -C 8 alkyl having primary amino, and 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 2 -C 14 acyl, and represents, for example, acetylamino, propionyla ino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetyla ino, phenylpropionylamino, phenylbutyrylamino and the like.
  • Alkoxy is alkoxy having the above C ⁇ -C 8 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 like, with a preference for alkoxy having 1 to 4 carbon atom(s) .
  • Cycloalkoxy is cycloalkoxy having the above C ⁇ C 8 cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, 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 C ⁇ -C 8 alkoxy, and includes, for example, benzyloxy, 1- phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4- phenylbutoxy, 1-methyl-l-phenylethoxy, l-methyl-2- phenylethoxy, 1-phenylpropoxy, 2-pheylpropoxy, 1-methyl-l- phenylpropoxy, l-methyl-2-phenylpropoxy, l-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 limited.
  • aminoalkoxy is aminoalkoxy consisting of the above amino and C ⁇ -C 8 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 Ci-Cs alkoxy and C ⁇ -C 8 alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
  • Phenoxyalkyl is phenoxyalkyl consisting of the above phenoxy and C ⁇ -C 8 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 are not particularly limited.
  • Hydroalkyl is hydroxyalkyl having the above C ⁇ -C 8 alkyl, and includes, for example, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and the like, with a preference for hydroxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
  • Alkoxycarbonyl is alkoxycarbonyl having the above C ⁇ -C 8 alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert- pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s) .
  • the alkoxycarbonyl of R 4 is preferably alkoxycarbonyl having 2 to 5 carbon atoms.
  • "Phenoxycarbonyl” is phenoxycarbonyl optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Aminocarbonyl is aminocarbonyl having the above amino including mono- or di-C ⁇ -C 8 alkyl-substituted amino, and includes, for example, aminocarbonyl (i.e., carbamoyi), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propyla inocarbonyl, dipropylaminocarbonyl and the like.
  • aminocarbonyl i.e., carbamoyi
  • methylaminocarbonyl dimethylaminocarbonyl
  • ethylaminocarbonyl ethylaminocarbonyl
  • diethylaminocarbonyl diethylaminocarbonyl
  • propyla inocarbonyl dipropylaminocarbonyl and the like.
  • Alkylthiocarbonyl is alkylthiocarbonyl having the above C ⁇ -C 6 alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec- 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 C ⁇ -C 8 alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
  • Cycloalkoxyalkyl is cycloalkoxyalkyl consisting of the above C 3 -C 8 cycloalkoxy and C ⁇ --C 8 alkyl, and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxy ethyl, 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 cycloalkoxyalkyl optionally has 1 to 3 substituent (s) on the cycloalkyl and substitution sites are not particularly limited.
  • Alkylsulfinyl is alkylsulfinyl having the above Ci- C 8 alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 5 carbon atom(s) .
  • the alkylsulfinyl of R 4 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 C ⁇ C 8 alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl having 1 to 5 carbon atom(s) .
  • the alkylsulfonyl of R 4 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.
  • Mercaptoalkyl is mercaptoalkyl having the above C ⁇
  • C 8 alkyl includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s).
  • Alkylthioalkyl is alkylthioalkyl consisting of the above C ⁇ -C 3 alkylthio and C ⁇ -C 8 alkyl, and includes, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) 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 the like. They may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
  • “Aralkyl” is aralkyl wherein the above C ⁇ -C 8 alkyl is substituted by the above C 6 -C 14 aryl, and includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. These may have 1 to 5 substituent (s) on the aryl moiety and substitution sites are not particularly limited.
  • Acyloxyacetyl is acyloxyacetyl having the above C 2 - C 14 acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.
  • Acyloxyalkyl is acyloxyalkyl having the above C 2 -C ⁇ 4 acyl and C ⁇ -C 8 alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2- butyryloxyethyl, 2-benzoyloxyethyl and the like.
  • 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 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 1 to 3 heteroatom(s) selected from the group consisting of 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.
  • R 9 is each independently hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, a inoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, 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) .
  • R 10 is alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , or phenylalkyl optionally having substituent (s) , and R 10 ' is hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl,
  • Phenylalkyl is phenylalkyl consisting of phenyl and the above Cx-Cs alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, l-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1- methyl-1-phenylpropyl, l-methyl-2-phenylpropyl, l-methyl-3- phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s) .
  • phenylalkyl optionally having substituent (s) are the same as those for the above-mentioned “aromatic heterocyclic group” and substitution sites are not particularly limited.
  • Dialkylphosphinyl is dialkylphosphinyl having the above C ⁇ -C 8 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 Q L -C 8 alkyl, and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).
  • substituted includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic group, phenylalkyl, hydroxy, carboxy, thiol, halogen, amino, formyl, carbamoyi, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, 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 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 R 2 and R3 in the formula (I) together with the attached carbon atom. By 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, 2, 3-dihydrobenzo [jb] thiophen-1-oxide and the like.
  • a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring' represents a group derived from naphthalene, 1,2- dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthalene, indan and the like. Of these, naphthyl such as naphthalen-1-yl and the like, and indanyl such as indan-4-yl and the like are preferable.
  • the group may have 1 to 4 substituent (s) and substitution sites are not particularly limited.
  • a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom (s) includes the following groups and the like.
  • 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- [j] furan-7-yl, 2, 3- (methylenedioxy) phenyl and 3,4-dihydro- 2H-benzopyran-8-yl are particularly preferable.
  • the group may have 1 to 3 substituent (s) and substitution sites are not particularly limited.
  • a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroato (s) , which is fused with a benzene ring includes the following groups and the like.
  • the group may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
  • Alkylcarbonylalkyl is, for example, C1-C4 alkyl- carbonyl-C ⁇ -C alkyl, and includes, for example, methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butylcarbonylmethyl and the like.
  • Arylaminocarbonyl is C 6 -C ⁇ o aryl-aminocarbonyl, and includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl and the like.
  • the arylaminocarbonyl optionally has 1 to 3 substituent (s) on the aryl and substitution sites are not particularly limited.
  • Alkylaminocarbonyl is C-C ⁇ 4 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 particularly limited.
  • Alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent means C ⁇ C 8 alkyl substituted by "a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s)", such as pyrrole, pyrroline, pyrazole, pyridine, piperidine, piperazine, homopiperadine or morpholine and the like, which optionally has a substituent such as C 1 -C4 alkyl, C6-C 10 aryl such as phenyl, naphthyl and the like, and includes, for example, (4-phenylpiperazin-l-yl) methyl, 2- (4-phenylpiperazin-l- yl) ethyl, 3- (4-phenylpiperazin-l-yl) propyl, (4- (naphthalen-1-yl) piperazin-1-yl) methyl, 2-
  • Phenyla inoalkyl is phenylamino-C ⁇ -C 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-C ⁇ -C 4 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.
  • “Alkyl” in the R 11 is C 1 -C4 alkyl, and includes, for examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
  • Alkylsulfonyl in the R u is C 1 -C 4 alkyl-sulfonyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.
  • Phenylsulfonyl in the R 11 is phenylsulfonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Phenylalkylsulfonyl in the R 11 is phenyl-C ⁇ -C 4 alkyl- sulfonyl, and includes, for example, benzylsulfonyl, 2- phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4- phenylbutylsulfonyl and the like.
  • the phenylalkylsulfonyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Alkylsulfinyl in the R 11 is C 1 -C 4 alkyl-sulfinyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.
  • Phenylsulfinyl in the R 11 is phenylsulfinyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Phenylalkylsulfinyl in the R u is phenyl-C ⁇ -C4 alkyl- sulfinyl, and includes, for example, benzylsulfinyl, 2- phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4- phenylbutylsulfinyl and the like.
  • the phenylalkylsulfinyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Alkoxycarbonyl in the R 11 is C ⁇ -C alkoxy-carbonyl, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
  • Phenylalkoxycarbonyl in the R 11 is phenyl-C ⁇ -C4 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 particularly limited.
  • Alkylcarbonyl in the R 11 is C 1 -C 4 alkyl-carbonyl and includes, for example, acetyl, propionyl, butylcarbonyl and the like.
  • Phenylcarbonyl in the R 11 is phenylcarbonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Phenylalkylcarbonyl in the R 11 is phenyl-C ⁇ -C4 alkylcarbonyl, 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 R 11 means phenoxycarbonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
  • Alkyl in the R 12 is C 1 -C 4 alkyl, and includes, for examples, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl and the like.
  • the compounds represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention.
  • 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, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like.
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • Me1drum' 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 (IX) .
  • the reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction.
  • a carboxylic acid solvent inert to the reaction.
  • the solvent formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
  • R 2 , R 3 , R 4 and R 5 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.
  • a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 0°C to 60°C.
  • 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 reaction.
  • a solvent inert 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, from 0°C to 200°C, preferably from 60°C to 100°C.
  • the carbonyl derivative of the formula (VII) which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983) .
  • the carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993) .
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the compounds (I) of the present invention can be produced by reacting a inopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII) .
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
  • R°, R 1 , R 2 , R 3 , R 4 and R 5 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.
  • a base includes, for example, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine and the like.
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a 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.
  • the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) such as acetic anhydride in the presence of a base.
  • a base includes, for example, triethyla ine, pyridine, 4-dimethylaminopyridine and the like.
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a 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, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
  • 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, recrystallization, various kinds of chromatography and the like.
  • a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column 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 ⁇ such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3 ⁇ .
  • the compounds of the present invention have a GSK-3 ⁇ -selective inhibitory activity and can be medicaments with small side-effect for 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 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.
  • 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 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 is orally administered once to several times a day, or 1 - 500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day. Examples
  • Example 1 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 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.
  • the title compound was prepared from ethyl nipecotate,
  • the title compound was prepared from ethyl morpholine-2- carboxylate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3-amino- pyrazole in the same manner as in Example 1.
  • the title compound was prepared from benzoylchloride, ethyl isonipecotate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 25. MP:228°C. MS (FAB) :452 (M + +l) .
  • 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 manner as in Example 25.
  • 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 Example 25. MP:243°C. MS (El) :425(M + ) .
  • 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.
  • the title compound was prepared from acetyl chloride, ethyl nipecotate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3- a inopyrazole in the same manner as in Example 25. MP:219°C.
  • the title compound was prepared from ethyl nipecotate,
  • 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 (El) :487 (M + ) .
  • Example 62 4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (2- oxocyclohexan-1-yl) -2ff-pyrazolo [3, 4-b]pyridine
  • the title compound was prepared from ethyl 2- cyclohexanonecarboxylate, 2-bromo-3-cyanobenzaldehyde and
  • the title compound was prepared from ethyl acetoacetate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 58. MP:230°C.
  • Example 70 4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (pyrrolidin-2-yl) -2ff-pyrazolo [3, 4-b]pyridine
  • the title compound was prepared from 4- (2,1,3- benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpyrrolidin-2-yl) -
  • 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 Example 1.
  • the title compound was prepared from 2, 1, 3-benzoxa- diazole-4-aldehyde, 3-aminopyrazole and methyl 2,2- dimethoxypropionate in the same manner as in Example 1.
  • methyl l-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2:1)) to give l-(l-tert- butoxycarbonylpyrrolidin-3-yl) -2-cyanoethan-l-one (2.35 g) as a colorless oil.
  • the title compound was prepared from ethyl isonipecotate, 4-indancarboxaldehyde and 3-aminopyrazole in the same manner as in Example 1.
  • 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.
  • the title compound was prepared from 4- aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3- cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
  • the title compound was prepared from ethyl nipecotate,
  • the title compound was prepared from ethyl nipecotate,
  • the title compound was prepared from ethyl nipecotate,
  • 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 GDI (2.8 g) were added to the obtained colorless 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 heated for 2 hours, and the solvent was evaporated under reduced pressure.
  • the title compound was prepared from 2, 2-dimethylglycine ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
  • Example 73 Example 74 Example 75
  • Example 77 Example 78
  • Example 81 Example 82 Example 83 Example 84
  • Example 85 Example 86 Example 87 Example 88
  • Example 89 Example 90
  • Example 91 Example 91
  • Example 93 Example 94 Example 95
  • Example 96 Example 97
  • Example 98
  • Example 100 Example 101
  • Example 102 Example 102
  • Example 105 Example 106
  • Example 107
  • Example 108 Example 109 Example 110 Example 111
  • Example 112 Example 113
  • Example 114 Example 115
  • Example 116 Example 117 Example 118 Example 119
  • Example 120 Example 121 Example 122 Example 123
  • Example 124 Example 125
  • Example 126 Example 127
  • Example 128 Example 129 Example 130
  • Example 131 Example 131
  • Example 132 Example 133
  • Example 134 Example 135
  • Example 136 Example 137
  • Example 138 Example 139
  • Example 140 Example 141
  • Example 143 Example 143
  • Example 144 Example 145
  • Example 146 Example 147
  • Example 152 Example 153
  • Example 154 Example 155
  • Example 156 Example 157
  • Example 158 Example 159
  • Example 2 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 compression-punched to give tablets containing 0.5 mg of the active ingredient per tablet.
  • Formulation Example 2 Formulation Example 2
  • Example 1 The compound of Example 1(1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, and the solution was filtered to remove pyrogen. The filtrate was transferred into an ampoule under sterile conditions. After sterilization, the ampoule was weld-sealed to • give injection containing 1.0 mg of the active ingredient.
  • glycogen synthase kinase-3 beta (GSK-3 ⁇ ) were evaluated and confirmed as follows.
  • the compounds of the present invention showed the IC 5 o values of 1 to 1000 nmol/L.
  • the IC50 values of the compounds are shown in the following Table 1.
  • CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser- Arg-Arg-Pro-Ser ( P) -Tyr-Arg .
  • 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 ⁇ (25-35) (20 ⁇ mol/L) and a test compound (GSK-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 using phosphorylated Tau-recognizing antibody
  • 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 ⁇ (25-35) (20 ⁇ mol/L) and a test compound (GSK-3 ⁇ inhibitor) , and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined, and the effect of the GSK-3 ⁇ inhibitor on the amyloid ⁇ -induced cytotoxicity was evaluated.
  • a test compound (GSK-3 ⁇ inhibitor) was 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.
  • the hippocampus was obtained from the 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 ⁇ ) , based on which the GSK-3 ⁇ -inhibitory effect of the GSK-3 ⁇ inhibitor in the gerbil brain was evaluated.
  • the compounds of the present invention show a selective and strong inhibitory action on glycogen synthase kinase-3 beta (GSK-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 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, or as immunopotentiators,

Abstract

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

Description

DESCRIPTION
DIHYDROPYRAZOLOPYRIDINE COMPOUNDS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta
(GSK-3β) -inhibitory activity, and use thereof.
BACKGROUND ART
It has been reported that glycogen synthase kinase-3 beta (GSK-3β) , a protein kinase, is involved in the causes of various diseases as noted in the following.
Type-II diabetes is a disease in which the insulin reactivity of pancreatic β cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced. GSK-3β acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GSK-3β-inhibitory activity actually lowers glucose in blood by a GSK-3β- inhibitory activity (Proc. Nat. Acad. Sci., 93, 8455
(1996) ) . Therefore, medicaments having a GSK-3β-inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof. 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-3β is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2)' It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons to induce neuronal death (Neurosci. Lett., 128, 195 (1991)) In addition to the above, (3) the direct involvement of GSK-3β in neuronal death through inactivation of pyruvate dehydrogenase by phosphorylation to decrease the production amount of acetylcholine necessary for maintaining cell activity (Proc. 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 GSK-3β activity in neurons to induce neuronal death (J. Neuroche ., 73, 578 (1999)). From the above, GSK-3β 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-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The relationship between anti-manic-depressive activity and GSK-3β inhibitory activity is unclear, but a suppressive activity on glutamic acid toxicity is considered to be partly responsible for maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642 (1998) ) . Based on the foregoing, GSK-3β 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-3β acts for suppressing immunological function by conversely phosphorylating NF-AT.
Therefore, GSK-3β inhibitors are considered to be 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 for hyperlipoproteinemia) disclose pyrazolo [3, 4-jb] pyridine compounds wherein the 6-position is either methyl, isopropyl or cyclopropyl. These publications do not disclose or suggest any action of these compounds on GSK-3β 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—J] - pyridine-5-carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods. The present inventors reproduced the following 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. 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 publications. In other words, 6-methyl-4-substituted phenyl-4, 7-dihydropyrazolo [3, 4-.σ]pyridine-5-carboxylate cannot be synthesized according to the methods described in these publications.
Figure imgf000004_0001
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- lif-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-3β) , and further, medicaments comprising them and pharmaceutical compositions comprising them.
The present inventors have intensively studied to achieve the above object, and have found that 4,7- dihydropyrazolo [3, 4-i)] pyridine derivatives have a selective and strong inhibitory activity on GSK-3β, 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-
3β-inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof. The present invention provides the following.
[1] A dihydropyrazolopyridine compound of the formula (I) :
Figure imgf000005_0001
wherein
R° is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, for yl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , phenylalkyl optionally having substituent (s) , or a group of the formula: -COOR8 (wherein R8 is hydrogen, alkyl, aryl optionally having substituen (s) or aralkyl optionally having substituent (s) ) ; R1 is hydrogen; R2 is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, a inoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent (s) , aromatic heterocyclic group or phenylalkyl; R3 is
( 1 ) alkyl or haloalkyl,
(2 ) cycloalkyl ,
(3) phenyl optionally having substituent (s) ,
(4) aromatic heterocyclic group, (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
(6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s) , or
(7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent (s) , or a group selected from the groups represented by the following formulas (II) and (III) :
Figure imgf000007_0001
(II) (III) wherein R6 and R7 are each phenyl optionally having substituent (s) or an aromatic heterocyclic group, or R2 and R3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent (s) ;
R4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group optionally having substituent (s) , cyano or nitro; and R5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CRaRb) nNR1:LR12 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, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R12 is hydrogen or alkyl, provided that when R°, R1 and R2 are each hydrogen, R4 is methoxycarbonyl and R5 is methyl, then R3 should not be phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R5 is alkyl, then R4 is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[2] The dihydropyrazolopyridine compound of the above- mentioned [1] , wherein R4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group having substituent (s) , cyano or nitro, and R5 is alkyl, phenyla inoalkyl, acyl, acylalkyl, aminocarbonyl, aryla inocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) , a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CH2) nNR^R12 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsul inyl, 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. [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: - (CH2) nNR1:LR12 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl or alkoxycarbonyl and R12 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof. [7] The dihydropyrazolopyridine compound of the above- described [1] or [2], wherein R° is hydrogen or a group of the formula: -COOR8 (wherein R8 is alkyl, aryl optionally ■ having substituent (s) or aralkyl optionally having substituent (s) ) , or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
[8] The dihydropyrazolopyridine compound of the above- described [1] or [2], which is selected from the group consisting of (2) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-
(piperidin-4-yl) -22Y-pyrazolo [3, 4-jb] pyridine,
(3) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2H-pyrazolo [3, 4-jb] pyridine,
(11) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- methylmorpholin-2-yl) -2H-pyrazolo [3, 4~b] pyridine,
(14) 4- (2, 1, 3-benzoxadiazol-4~yl) -5-cyano-4, 7-dihydro-6- (1- methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2H-pyrazolo [3, 4-b] - pyridine,
(23) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- (N,N-dimethylamino) cyclohexyl) -2H-pyrazolo [3, 4-jb] pyridine,
(27) 6-(l-acetyl-l,2,3, 6-tetrahydropyridin-4-yl) -4- (2,1,3- benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2H-pyrazolo [3, 4-b] - pyridine,
(33) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- ethylpiperidin-4-yl) ~2H-pyrazolo [3, 4-_b] pyridine,
(37) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (piperidin-4-yl) -2i-pyrazolo [3, 4-jb] pyridine,
(38) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2H-pyrazolo [3, 4-jb] pyridine, (41) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-3-yl) -2iϊ-pyrazolo [3, 4-b] pyridine, (46) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (4- methylmorpholin-2-yl) -2if-pyrazolo [3, 4-jb] pyridine, (48) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methyl-1, 2, 3, 6-tetrahydropyridin-4~yl) -2H-pyrazolo [3, 4-b] - pyridine,
(51) 6- (l-acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) - 5-cyano-4, 7-dihydro-2if-pyrazolo [3, 4-b] pyridine,
(52) 6- (l-benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) - 5-cyano-4, 7-dihydro-2iϊ-pyrazolo [3, 4-b] pyridine,
(53) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methanesulfonylpiperidin-4-yl) -2JT-pyrazolo [3, 4-jb] pyridine, (59) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- oxocyclohexan-1-yl) -2H-pyrazolo [3, 4-b] pyridine,
(62) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (2- oxocyclohexan-1-yl) -2H-pyrazolo [3, 4-b] pyridine,
(63) 6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7- dihydro-2H-pyrazolo [3, 4-Jb] pyridine,
(73) 5-cyano-4, 7-dihydro-4- (2,3- (methylenedioxy) phenyl) -6- (piperidin-4-yl) -2-ff-pyrazolo [3, 4-Jb] pyridine, (75) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2ff- pyrazolo [3, 4-j ]pyridine-6-carboxylic acid phenylamide, (78) 4- (2-chlorophenyl) -5-cyano-4, 7-dihydro-6- (4-phenyl- piperazin-l-yl)methyl-2H-pyrazolo [3, 4-Jb] pyridine,
(81) 6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7- dihydro-2J?-pyrazolo [3, 4-b] pyridine,
(82) 6-acetyl-4- (2,1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7- dihydro~2#-pyrazolo [3, 4-jb] pyridine,
(84) 4- (2-bromo-3-cyanophenyl) -5- (pyridin-2-yl) -4, 7- dihydro-6-propyl-2H-pyrazolo [3, 4-b] pyridine, (86) 4- (2-chlorophenyl) -5-cyano-4, 7-dihydro-6- (pyrrolidin- 3-yl) -2iϊ-pyrazolo [3, 4-Jb] pyridine, and
(87) 4- (2,l,3-benzoxadiazol-4-yl)-5- (pyridin-2-yl) -4, 7- dihydro-6-propyl-2H-pyrazolo [3, 4-Jb] pyridine, a tautomer thereof, an optically active form thereof, or a 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. [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. [11] A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described [1], an optically active form thereof and a pharmaceutically acceptable salt thereof.
[12] The medicament of the above-described [9], which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity. [13] The medicament of the above-described [9], which is used for prevention and/or treatment of a neurodegenerative disease. [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 sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontote poral dementia, AIDS encephalopathy, Huntington' s disease and manic-depressive 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.
Figure imgf000013_0001
(I-a) (I-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 (i.e., a yl) , hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, 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 R5 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., amyl) , hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like. Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable. "Acyl" means C2-Cι acyl, 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_Ci2 arylcarbonyl" such as benzoyl, naphthoyl and the like, and "C-Ci2 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. "Acylalkyl" is acylalkyl consisting of the above Ci- C8 alkyl and the above C2-C14 acyl, and includes, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyryl ethyl, 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 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 . "Amino" is primary amino, secondary or tertiary amino having the above Cι-C8 alkyl, and includes, for example, amino, mono- or di-Cι-C8 alkyl-substituted amino such as methylamino, dimethylamino, ethyla ino, diethylamino, propylamino, dipropylamino, butyla ino, dibutylamino and 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, 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 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
"Haloalkyl" is the above Cι-C8 alkyl substituted by 1 to 5 halogen (s), and represents fluoromethyl, chloromethyl, difluoro ethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl and the like.
"Aminoalkyl" is Cι-C8 alkyl having primary amino, and 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 C2-C14 acyl, and represents, for example, acetylamino, propionyla ino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetyla ino, phenylpropionylamino, phenylbutyrylamino and the like. "Alkoxy" is alkoxy having the above Cχ-C8 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 like, with a preference for alkoxy having 1 to 4 carbon atom(s) .
"Cycloalkoxy" is cycloalkoxy having the above C~C8 cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, 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 Cι-C8 alkoxy, and includes, for example, benzyloxy, 1- phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4- phenylbutoxy, 1-methyl-l-phenylethoxy, l-methyl-2- phenylethoxy, 1-phenylpropoxy, 2-pheylpropoxy, 1-methyl-l- phenylpropoxy, l-methyl-2-phenylpropoxy, l-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 limited.
"Aminoalkoxy" is aminoalkoxy consisting of the above amino and Cι-C8 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 Ci-Cs alkoxy and Cχ-C8 alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
"Phenoxyalkyl" is phenoxyalkyl consisting of the above phenoxy and Cχ-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 are not particularly limited.
"Hydroxyalkyl" is hydroxyalkyl having the above Cι-C8 alkyl, and includes, for example, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and the like, with a preference for hydroxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
"Alkoxycarbonyl" is alkoxycarbonyl having the above Cι-C8 alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert- pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s) . The alkoxycarbonyl of R4 is preferably alkoxycarbonyl having 2 to 5 carbon atoms. "Phenoxycarbonyl" is phenoxycarbonyl optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
"Aminocarbonyl" is aminocarbonyl having the above amino including mono- or di-Cι-C8 alkyl-substituted amino, and includes, for example, aminocarbonyl (i.e., carbamoyi), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propyla inocarbonyl, dipropylaminocarbonyl and the like. "Alkylthiocarbonyl" is alkylthiocarbonyl having the above Cι-C6 alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec- 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 Cι-C8 alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
"Cycloalkoxyalkyl" is cycloalkoxyalkyl consisting of the above C3-C8 cycloalkoxy and Cι--C8 alkyl, and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxy ethyl, 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 cycloalkoxyalkyl optionally has 1 to 3 substituent (s) on the cycloalkyl and substitution sites are not particularly limited.
"Alkylsulfinyl" is alkylsulfinyl having the above Ci- C8 alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 5 carbon atom(s) . The alkylsulfinyl of R4 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 Cι~ C8 alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl 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. "Mercaptoalkyl" is mercaptoalkyl having the above Cι~
C8 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). "Alkylthioalkyl" is alkylthioalkyl consisting of the above Cι-C3 alkylthio and Cι-C8 alkyl, and includes, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) 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 the like. They may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
"Aralkyl" is aralkyl wherein the above Cχ-C8 alkyl is substituted by the above C6-C14 aryl, and includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. These may have 1 to 5 substituent (s) on the aryl moiety and substitution sites are not particularly limited.
"Acyloxyacetyl" is acyloxyacetyl having the above C2- C14 acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.
"Acyloxyalkyl" is acyloxyalkyl having the above C2-Cι4 acyl and Cι-C8 alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2- 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 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 1 to 3 heteroatom(s) selected from the group consisting of 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) " includes the following groups and the like.
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
wherein R9 is each independently hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, a inoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, 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) .
"Saturated 3 to 7 membered carbocyclic ring having substituent (s) " includes the following groups and the like.
Figure imgf000020_0004
wherein R10 is alkyl, acyl, 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 phenylalkyl optionally having substituent (s) , and R10' is hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl 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 of the substituent is generally 1 to 6 and substitution sites are not particularly limited.
"Phenylalkyl" is phenylalkyl consisting of phenyl and the above Cx-Cs alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, l-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1- methyl-1-phenylpropyl, l-methyl-2-phenylpropyl, l-methyl-3- phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s) . The kind and the number of the substituent of the
"phenylalkyl optionally having substituent (s) " are the same as those for the above-mentioned "aromatic heterocyclic group" and substitution sites are not particularly limited.
"Dialkylphosphinyl" is dialkylphosphinyl having the above Cι-C8 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 QL-C8 alkyl, and includes, for example, 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 group, phenylalkyl, hydroxy, carboxy, thiol, halogen, amino, formyl, carbamoyi, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, 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 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 R 2 and R3 in the formula (I) together with the attached carbon atom. By 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, 2, 3-dihydrobenzo [jb] thiophen-1-oxide and the like.
"A group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring' represents a group derived from naphthalene, 1,2- dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthalene, indan and the like. Of these, naphthyl such as naphthalen-1-yl and the like, and indanyl such as indan-4-yl and the like are preferable. The group may have 1 to 4 substituent (s) and substitution sites are not particularly limited.
"A group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom (s) " includes the following groups and the like.
Figure imgf000023_0001
Figure imgf000023_0002
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- [j] furan-7-yl, 2, 3- (methylenedioxy) phenyl and 3,4-dihydro- 2H-benzopyran-8-yl are particularly preferable. The group may have 1 to 3 substituent (s) and substitution sites are not particularly limited. "A group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroato (s) , which is fused with a benzene ring" includes the following groups and the like.
Figure imgf000024_0001
The group may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
"Alkylcarbonylalkyl" is, for example, C1-C4 alkyl- carbonyl-Cι-C alkyl, and includes, for example, methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butylcarbonylmethyl and the like.
"Arylaminocarbonyl" is C6-Cιo aryl-aminocarbonyl, and includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl and the like. The arylaminocarbonyl optionally has 1 to 3 substituent (s) on the aryl and substitution sites are not particularly limited.
"Aralkylaminocarbonyl" is C-Cχ4 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 particularly limited.
"Alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent" means Cι~C8 alkyl substituted by "a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s)", 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-C10 aryl such as phenyl, naphthyl and the like, and includes, for example, (4-phenylpiperazin-l-yl) methyl, 2- (4-phenylpiperazin-l- yl) ethyl, 3- (4-phenylpiperazin-l-yl) propyl, (4- (naphthalen-1-yl) piperazin-1-yl) methyl, 2- (4- (naphthalen-1- yl)piperazin-l-yl) ethyl, (4-methylhomopiperazin-l-yl)methyl and the like.
"Phenyla inoalkyl" is phenylamino-Cι-C 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-Cι-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. "Alkyl" in the R11 is C1-C4 alkyl, and includes, for examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
"Alkylsulfonyl" in the Ru is C1-C4 alkyl-sulfonyl, and includes, for example, methylsulfonyl, ethylsulfonyl, 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-Cι-C4 alkyl- sulfonyl, and includes, for example, benzylsulfonyl, 2- phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4- phenylbutylsulfonyl and the like. The phenylalkylsulfonyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited. "Alkylsulfinyl" in the R11 is 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 substitution sites are not particularly limited.
"Phenylalkylsulfinyl" in the Ru is phenyl-Cι-C4 alkyl- sulfinyl, and includes, for example, benzylsulfinyl, 2- phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4- phenylbutylsulfinyl and the like. The phenylalkylsulfinyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
"Alkoxycarbonyl" in the R11 is Cι-C alkoxy-carbonyl, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
"Phenylalkoxycarbonyl" in the R11 is phenyl-Cι-C4 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 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 optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
"Phenylalkylcarbonyl" in the R11 is phenyl-Cχ-C4 alkylcarbonyl, 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 R11 means phenoxycarbonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
"Alkyl" in the R12 is C1-C4 alkyl, and includes, for examples, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl and the like.
The compounds represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention. Such acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, 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 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
Figure imgf000027_0001
wherein R2, R3, R4 and R5 are as defined above.
Me1drum' 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 (IX) . The reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction. As the solvent, formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
Figure imgf000028_0001
wherein R2, 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, 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.
Figure imgf000028_0002
(X) 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 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, from 0°C to 200°C, preferably from 60°C to 100°C. The carbonyl derivative of the formula (VII) , which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 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
Figure imgf000029_0001
wherein R1, R2, R3, R4 and R5 are as defined above.
The compounds (I) of the present invention can be produced by reacting a inopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII) . The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
Of the compounds (I) of the present invention, a compound wherein R° is a substituent other than hydrogen can be synthesized as follows. Third Production Method
Figure imgf000030_0001
(XI) (XII) (I)
wherein R°, R1, R2, R3, R4 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 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
Figure imgf000030_0002
(XI) (XIII) (I) wherein R°, R1, R2, R3, R4 and R5 are as defined above, provided that R° is not hydrogen.
The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) such as acetic anhydride in the presence of a base. Suitable base includes, for example, triethyla ine, 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, 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. 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, 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 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-3β such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3β. Therefore, the compounds of the present invention have a GSK-3β-selective inhibitory activity and can be medicaments with small side-effect for 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 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, 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 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 is orally administered once to several times a day, or 1 - 500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day. Examples
The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples. Example 1
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonyl- piperidin-4-yl) -5-cyano-4, 7-dihydro-2#-pyrazolo [3, 4-b] - pyridine 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 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 L) was added n-BuLi (44 m ol) at -78°C and stirred for three hours. Further, ethyl Ν-Boc-piperidine-4-carboxylate (16.3 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 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 ) -l-cyanoethan-2-one (1.7 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 (2.0 g) as colorless crystals. MP:22β°C. Anal . Calcd . For : C23H25Ν7O3 : C, 61.73 ; H, 5.63 ; N, 21.97. Found: C, 61.45; H, 5.82 ;N, 21.61. MS (El) :447 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.42 (9H,m), 1.59-1.62 (2H,m) , 1.89-1.92 (2H,m) , 2.62-2.86 (3H,m) , 4.05-4.08 (2H,m) , 5.40(lH,s), 7.26(1H,S), 7.41 (1H, d, J=6.6Hz) , 7.58 (lH,dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz) , 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-j ]pyridine 4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonyl- piperidin-4-yl) -5-cyano-4, 7-dihydro-2iY-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 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 crystals. MP:216°C. MS (El) :348 (M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.78-1.81 (2H,m) , 2.07-2.11 (2H,m), 2.80-2.86(3H,m) , 3.27-3.30 (3H,m) , 5.39(lH,s), 7.27 (1H,S), 7.43 (lH,d, J=6.6Hz) , 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (lH,d, J=9.0Hz) , 9.86 (lH,brs) , 12.24 (lH,brs) . Example 3
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro~6- (1- methylpiperidin-4-yl) -2iT-pyrazolo [3, 4-b] pyridine 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 37% formaldehyde (0.18 g) , sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) at room temperature and the mixture was stirred overnight. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals. MP:>270°C.
MS (El) :361 (M+) .
1H-NMR (400MHz, DMSO-ds)δ (ppm) : 1.57-1.60 (2H,m) , 1.82-
1.88(2H,m), 2.01-2.06 (2H,m) , 2.15(3H,s), 2.58-2.61 (lH,m) ,
2.85-2.88 (2H,m) , 5.40(lH,s), 7.26(lH,s), 7.40 (IH, d, J=6.6Hz) , 7.58 (lH,dd, J=9.0Hz and 6.6Hz), 7.91 (IH, d, J=9.0Hz) ,
9.76(lH,brs) , 12.17 (lH,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] - 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. Anal . Calcd . For : C23H25N7O3 : C, 61.73 ; H, 5.63 ; N, 21.97.
Found: C, 61.56 ;H, 5.66 ;N, 21.67.
MS (El) :447 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.32-1.40 (2H,m) , 1.39(9H,s) ,
1.69-1.78 (2H,m) , 2.69-2.76 (2H,m) , 3.16-3.19 (lH,m) , 3.92- 3.95(2H,m), 5.42(lH,s), 7.28(lH,s), 7.42 (IH, d, J=6.6Hz) ,
7.58 (lH,dd, =9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) ,
9.87 (lH,brs) , 12.21 (lH,brs) .
Example 5
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (piperidin-3-yl) -2iϊ-pyrazolo [3, 4-j ]pyridine
The title compound was prepared from 4- (2, 1, 3-benzoxa- diazol-4-yl) -6- (l-t-butoxycarbonylpiperidin-3-yl) -5-cyano-
4, 7-dihydro-2Jf-pyrazolo [3, 4-jb] pyridine in the same manner as in Example 2. MP:202°C.
Anal .Calcd. For :Cι8H17N70:C, 62.24;H, 4.93;N, 28.23. Found: C, 61.97 ;H, 5.13 ;N, 27.89. MS (El) :347(M+) .
1H-NMR (400MHz, DMSO-d6)δ (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(lH,s), 7.26(lH,s), 7.39(lH,d, J=6.6Hz) , 7.58 (IH, dd, J=9.0Hz and
6.6Hz), 7.91 (lH,d, J=9.0Hz) , 10.39 (lH,brs) , 12.17 (lH,brs) . Example 6
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-3-yl) -2ff~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-3-yl) -2H- pyrazolo [3, 4-i?] pyridine in the same manner as in Example 3. MP:228°C. MS (El) :361 (M+) . 1H-NMR (400MHz, DMSO-d6)δ (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(lH,s), 7.27(lH,s), 7.40 (lH,d, J=6.6Hz) , 7.59 (IH, dd, J=9.0Hz and 6.6Hz), 7.92 (lH,d, J=9.0Hz) , 10.16 (lH,brs) , 12.20 (lH,brs) . Example 7 4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (1- t-butoxycarbonyl- piperidin-2-yl) -5-cyano-4, 7-dihydro-2H-pyrazolo [3, -b] - pyridine
The title compound was prepared from ethyl pipecolinate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1. MS (El) :447 (M+) .
^Η-NMR (400MHz, DMSO-d6)δ (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), 7.26 and 7.29(lH,s), 7.38- 7.44(lH,m), 7.54-7.60 (lH,m) , 7.90-7.93 (lH,m) , 9.63 and 9.73(lH,brs) , 12.16 (lH,brs) . Example 8
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (piperidin-2-yl) -2#-pyrazolo [3, 4-b] pyridine The title compound was prepared from 4- (2, 1, 3-benzoxa- diazol-4-yl) -6- (l-t-butoxycarbonylpiperidin-2-yl) -5-cyano- 4, 7-dihydro-2iϊ-pyrazolo [3, 4-b] pyridine in the same manner as in Example 2. MS (El) :347(M+) .
^•H-N R (400MHz, DMSO-d6)δ (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 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- pyrazole in the same manner as in Example 1.
MS (El) :449(M+) .
1H-NMR (400MHz, DMSO-d6)δ (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- 7.45(lH,m), 7.57-7.62 (lH,m) , 7.93-7.96 (lH,m) , 9.84 and
9.92 (lH,brs) , 12.23 (IH, brs) .
Example 10
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-
(morpholin-2-yl ) -2ff-pyrazolo [ 3 , 4-jb] pyridine The title compound was prepared from 4- (2, 1, 3-benzoxa- diazol-4-yl) -6- (4-t-butoxycarbonylmorpholin-2-yl) -5-cyano-
4, 7-dihydro-2H-pyrazolo [3, 4-jb] pyridine in the same manner as in Example 2.
MS (El) :349(M+) . ^Ή-NMR (400MHz, DMSO-d6)δ (ppm) : 2.64-2.95 (4H,m) , 3.53(lH,br), 3.55-3.57(lH,m) , 3.82-3.85 (lH,m) , 4.41-4.45 (lH,m) , 5.43 and 5.44(lH,s), 7.24 and 7.28(lH,s) , 7.38-7.41 (lH,m) , 7.56- 7.61(lH,m), 7.91-7.94(lH,m) , 9.74 and 9.76 (lH,brs) , 12.19(lH,brs) . Example 11
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6- (4- methylmorpholin-2-yl) -2H-pyrazolo [3, 4-Jb] 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-Jb] pyridine in the same manner as in Example 3. MP:143°C.
MS (El) :363(M+) .
^-H-NMR ( 400MHz, DMSO-d6)δ (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 (IH, d, J=6.6Hz) , 7.58 (lH,dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) , 9.80(lH,brs) , 12.20 (lH,brs) . Example 12
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (1-t-butoxycarbonyl-l, 2,3,6- tetrahydropyridin-4-yl) -5-cyano-4, 7-dihydro-2g-pyrazolo- [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. MP:222°C.
MS (El) :445(M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.41 (9H,s), 2.35-2.39 (2H,m) ,
3.46-3.48(2H,m) , 3.90-3.92 (2H,m) , 5.43(lH,s), 6.06-6.09 (lH,m), 7.28(lH,s), 7.45 (IH, d, J=6.6Hz) , 7.60 (IH, dd, =9.0Hz and 6.6Hz), 7.93 (IH, d, J=9.0Hz) , 9.94 (lH,brs) , 12.19 (lH,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- diazol-4-yl) -6- (1-t-butoxycarbonyl-l, 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 (El) :345(M+) . XH-NMR (400MHz, DMSO-d6)δ (ppm) : 2.26-2.32 (2H,m) , 2.87-
2.90(2H,m), 3.30-3.36 (3H,m) , 5.42(lH,s), 6.09-6.10 (lH,m) , 7.30(lH,s), 7.43 (lH,d, J=6.6Hz) , 7.60 (IH, dd, J=9.0Hz and 6.6Hz), 7.92(lH,d, J=9.0Hz) , 9.87 (lH,brs) , 12.18 (lH,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-jb] - 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, -b] pyridine in the same manner as in Example 3. MP:218°C. MS (El) :359(M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 2.24 (3H,s), 2.35-2.42 (2H,m) , 2.91-2.93 (2H,m) , 3.31-3.33 (2H,m) , 5.42(lH,s), 6.04-6.05 (lH,m), 7.27(lH,s), 7.43 (IH, d, J=6.6Hz) , 7.59 (IH, dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) , 9.87 (lH,brs) , 12.17 (lH,brs) . Example 15
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (2- (N- t-butoxycarbonyl-N- methylamino) ethyl) -5-cyano-4, 7-dihydro-2ff-pyrazolo [3, 4-b] - pyridine
To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 L) , dimethylaminopyridine (1.5 g) and di-tert-butyldicarbonate (30 g) at 0°C and the mixture was stirred at 40°C for four 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) at 0°C and the mixture was stirred at room temperature for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 3- (N-Boc-N-methylamino ) propionate (4.3 g) as a colorless oil. Subsequently, the title compound was prepared from ethyl 3- (N-Boc-N-methylamino ) propionate,
2, 1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1. MP:240°C.
Anal. Calcd. For -C21H23N7O3-C, 59.85^,5.50;]^ 23.26. Found:C,59.69;H, 5.45;N, 23.22. MS (El) :421 (M+) .
^Η-NMR (400MHZ, DMSO-d6)δ (ppm) : 1.26 and 2.32 (9H, s) , 2.62-
2.63(2H,m), 2.81(3H,s), 3.48-3.55 (2H,m) , 5.40(lH,s), 7.27 (lH,s), 7.40(lH,d, J=6.6Hz) , 7.57 (IH, dd, J=9.0Hz and 6.6Hz),
7.92 (lH,d, J=9.0Hz) , 10.07 (lH,brs) , 12.15 (lH,brs) . Example 16
4- (2,1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7~dihydro-6~ (2- (N- methylamino) ethyl) -2H-pyrazolo [3, 4-Jb] pyridine
The title compound was prepared from 4- (2, 1, 3-benzoxa- diazol-4-yl) -6- (2- (N- -butoxycarbonyl-N-methylamino) ethyl) - 5-cyano-4, 7-dihydro-2H-pyrazolo [3, 4-Jb] pyridine in the same manner as in Example 2.
MP:174°C.
MS (El) :321 (M+) .
1H-ΝMR (400MHz, DMSO-d6)δ (ppm) : 2.29 (3H,s), 2.50-2.78 (4H,m) , 3.31(3H,br), 5.39(lH,s), 7.24(lH,s), 7.43 (IH, d, J=6.6Hz) ,
7.58 (lH,dd, J=9.0Hz and 6.6Hz), 7.91 (IH, d, J=9.0Hz) .
Example 17
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (2- (N-t-butoxycarbonyl- amino) ethyl) -5-cyano-4, 7-dihydro-2ff-pyrazolo [3, -b] pyridine 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 : C20H21Ν7O3 :C,58.96;H,5.20;N,24.06. Found: C, 58.81 ;H, 5.19; N, 23.82.
MS (El) :407 (M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.33 (9H,s), 2.55-2.60 (2H,m) , 3.23-3.33(2H,m) , 5.41(lH,s) , 6.81 (lH,brs) , 7.25(lH,s), 7.44(lH,d, J=6.6Hz) , 7.57 (IH, dd, J=9.0Hz and 6.6Hz), 7.92 (lH,d, J=9.0Hz) , 9.94 (lH,brs) , 12.14 (lH,brs) . Example 18
6- (2-Aminoethyl) -4- (2,1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7- dihydro-2Jf-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-jb] pyridine in the same manner as in Example 2.
MS (El) :307 (M+) .
1H-ΝMR (400MHz, DMSO-d6)δ (ppm) : 2.50-2.54 (2H,m) , 2.88 (2H,t, J=7.3Hz) , 3.35(4H,br), 5.40(lH,s), 7.25(lH,s),
7.44 (lH,d, J=6.6Hz) , 7.58 (IH, dd, J=9.0Hz and 6.6Hz),
7.92 (lH,d, J=9.0Hz) .
Example 19
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (2- (N,N- dimethyla ino) ethyl ) -2H-pyrazolo [3, 4-Jb] 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-jb] pyridine in the same manner as in
Example 3. MP:215°C.
MS (El) :335(M+) .
1H-Ν R (400MHz, DMSO-d6)δ (ppm) : 2.19 (6H,s), 2.45-2.62 (4H,m) ,
5.41(lH,s), 7.27(lH,s), 7.43 (IH, d, J=6.6Hz) ,
7.58 (lH,dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, =9.0Hz) , 10.04 (lH,brs) , 12.16 (lH,brs) . Example 20
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- ( (N- t-butoxycarbonyl-N- methylamino) methyl) -5-cyano-4, 7-dihydro-2Jf-pyrazolo [3, 4-b] - pyridine The title compound was prepared from glycine ethyl ester hydrochloride, 2, 1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 15. MP:207°C. Anal.Calcd.For:C2oH2iΝ7θ3:C,58.96;H,5.20;Ν,24.06. Found:C,58.80;H,5.12;N,24.38. MS (El) :407 (M+) . XH-NMR (400MHz, DMSO-d6)δ (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 (lH,d, J=6.6Hz) , 7.58 (IH, dd, J=9.0Hz and 6.6Hz), 7.94 (lH,d, J=9.0Hz) , 9.33 (lH,brs) , 12.15 (lH,brs) . Example 21
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- ( (N- methylamino) methyl) -2H-pyrazolo [3, 4-Jb] pyridine trifluoroacetate
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- ( (N-t-butoxycarbonyl-N- methylamino) methyl) -5-cyano-4, 7-dihydro-2JJ-pyrazolo [3, 4-i>] - 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 (El) :307 (M+) .
1H-ΝMR(400MHz,DMSO-d6)δ(ppm) : 3.10 (3H,s), 4.51-4.68 (2H,m) , 7.24 (lH,d, J=6.6Hz) , 7.45(lH,s), 7.52 (IH, dd, =9.0Hz and
6.6Hz), 7.89 (lH,d, J=9.0Hz) , 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- (Ν- methylamino) cyclohexyl ) -2H-pyrazolo [ 3 , 4-Jb] 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. MS (El) :375(M+) .
XH-ΝMR ( 400MHz, DMSO-d6)δ (ppm) : 1.32-1.35 (2H,m) , 1.81-2.12 (6H,m), 2.57(3H,s), 2.65-2.69 (lH,m) , 2.81-2.85 (lH,m) , 5.39 (lH,s), 7.28(lH,s), 7.41 (lH,d,J=6.6Hz) , 7.59 (IH, dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) , 8.54 (lH,br)', 9.79 (lH,brs) , 12.22 (lH,brs) . Example 23
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano~4, 7-dihydro-6- (4- (N,N- dimethyla ino) 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-methy1amino) - cyclohexyl) -2H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 3. MP:241°C. MS (El) :389(M+) . 1H-NMR (400MHz, DMSO-d6)δ (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 4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- phenylpiperidin-4-yl) ~2.ff-pyrazolo [3, 4-jb]pyridine
To a solution of ethyl isonipecotate (8.9 g) in CH2C1 (500 mL) was added triphenyl bismus (25 g) and Copper (II) acetate (10.3 g) at room temperature, the mixture 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 l-phenylpiperidine-4-carboxylate (8.6 g) as 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 l-phenylpiperidine-4-carboxylate (8.6 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 acetate (10:1)) to give 1- (l-phenylpiperidin-4-yl) -2- cyanoethan-1-one (2.0 g) as colorless crystals. A solution of 2, 1, 3-benzoxadiazole-4-aldehyde (0.3 g) , 3-aminopyrazole (0.2 g) and 1- (l-phenylpiperidin-4-yl) -2-cyanoethan-l-one (0.5 g) in acetonitrile (10 L) 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++l) .
^•H-NMR (400MHz, DMSO-d6)δ (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-
3.84(2H,m), 5.41(lH,s), 6.75 (IH, dd, J=7.3Hz and 7.2Hz) , 6.94-6.96(2H,m) , 7.18-7.27 (3H,m) , 7.42 (IH, d, J=6.6Hz) , 7.59
(lH,dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) , 9.81 (lH,brs) ,
12.17 (lH,brs) .
Example 25
6- (l-Acetylpiperidin-4-yl) -4- (2, 1, 3-benzoxadiazol-4-yl) -5- cyano-4, 7-dihydro-2JT-pyrazolo [3, 4-b] pyridine
To a solution of ethyl isonipecotate (8.0 g) in THF (100 L) 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 ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl l-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 l-acetylpiperidine-4-carboxylate (10 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 acetate (10:1)) to give 1- (l-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- (l-acetylpiperidin-4-yl) -2-cyanoethan-l-one (0.4 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 (0.49 g) as yellow crystals .
MP:248°C.
MS (FAB) :340(M++1) . 1H-N R (400MHz, DMSO-ds)δ (ppm) : 1.62-1.64 (2H,m) , 1.82-1.84
(lH,m), 2.00-2.02 (4H,m) , 2. 9-2.50 (lH,m) , 2.94-3.07 (2H,m) , 3.89-3.92 (lH,m) , 4.48-4.51 (lH, ) , 5.40(lH,s), 7.27(lH,s), 7.42 (lH,d, J=6.6Hz) , 7.59 (IH, dd, =9.0Hz and 6.6Hz), 7.92 (lH,d, J=9.0Hz) , 9.81 (lH,brs) , 12.18 (lH,brs) . Example 26
4- (2, 1, 3-Benzoxadiazol-4-yl) -6- (l-benzoylpiperidin-4-yl) -5- cyano-4, 7-dihydro-2FJ-pyrazolo [3, 4-b] pyridine
The title compound was prepared from benzoylchloride, ethyl isonipecotate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 25. MP:228°C. MS (FAB) :452 (M++l) .
^•H-NMR (400MHz, DMSO-d6)δ (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, ) , 4.60-4.63 (lH,m) , 5.41(lH,s), 7.28(lH,s), 7.43-7.46 ( 6H,m) ,
7.56-7.59 (lH,m) , 7.92 (IH, d, =9.0Hz) , 9.90 (lH,brs) ,
12.21 (lH,brs) .
Example 27
6- (1-Acetyl-l, 2, 3, 6-tetrahydropyridin-4-yl) -4- (2, 1, 3- benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2H-pyrazolo [3, 4-b] - pyridine
The title compound was prepared from acetyl chloride, ethyl 1, 2, 3, 6-tetrahydropyridine-4-carboxylate, 2,1,3- benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 25.
MP:237°C.
MS (El) :387(M+) .
XH-NMR (400MHz, DMSO-d6)δ (ppm) : 2.00 and 2.04 (3H, s) , 2.46- 2.49(2H,m), 3.55-3.58 (2H,m) , 4.00-4.06 (2H,m) , 5.44(lH,s), 6.10(lH,s), 7.29(lH,s), 7.45 (IH, d, =6.6Hz) ,
7.59(lH,dd, J=9.0Hz and 6.6Hz), 7.93 (IH, d, J=9.0Hz) , 9.94 (lH,brs) , 12.17 (lH,brs) . Example 28
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- (ethoxycarbonyl) piperidin-4-yl) -2.H"-pyrazolo [3, 4-b] pyridine 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 (El) :419(M+) .
1H-NMR(400MHz,DMSO-d6)δ(ppm) : 1.19 (3H, t, J=7.3Hz) , 1.61- 1.63(2H,m), 1.90-1.94 (2H,m) , 2.84-2.88 (3H,m) , 4.02-
4.07 (4H, ), 5.40(lH,s), 7.26(lH,s), 7.41 (IH, d, J=6.6Hz) , 7.58 (lH,dd, =9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) , 9.80(lH,brs), 12.17 (lH,brs) . Example 29 4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- timethanesulfonylpiperidin-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 Example 25. MP:243°C. MS (El) :425(M+) .
1H-NMR(400MHz,DMSO-d6)δ(ppm) : 1.73-1.76 (2H,m) , 2.04-2.08
(2H,m), 2.74-2.78 (3H,m) , 2.88(3H,s), 3.66-3.69 (2H,m) , 5.41(lH,s), 7.27(lH,s), 7.42 (IH, d, J=6.6Hz) ,
7.58(lH,dd, J=9.0Hz and 6.6Hz), 7.93 (IH, d, J=9.0Hz) ,
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- -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 (El) :418 (M+) . 1H-NMR (400MHz, DMSO-ds)δ (ppm) : 1.61-1.63 (2H,m) , 2.00-2.06 (2H,m), 2.65-2.67 (2H,m) , 2.75(6H,s), 2.81-2.85 (lH,m) , 3.64- 3.67(2H,m), 5.40(lH,s), 7.27(lH,s), 7.41 (IH, d, J=6.6Hz) , 7.59 (lH,dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz) , 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- 4, 7-dihydro-6- (piperidin-4-yl) -2iϊ-pyrazolo [3, 4-b] pyridine (1.5 g) in MeOH (30 mL) was added diisopropylethylamine (4.2 g) , and lJϊ-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (1.0 g) as yellow crystals . MP:>270°C. MS (El) :389(M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.53-1.56 (2H, ) , 1.86-1.91 (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 (lH,d, J=6.6Hz) , 7.59 (IH, dd, J=9.0Hz and 6.6Hz),
7.91(lH,d, J=9.0Hz) , 9.79 (lH,brs) , 12.21 (lH,brs) .
Example 32 6- (l-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- a inopyrazole in the same manner as in Example 25. MP:219°C.
Anal . Calcd. For : C2oHi9N702 : C, 61.69;H, 4.92 ;N, 25.18.
Found:C, 61.36; H, 4.90 ;N, 25.12.
MS (El) :389(M+) .
1H-N R (400MHz, DMSO-d6) δ (ppm) : 1.25-1.49 (lH, ) , 1.74-1.78 (2H,m), 2.00(3H,s), 2.01-2.04 (lH,m) , 2.49-2.98 (3H,m) , 3.78-
3.81(lH,m), 4.37-4.40(lH,m) , 5.29 and 5.42 (IH, s) , 7.28(lH,s), 7.41-7.48 (lH,m) , 7.58-7.62 (lH,m) , 7.92-
7.95(lH,m), 9.90 (lH,brs), 12.21 (lH,brs) .
Example 33
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- ethylpiperidin-4-yl) -2ff-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. MP:231°C.
MS (El) :375(M+) .
XH-NMR (400MHz, DMSO-d6)δ (ppm) : 0.99 (3H, t, J=7.3Hz) , 1.60-
1.63(2H,m), 1.85-1.88 (2H, ) , 2.00-2.04 (2H,m) , 2.31-
2.34 (2H, ), 2.64-2.66 (lH,m) , 2.97-3.00 (2H,m) , 5.39(lH,s), 7.26(lH,s), 7.40 (lH,d, J=6.6Hz) , 7.58 (IH, dd, J=9. OHz and
6.6Hz), 7.92(lH,d, J=9.0Hz) , 9.75 (lH,brs) , 12.18 (lH,brs) .
Example 34
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- propylpiperidin-4-yl) -2fl-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 propionaldehyde in the same manner as in Example 3.
MP:246°C. Anal. Calcd. For -C21H23N7O-C, 64.76;H, 5.95;N, 25.18.
Found: C, 64 ,23;H, 5.87 ;N, 24.86.
MS (El) :389 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 0.84 (3H, t, J=7.3Hz) , 1.40-1.45
(2H,m), 1.59-1.62 (2H,m) , 1.82-1.86 (2H,m) , 2.00-2.05 (2H,m) , 2.21 (2H,t, J=7.3Hz) , 2.62-2.65 (lH,m) , 2.94-2.97 (2H,m) , 5.39
(lH,s), 7.26(lH,s), 7.40 (IH, d, =6.6Hz) , 7.58 (IH, dd, J=9. OHz and 6.6Hz), 7.91 (lH,d, J=9. OHz) , 9.77 (lH,brs) , 12.18 (lH,brs)
Example 35
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1-iso- propylpiperidin-4-yl) -2H-pyrazolo [3, 4-b] pyridine
The title compound was prepared from 4- (2, 1, 3-benzoxa- diazol-4-yl) -5-cyano-4, 7-dihydro-6- (piperidin-4-yl) -2H- pyrazolo [3, 4-b]pyridine and acetone in the same manner as in Example 3. MP:260°C. MS (El) :389(M+) .
^■H-N R (400MHz, DMSO-d6)δ (ppm) : 1.22 (6H, d, J=7.3Hz) , 1.82-3.42
(10H,m), 5.40(lH,s), 7.27(lH,s), 7.42 (IH, d, J=6.6Hz) ,
7.59 (lH,dd, J=9. OHz and 6.6Hz), 7.92 (IH, d, J=9. OHz) ,
9.66(lH,brs) , 12.22 (lH,brs) . Example 36
4- (2-Bromo-3-cyanophenyl) -6- (l-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 manner as in Example 1.
MP:>270°C.
Anal . Calcd . For : C24H25BrN6θ2 : C, 56.59 ; H, 4.95 ; N, 16.50.
Found:C,56.47;H, 4.87 ;N, 16.52.
MS (El) :509(M+) . 1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.41 (9H,s), 1.59-1.66 (2H,m) , 1.85-1.90 (2H,m) , 2.65-2.82 (3H,m) , 4.05-4.07 (2H,m) , 5.47(lH,s), 7.33(lH,s), 7.56-7.60 (2H,m) , 7.84 (IH, d, J=7.3Hz) , 9.81 (lH,brs) , 12.26 (lH,brs) . Example 37 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- (l-t-butoxycarbonylpiperidin-4-yl) -5-cyano-4, 7- dihydro-2H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 2. MP:>270°C. MS (El) :409 (M+) .
^-NMR (400MHz, DMSO-d6)δ (ppm) : 1.53-1.56 (2H,m) , 1.83- 1.87 (2H, ), 2.46-2.50 (3H,m) , 2.71-2.74 (lH,m) , 3.00- 3.04 (lH, ), 5.45(lH,s), 7.32(lH,s), 7.56-7.58 (2H,m) , 7.81 (lH,d, J=7.3Hz) , 9.74 (lH,brs) , 12.26 (lH,brs) . Example 38
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- timethylpiperidin-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) -2Jϊ-pyrazolo- [3, 4-b] pyridine in the same manner as in Example 3. MP:>270°C. MS (El) :423(M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.65-1.71 (2H,m) , 2.02-2.08 (3H,m), 2.29(3H,s), 2.48-2.52 (lH, ) , 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 (lH,d, J=7.3Hz) , 9.83 (lH,brs) , 12.32 (lH,brs) .
Example 39
4- (2-Bromo-3-cyanophenyl) -6- (l-t-butoxycarbonylpiperidin-3- 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. Anal.Calcd.For:C24H25BrN602:C,56.56;H,4.95;N, 16.50.
Found: C, 56.49;H, 4.85;N, 16.50.
MS (El) :509(M+) .
XH-]S!MR (400MHz, DMS0-d6)δ (ppm) : 1.37 and 1.39 (9H, s) , 1.68-
2.06(4H,m), 2.65-2.75 (2H,m) , 3.30-3.32 (lH,m) , 3.94-3.97 (2H,m), 5.47 and 5.49(lH,s) , 7.34(lH,s), 7.58-7.61 (2H,m) ,
7.82-7.86 (lH, ) , 9.89 (lH,brs) , 12.31 (lH,brs) .
Example 40
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (piperidin-
3-yl) ~2jj-pyrazolo [3, 4-b] pyridine trifluoroacetate The title compound was prepared from 4- (2-bromo-3-cyano- phenyl) -6- (1- t-butoxycarbonylpiperidin-3-yl) -5-cyano-4, 7- dihydro-2Jϊ-pyrazolo [3, 4-b] pyridine in the same manner as in
Example 21.
MP : 225°C . Anal . Calcd . For :
Figure imgf000050_0001
: C, 48 .20 ; H, 3 . 47 ; N, 16. 06 .
Found : C, 47 . 98 ; H, 3 . 52 ; N, 15 . 97 . MS (El) :409(M+) .
1H-NMR (400MHz, DMSO-d6)δ (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- time thylpiperidin-3-yl) -2ff-pyrazolo [3, 4-b]pyridine
The title compound was prepared from 4- (2-bromo-3-cyano- phenyl) -5-cyano-4, 7-dihydro-6- (piperidin-3-yl) -2if~pyrazolo- [3, 4-b] pyridine trifluoroacetate in the same manner as in Example 3. MP:174°C. MS (El) :423 (M+) . XH- MR (400MHz, DMSO-d6)δ (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 (lH,m), 5.47(lH,s), 7.33(lH,s), 7.57-7.58 (2H,m) , 7.84 (lH,d, =7.3Hz) , 10.06 (lH,brs) , 12.29 (lH,brs) . Example 42 4- (2-Bromo-3-cyanophenyl) -6- (l-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 (El) :509(M+) .
^■H-N R (400MHz, DMSO-d6)δ (ppm) : 1.35(9H,s), 1.34-1.90 (6H,m) , 3.48-3.52 (2H, ) , 4.42-4.48 (lH,m) , 5.43 and 5.46 (IH, 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) . Example 43
4- (2-Bromo-3-cyanophenyl) -5-cyano~4, 7-dihydro-6- (piperidin- 2-yl) -2ff-pyrazolo [3, 4-b] pyridine trifluoroacetate
The title compound was prepared from 4- (2-bromo-3-cyano- phenyl) -6- (l-t-butoxycarbonylpiperidin-2-yl) -5-cyano-4, 7- dihydro-2H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 21. MP:232°C.
MS (El) :409(M+) .
1H-NMR ( 400MHz, DMSO-d6)δ (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-2f-"-pyrazolo [3, 4-b] pyridine The title compound was prepared from ethyl morpholine-2- carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. MP:219°C. MS (El) :511 (M+) . 1H-NMR (400MHz, DMSO-d6)δ (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 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- -butoxycarbonylmorpholin-2-yl) -5-cyano-4, 7- dihydro-2H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 21. MP:236°C. MS (El) :411 (M+) .
1H-NMR (400MHz, DMSO-ds)δ (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) , 5.55(lH,s), 7.36(lH,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) -2ff-pyrazolo [3, 4-b] pyridine The title compound was prepared from 4- (2-bromo-3-cyano- phenyl) -5-cyano-4, 7-dihydro-6- (morpholin-2-yl) -2iϊ-pyrazolo- [3, 4-b]pyridine trifluoroacetate in the same manner as in Example 3. MP:180°C. MS (El) :425(M+) .
5 1H-N R (400MHz, DMSO-d6)δ (ppm) : 2.18-2.20 (lH, ) , 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, ) , 4.48- 4.50(lH,m), 5.51(lH,s), 7.35(lH,s), 7.56-7.61 (2H,m) , 7.84- 7.86(lH,m), 9.81 and 9.84 (lH,brs) , 12.31 (lH,brs) .
10 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-
25 benzaldehyde and 3-aminopyrazole in the same manner as in Example 1, and Example 2 followed. MP:226°C. MS (El) :407 (M+) .
1H-NMR (400MHz, DMS0-d6)δ (ppm) : 2.36-2.40 (2H,m) , 2.95-2.98 20 (2H,m), 3.56-3.60 (3H,m) , 5.51(lH,s), 6.15(lH,s), 7.34(lH,s),
7.56-7.60 (2H,m) , 7.84 (IH, d, J=7.3Hz) , 9.93 (lH,brs) ,
12.32 (lH,brs) .
Example 48
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1-methyl- 25. 1,2,3, 6-tetrahydropyridin-4~yl) -2Jϊ-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) -2-ff-pyrazolo [3, 4-b] pyridine in the same manner as in
Example 3. 30 MP:233°C.
MS (El) :421 (M+) .
XH-NMR (400MHz, DMSO-d6)δ (ppm) : 2.31 (3H,s), 2.56-2.67 (4H,m) ,
3.00-3.03(2H,m) , 5.50(lH,s), 6.10(lH,s), 7.34(lH,s), 7.58-
7.60(2H,m), 7.83 (IH, d, J=7.3Hz) , 9.91 (lH,brs) , 12.29 (lH,brs) . 35 Example 49
4- (2-Bromo-3-cyanophenyl) -6- ( (N- t-butoxycarbonyl-N-methyl- amino) methyl) -5-cyano-4, 7-dihydro-2H-pyrazolo [3, 4-b] - pyridine
The title compound was prepared from glycine ethyl ester hydrochloride, 2-bromo-3-cyanobenzaldehyde and 3-amino- pyrazole in the same manner as in Example 15. MS (El) :469(M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.39(9H,s), 2.85(3H,s), 4.15- 4.18(2H,m), 5.49(lH,s), 7.37(lH,s), 7.56-7.57 (2H,m) , 7.83(lH,d, J=7.3Hz) , 9.78-9.93 (lH,br) , 12.31 (lH,brs) . Example 50
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- ( (N-methyl- amino) methyl) -2fl~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- cyano-4, 7-dihydro-2i-pyrazolo [3, 4-b] pyridine in the same manner as in Example 21. MP:258°C. MS (El) :369(M+) .
1H-ΝMR (400MHz, DMSO-d6)δ (ppm) : 3.10 (3H,s), 4.46-4.66 (2H,m) , 5.50(lH,s), 7.47-7.48 (2H,m) , 7.65(lH,s), 7.80-7.81 (2H,m) ,
8.09(lH,br), 10.81 (lH,brs) , 12.38 (lH,brs) .
Example 51
6- (l-Acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5- cyano-4, 7-dihydro-2iT~pyrazolo [3, 4-b] pyridine 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:>280°C.
MS (El) :451 (M+) . αH-NMR (400MHz, DMSO-d6)δ (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(lH,s), 7.34(lH,s), 7.56- 7.58 (2H, ), 7.84 (IH, d, J=7.3Hz) , 9.81 (lH,brs) , 12.27 (lH,brs) Example 52 6- (l-Benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) -5- cyano-4, 7-dihydro-2fT-pyrazolo [3, 4-b] pyridine The title compound was prepared from benzoyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3- aminopyrazole in the same manner as in Example 25. MP:>280°C. MS (FAB) :514 (M++l) .
^•H-N R (400MHz, DMSO-d6)6 (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(lH,s), 7.34-7.58(8H,m), 7.84 (IH, d, J=7.3Hz) , 9.90 (lH,brs) , 12.31 (lH,brs) . Example 53
4- (2-Bromo-3-cyanophenyl) -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-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 25. MP:>280°C. MS (El) :487 (M+) .
^■H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.75-2.07 (4H,m) , 2.76-2.79
(2H,m), 2.89(3H,s), 3.66-3.69 (2H,m) , 5.48(lH,s), 7.34(lH,s), 7.56-7.58 (2H,m) , 7.84 (IH, d, J=7.3Hz) , 9.84 (lH,brs) ,
12.30(lH,brs) .
Example 54
6- (l-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 : C23H26CIN.3O2 : C, 62.79 ; H, 5.96;N, 15.92. Found: C, 62.81 ;H, 5.87;N, 16.01.
MS (El) :439(M+) .
XH-NMR ( 400MHz, DMSO-d6)δ (ppm) : 1.41 (9H,s), 1.58-1.67 (2H,m) , 1.86-1.91 (2H,m) , 2.84-2.90 (3H,m) , 4.06-4.09 (2H,m) , 5.35(1H,S), 7.21-7.33(4H,m) , 7.42 (IH, d, =7.3Hz) , 9.69(lH,brs) , 12.18 (lH,brs) . Example 55
4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (piperidin-4-yl) - 2ff-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 (El) :339(M+) . XH-NMR (400MHz, DMSO-d6)δ (ppm) : 1.84-1.92 (2H,m) , 2.10-2.16
(2H,m), 2.96-3.00 (3H,m) , 3.30-3.40 (2H,m) , 5.36(lH,s), 7.22-
7.33(4H,m) , 7.42 (IH, d, =7.2Hz) , 8.56(lH,br), 9.76 (lH,brs) ,
12.26(lH,brs) .
Example 56 4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (1-methyl- piperidin-4-yl) -2H-pyrazolo [3, 4-b] yridine
The title compound was prepared from 4- (2-chlorophenyl) -
5-cyano-4, 7-dihydro-6- (piperidin-4-yl) -2Jϊ-pyrazolo [3, 4-b] - pyridine trifluoroacetate in the same manner as in Example 3.
MP:>270°C.
Anal. Calcd. For :C19H2oClN5:C, 64.49; H, 5.70 ;N, 19.79.
Found: C, 64.71 ;H, 5.68 ;N, 19.59.
MS (El) :353 (M+) . ^-H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.56-1.65 (2H,m) , 1.84-1.90
(2H,m), 2.02-2.06(2H,m) , 2.16(3H,s), 2.60-2.65 (lH,m) , 2.85- 2.88(2H,m), 5.34(lH,s), 7.21-7.33 (4H,m) , 7.41 (IH, d, J=7.3Hz) , 9.63 (lH,brs) , 12.17 (lH,brs) . Example 57 2-Acetyl-6- (l-acetylpiperidin-4-yl) -4- (2-chlorophenyl) -5- cyano-4, 7-dihydro-2H-pyrazolo [3, 4-b]pyridine
To a solution of 4- (2-chlorophenyl) -5-cyano-4, 7-dihydro- 6- (piperidin-4-yl) -2H-pyrazolo [3, 4-b]pyridine (1.0 g) in pyridine (1.2 mL) was added acetic anhydride (0.42 mL) at room temperature and the mixture was stirred for two hours . The mixture was evaporated under reduced pressure and the residue was washed with methanoi and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals. MS (El) :423(M+) . ^Η-NMR (400MHz, DMSO-d6)δ (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 (lH,m), 3.11-3.18 (2H,m) , 3.91-3.94 (lH,m) , 4.49-4.52 (lH,m) , 5.37(lH,s), 7.32-7.37 (3H,m) , 7.48 (IH, d, J=7.3Hz) , 7.84(lH,s), 10.24(lH,brs) . Example 58
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (2- oxocyclohexan-1-yl) -2ff-pyrazolo [3, 4-b]pyridine
To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 L) was added ethyleneglycol (10.1 g) and 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 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 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 acetate (10:1)) to give l-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 l-cyano-2- (1, 4-dioxa-spiro [4, 5] - decan-6-yl) ethan-2-one (1.2 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 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 methanoi (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 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:>270°C.
MS (El) :360 (M+) .
1H- MR(400MHz,DMSO-d6)δ(ppm) : 1.74-1..80 (5H,m) , 2.60-2.65
(3H,m), 3.31-3.35(lH,m) , 5.98(lH,s), 6.92 (IH, d, J=6.6Hz) ,
7.39(lH,s), 7.47 (lH,dd,J=9. OHz and 6.6Hz), 7.8 (lH,d,J=9. OHz) , 9.33 (lH,brs) , 12.15 (lH,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] yridine 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++l) .
^-H-NMR (400MHz, DMSO-d6)δ (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(lH,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) -2-H-pyrazolo [3, 4-b] pyridine The title compound was prepared from ethyl 2- cyclopentanonecarboxylate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 58. MS (FAB) :347 (M++l) .
^•H-NMR (400MHz, DMSO-d6)δ (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 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-yl) -5-cyano-4, 7- dihydro-2H-pyrazolo [3, 4-b] pyridine 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++l) . ^Η-NMR (400MHz, DMSO-ds)δ (ppm) : 2.22 (3H,s), 3.63-3.66 (2H,m) ,
5.48(lH,s), 7.30(lH,s), 7.47 (IH, d, J=6.6Hz) ,
7.61 (lH,dd,J=9. OHz and 6.6Hz), 7.94 (IH, d, J=9. OHz) ,
10.00(lH,brs) , 12.21 (lH,brs) .
Example 62 4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (2- oxocyclohexan-1-yl) -2ff-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. MP:273°C.
MS (El) :422 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.72-1.81 (5H,m) , 2.59-2.65
(3H,m), 3.30-3.32(lH,m) , 5.91(lH,s), 7.05 (IH, d, J=7.3Hz) ,
7.40-7.43(2H,m) , 7.52(lH,s), 7.74 (IH, d, J=7.3Hz) , 9.33 (lH,brs) , 12.24 (lH,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, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 58. MP:230°C.
MS (El) :382 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 2.23 (3H,s), 3.60-3.67 (2H,m) ,
5.50(lH,s), 7.39(lH,s), 7.60 (IH, dd, J=7.3Hz and 7.2Hz), 7.70(lH,d, J=7.3Hz) , 7.83 (IH, d, =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 4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (1-t-butoxy- carbonylpiperidin-4-yl) -2if-pyrazolo [3, 4-b] pyridine (2.0 g) was added to 4N-HC1 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 washed by ethanol, and the precipitated crystals were collected by filtration to give the title compound (1.2 g) as yellow crystals.
MS (El) :339(M+) .
XH- MR (400MHz, DMS0-d6)δ (ppm) : 1.83-1.90 (2H,m) , 2.07- 2.15(2H,m), 2.94-2.97 (3H,m) , 3.34-3.37 (2H,m) , 5.36(lH,s),
7.22-7.33(4H,m) , 7. 2 (IH, d, J=7.3Hz) , 8.41(lH,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- (piperidin-4-yl) -2-H-pyrazolo [3, 4-b] pyridine hydrochloride The title compound was prepared from 4- (2, 1, 3-benzoxa- diazol-4-yl) -6- (l-t-butoxycarbonylpiperidin-4-yl) -5-cyano-
4, 7-dihydro-2Jϊ-pyrazolo [3, 4-b] pyridine in the same manner as in Example 64. MP:>270°C.
Anal.Calcd.For:Cι8Hι7N7OHCl:C,56.09;H,5.20;N,24.10.
Found:C,55.80;H, 5.00;N, 23.80.
MS (El) :347 (M+) . αH-NMR (400MHz, DMSO-d6)δ (ppm) : 1.82-1.85 (2H,m) , 2.14-2.20 (2H,m), 2.93-2.99(3H,m) , 3.34-3.36 (2H,m) , 5.40(lH,s), 7.27(lH,s), 7.43(lH,d, J=6.6Hz) , 7.58 (IH, dd, J=9. OHz and 6.6Hz), 7.92 (lH,d,J=9. OHz) , 8.44(lH,br), 9.21(lH,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- (l-t-butoxycarbonylpiperidin-4-yl) -5-cyano- 4, 7-dihydro-2H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 64. MP:>270°C.
MS (El) :409(M+) .
1H-NMR (400MHz, DMSO-d6)δ (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 (lH,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- carbonylpyrrolidine-2-carboxylate, 2-bromo-3-cyano- benzaldehyde and 3-aminopyrazole in the same manner as in Example 1. MS (El) :495(M+) .
1H-NMR (400MHz, DMSO-ds)δ (ppm) : 1.47 (9H,s), 1.82-1.97 (4H,m) , 2.31(lH,m), 3.50(lH,m), 4.53(lH,m), 5.47(lH,s), 7.51-7.91
(4H,m) , 9.83(lH,m), 12.26(lH,s).
Example 68
4- (2-Bromo-3-cyanophenyl) -5-cyano-6- (pyrrolidin-2-yl) -4, 7- dihydro-2fl-pyrazolo [3, 4-b] pyridine The title compound was prepared from 4- (2-bromo-3-cyano- phenyl) -5-cyano-6- (l-t-butoxycarbonylpyrrolidin-2-yl) -4, 7- dihydro-2H-pyrazolo [3, 4-b] pyridine in the same manner as in
Example 2.
MP : >240°C . MS (El ) : 395 (M+) .
XH-NMR ( 400MHz , DMSO-d6) δ (ppm) : 1 . 39-1 . 55 ( lH, m) , 1 . 97 ( 2H, m) , 2.30(lH,m), 3.32 (2H,m), 4.10-4.28 (lH,m) , 5.41(lH,s), 6.52(lH,s), 7.34-7.47 (2H,m) , 7.70 (IH, dd, J=8.3Hz and 9.0Hz), 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- diazole-4-aldehyde and 3-aminopyrazole in the' same manner as in Example 1. MS (El) :433(M+) . ϊ-NMR (400MHz, DMSO-d6)δ (ppm) : 1.40 (9H,s), 1.78-1.89 (4H,m) ,
2.11-2.31 (lH,m) , 3.72 (lH,m) , 4.53 (lH,m) , 5.40(lH,s), 7.26(lH,s), 7.30-7.40 (lH,m) , 7.58 (IH, 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) -2ff-pyrazolo [3, 4-b]pyridine The title compound was prepared from 4- (2,1,3- benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpyrrolidin-2-yl) -
5-cyano-4, 7-dihydro-2Jϊ-pyrazolo [3, 4-b] pyridine in the same manner as in Example 2.
MP:>240°C. MS (El) :333 (M+) .
1H-NMR ( 400MHz, DMSO-d6)δ (ppm) : 1.41-1.46 (lH,m) , 1.97-2.14 (4H,m), 3.72(lH,m), 4.11-4.32 (lH,m) , 5.52(lH,s), 7.00(lH,s), 7.26(lH,s), 7.30-7.42 (lH,m) , 7.58 (IH, dd, J=6.4Hz and 9.6Hz), 7.91 (lH,d, J=9.3Hz) , 11.87(lH,s). Example 71
6- (l-t-Butoxycarbonylpyrrolidin-2-yl) -4- (2-chlorophenyl) -5- cyano-4, 7~dihydro-2ff~pyrazolo [3, 4-b] pyridine
The title compound was prepared from ethyl 1-t-butoxy- carbonylpyrrolidine-2-carboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. MS (El) :425(M+) . XH-NMR ( 400MHz, DMSO-d6)δ (ppm) : 1.36 (9H,s), 1.86(4H,m), 2.32(lH,m), 3.54 (lH,m), 4.57(lH,m), 5.38(lH,s), 7.23- 7.27 (4H,m), 7.42 (IH, d, J=7.6Hz) , 9.68(lH,s), 12.17(lH,s). Example 72 6- (l-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4, 7-dihydro-4- (2,3- (methylenedioxy) phenyl) -2£f-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 Example 1.
MS (El) :449(M+) .
1H-NMR (400MHz, DMSO-ds)δ (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 (lH,d, J=9.5Hz) , 6.00-6.02 (lH,m) , 6.64 (lH,d, J=2.9Hz) ,' 6.78 (lH,d, J=1.7Hz) , 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] yridine
The title compound was prepared from 6- (1- t-butoxy- 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 (El) :390 (M+) .
1H-NMR ( 400MHz, DMS0-d6)δ (ppm) : 1.27-1.88 (5H,m) , 2.49-2.96 (5H,m), 5.02(lH,s), 6.00-6.02 (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 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 (El) :375(M+) .
XH-ΝMR (400MHz, DMSO-d6)δ (ppm) : 5.50 (lH,s) , 7.13(lH,dd,J=7.lHz and 7.6Hz) , 7.25-7.46 (7H,m) ,
7.66(2H,dd, J=8.3Hz) , 10.4(lH,s), 10.76(lH,s), 12.3(lH,s). Example 75
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7~dih.ydro-2.H- 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 (El) :383 (M+) .
^Ή-ΝMR (400MHZ, DMS0-d6)δ (ppm) : 5.59 (lH,s), 7.11-7.15 (lH,dd, J=7.3Hz and 7.6Hz), 7.33-7.36 (3H,m) , 7.51 (lH,d, =6.6Hz) , 7.63-7.68 (3H,m) , 7.96 (IH, d, J=9. OHz) , 10.52(lH,s), 10.76(lH,s), 12.3(lH,s). Example 76
4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- [4- (naphthalen-1- yl) piperazin-l~yl]methyl-2H~pyrazolo [3, 4-b]pyridine trihydrochloride
4- (2-Chlorophenyl) -5-cyano-6- ( t-butyldimethylsilyl- oxy) methyl-4, 7-dihydro-2Jϊ-pyrazolo [3, 4-b] pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2- chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. To a solution of 4- (2-chlorophenyl) -5- cyano-6- ( -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 temperature for 1 hour. To the reaction mixture was added ethyl acetate (800 L) , 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 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-2iϊ-pyrazolo [3, 4-b] - pyridine (12.7 g) and carbon tetrabromide (15.4 g) in methylene chloride (340 mL) was added triphenylphosphine (12.2 g) in methylene chloride (100 mL) under ice-cooling and the mixture was stirred at room temperature for 13 hours . The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give 4- (2-chlorophenyl) -5-cyano-6-bromomethyl- 4, 7-dihydro-2Jf-pyrazolo [3, 4-b] pyridine (3.84 g) as a pale- yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mL) was added 1- (naphthalen-1-yl) piperazine (334 mg) and the mixture was stirred under ice-cooling for 30 minutes. To this reaction mixture was added a solution of 4- (2-chlorophenyl) -5-cyano-6-bromomethyl-4, 7-dihydro-2iJ- 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 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 obtained oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals.
MP:203-205°C (decomposition) MS (El) :481 (M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 3.31-3.70 (8H, ) , 4.33 (2H,m), 4.85(3H,m), 5.54(lH,s), 7.19 (lH,d, J=7.3Hz) , 7.29-7.54 (8H,m) ,
7.67 (lH,d, J=8.1Hz) , 7.92 (IH, d, J=7.1Hz) , 8.15 (IH, d, J=7.3Hz) ,
10.35(lH,s), 11.28 (lH,brs) .
Example 77
4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (4-methyl- homopiperazin-1-yl) methyl-2ff-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 in Example 76.
MP:204-206°C (decomposition) MS (El) :382 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 2.22 (2H,m), 2.78 (3H,s), 3.24-4.11 (12H,m) , 5.48(lH,s), 7.14-7.35 (4H,m) , 7.45(lH,d, J=8.0Hz) , 10.17 (lH,brs) , 11.51 (lH,brs) . Example 78
4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (4-phenylpiperazin-l-yl) methyl-2H-pyrazolo [3, 4-b] pyridine trihydrochloride
The title compound was prepared from 4- (2-chlorophenyl) - 5-cyano-6-bromomethyl-4, 7-dihydro-2iϊ-pyrazolo [3,4- b] pyridine and 1-phenylpiperazine in the same manner as in Example 76.
MP:217-220°C (decomposition) MS (El) :430 (M+) . 1H-N R (400MHz, DMSO-d6)δ (ppm) : 3.20-4.00 (9H,m) , 4.27 (2H,m), 5.51(lH,s), 6.86(lH,t, J=7.1Hz) , 7.01 (2H, d, J=8. OHz) , 7.24- 7.39(6H,m), 7.45 (IH, d, J=9.9Hz) , 9.50 (lH,brs) , 10.37(lH,s), 11.40 (lH,brs) . Example 79 4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-phthalimidomethyl- 2iϊ-pyrazolo [3, 4-b]pyridine
To a solution of 4- (2-chlorophenyl) -5-cyano-6- bromomethyl-4, 7-dihydro-2iϊ-pyrazolo [3, 4-b] pyridine (0.8 g) in DMF (10 mL) was added potassium phthalimide (445 mg) 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 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 MS (El) :416(M+) .
XH-NMR ( 400MHz , DMSO-d6 ) δ (ppm) : 4 . 66 (2H, d, J=2 . 4Hz ) , 5.40(lH,s), 7.24-7.45(5H,m) , 7.82-7.94 (4H,m) , 10.04(lH,s), •12.23(lH,s) . Example 80
6-Acetyl-4- (2-chlorophenyl) -5-cyano-4, 7~dih.ydro~2.H- pyrazolo [3, 4-b] yridine
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 a solution of 4- (2-chlorophenyl) -5-cyano-4, 7-dihydro-6-
(1, 1-dimethoxyethyl) -2Jf-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 obtained residue was crystallized from ethyl acetate to give the title compound (370 mg) as white crystals.
MP: 225-228°C (decomposition) MS (El) :298 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 2.56(3H, s), 5.49 (lH,s), 7.25-7.36(4H,m) , 7.45 (IH, d, J=7.8Hz) , 10.12(lH,s), 12.50 (lH,brs) . Example 81
6-Acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7~dihydro-2.H- pyrazolo [3, 4-b] pyridine The title compound was prepared from 2-bromo-3-cyano- benzaldehyde, 3-aminopyrazole and methyl 2, 2-dimethoxypropionate in the same manner as in Example 1.
MP: >230°C
MS (El) :368 (M+) . XH- MR (400MHz, DMSO-d6)δ (ppm) : 2.42 (3H,s), 5.54 (lH,s),
7.32(lH,brs) , 7.50-7.59 (2H,m) , 7.80 (IH, dd, J=l .7Hz and
7.3Hz), 10.19(lH,s), 12.39 (lH,brs) .
Example 82
6-Acetyl-4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro- 2iϊ-pyrazolo [3, 4-b] pyridine
The title compound was prepared from 2, 1, 3-benzoxa- diazole-4-aldehyde, 3-aminopyrazole and methyl 2,2- dimethoxypropionate in the same manner as in Example 1.
MP: 230°C (decomposition) MS (El) :306 (M+) . XH-N R (400MHz, DMSO-d6)δ (ppm) : 2.55 (3H,s), 5.54 (lH,s), 7.33(lH,s), 7.49(lH,d, J=6.6Hz) , 7.61 (IH, 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- (l-Benzyl-2-oxopyrrolidin-4-yl) -4- (2-chlorophenyl) -5- cyano-4, 7-dihydro-2ff-pyrazolo [3, 4-b] pyridine
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl l-benzyl~2- oxopyrrolidine-4-carboxylate in the same manner as in Example 1. MP: >230°C
Anal. Calcd. for : C24H20CIN5O: C, 67.05;H, 4.69;N, 16.29. Found: C, 66.86;H, 4.56;N, 16.31. MS (El) :429 (M+) .
1H-NMR (400MHz, DMS0-d6)δ (ppm) : 2.60 (IH, dd, J=9.5Hz and 16.4Hz), 2.81 (lH,dd, =10.5Hz and 16.4Hz) , 3.39 (lH, ) ,
3.47 (lH, ), 4.42(2H,m), 5.36(lH,s), 7.23-7.43 (10H,m) ,
10.04(lH,s) , 12.21(lH,s) .
Example 84
4- (2-Bromo-3-cyanophenyl) -5- (pyridin-2~yl) -4, 7-dihydro-6- propyl-2H-pyrazolo [3, 4-b] pyridine
To a solution of 2-picoline (10 g) in THF (75 L) was added n-BuLi (113 mmol) at -40°C. Further, methyl butanoate (15.8 L) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give 2- (2-oxopentanyl) - pyridine (4.8 g) as a yellow oil. A solution of 2-bromo-3- cyanobenzaldehyde (1.5 g) , Me1drum' s acid (1.0 g) , 2- (2- oxopentanyl) pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 mL) was heated under reflux for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg) . To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the 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 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 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) Anal . Calcd . for : C2ιHι8BrN5 : C, 60.01 ; H, 4.32 ; N, 16.66.
Found:C,59.83;H, 4.42 ;N, 16.26.
MS (El) :420(M+) .
XH-NMR (400MHz, DMS0-d6)δ (ppm) : 0.83 (3H, t, J=7.6Hz) ,
1.62(2H,m), 2.24(lH,m), 2.33 (lH, ) , 5.93(lH,s), 6.98(lH,dd, J=4.9Hz and 7.3Hz), 7.05 (IH, d, J=7.8Hz) , 7.28 (lH,m),
7.39(lH,m), 7.51-7.60 (3H,m) , 8.36 (IH, d, J=3.6Hz) , 8.52(lH,s), 11.84 (lH,s) . Example 85
6- (l-tert-Butoxycarbonylpyrrolidin-3-yl) -4- (2-chlorophenyl) -5-cyano-4, 7~dihydro~2H-pyrazolo [3, 4-b] pyridine To a solution of methyl l-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 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 vacuo and the residue 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 l-benzyl-3- pyrrolidinecarboxylate (4.8 g) as a pale yellow oil. A suspension of methyl l-benzyl-3-pyrrolidinecarboxylate (4.8 mg) , 5% palladium on carbon (300 mg) and ammonium formate (2.8 g) in methanoi (50 mL) -water (5 mL) was refluxed for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chlorofor -methanol (9:1)) to give methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) was added dimethylaminopyridine
(161 mg) and di-tert-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: hexane-ethyl acetate (2:1)) to give methyl 1-tert- butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added n-BuLi (12.4 mmol) at -78°C. Further, methyl l-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2:1)) to give l-(l-tert- butoxycarbonylpyrrolidin-3-yl) -2-cyanoethan-l-one (2.35 g) as a colorless oil. A solution of 2-chlorophenylaldehyde (1.4 g) , 3-aminopyrazole (819 mg) and 1- (1- tert-butoxy- carbonylpyrrolidin-3-yl) -2-cyanoethan-l-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 the precipitated crystals were collected by filtration to give the title compound (2.18 g) as colorless crystals. Anal . Calcd. For : C22H24CIN5O2 : C, 62.04 ; H, 5.68 ;N, 16.44. Found: C, 61.94 ;H, 5.69 ;N, 16. 5. MS (El) :425(M+) . 1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.14 (9H,s), 2.07 (lH,m),
2.32(lH,m), 3.29-3.58 (5H,m) , 5.37(lH,s), 7.22-7.34 (4H,m) ,
7.42(lH,d, J=8.3Hz) , 9.78(lH,s), 12.20(lH,s).
Example 86
4- (2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (pyrrolidin-3-yl) - 2-H-pyrazolo [3, 4-b] pyridine
6- (l-tert-Butoxycarbonylpyrrolidin-3-yl) -4- (2-chlorophenyl) -5-cyano-4, 7-dihydro-2H"-pyrazolo [3, 4-b]pyridine (706 mg) was added to 4N-HC1 dioxane solution (5 L) at room temperature and the mixture was stirred for 2 hours. The 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) MS (El) :325(M+) .
XH-NMR (400MHz, DMSO-d6)δ (ppm) : 2.24 (2H,m), 3.15(lH,m), 3.26-3.55(3H,m) , 3.64(lH,m), 5.34(lH,s), 5.40 (lH,brs) , 7.23-7.32 (4H,m) , 7.43 (IH, d, J=7.3Hz) , 9.38 (lH,brs) , 9.51 (lH,brs) , 9.97(lH,s). Example 87 4- (2, 1, 3-Benzoxadiazol-4-yl) -5- (pyridin-2~yl) -4, 7-dihydro- 6-propyl-2ff-pyrazolo [ 3 , 4-b] pyridine
The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, Me1drum/ s acid, 2- (2- oxopentanyl) pyridine and ammonium acetate in the same manner as in Example 84. MS (El) :358 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 0.84 (3H, t, J=7.3Hz) ,
1.64 (2H, ), 2.27(lH,m), 2.35(lH,m), 5.96(lH,s), 6.95(lH,m),
7.11-7.18 (3H,m) , 7.40(lH,m), 7.51(lH,m), 7.69 (IH, d, J=9.3Hz) , 8.35(lH,m), 8.54(lH,s), 11.78 (lH,brs) .
Example 88
6~ (l-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, 4-indancarboxaldehyde and 3-aminopyrazole in the same manner as in Example 1.
MS (El) :445(M+) .
^Η-NMR (400MHz, DMSO-d6)δ (ppm) : 1.41(9H,s), 1.56-1.59 (2H,m) , 1.88-1.06(4H,m) , 2.58-2.83 (7H,m) , 4.06(2H,m), 4.96(lH,s), 6.90(lH,m), 7.04-7.07 (2H,m) , 7.14(lH,s), 9.55(lH,s), 12.08 (lH,s) . Example 89
6- (l-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4, 7-dihydro-4- (2, 3-dihydrobenzo [b] furan-7-yl) -2Jf-pyrazolo [3, 4-b]pyridine 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 (El) :445(M+) .
^■H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.42 (9H,s), 1.57-1.66 (2H, ) , 1.88(4H,m), 2.73-2.90 (3H,m) , 3.17 (2H, ) , 4.09(2H,m),
4.54(2H,m), 5.01(lH,s), 6.76(lH,m), 6.84 (lH,d, =7.1Hz) , 7.05(lH,d, J=6.6Hz) , 7.22(lH,s), 9.52(lH,s), 12.06(lH,s). Example 90
6- (l-t-Butoxycarbonylpiperidin-4-yl) -5-cyano-4, 7-dihydro-4- (3, 4-dihydro-2.H-benzopyran-8-yl) -2-H-pyrazolo [3, 4-b]pyridine The title compound was prepared from ethyl isonipecotate, 8- (3, 4-dihydro-2iϊ-benzopyrane) carboxaldehyde and 3-aminopyrazole in the same manner as in Example 1. MS (El) :461 (M+) .
^•H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.42 (9H,s), 1.58-1.69 (2H,m) , 1.80-2.00 (4H,m), 2.73-2.95 (5H,m) , 4.09(2H,m), 4.22(2H,m),
5.14(lH,s), 6.74(lH,m), 6.84-6.89 (2H,m) , 7.21(lH,s),
9.48UH,s) , 12.03 (lH,s) .
Example 91
6- (l-t-Butoxycarbonylpiperidin-4-yl) -4- (2-chloro-3- trifluoromethylphenyl) -5-cyano-4, 7-dihydro-2JJ-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. MS (El) :461 (M+) .
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.41 (9H,s), 1.62(2H,m), 1.89
(2H,m), 2.60-2.90 (3H,m) , 4.10(2H,m), 5.54(lH,s), 7.32(lH,s),
7.52-7.56(2H,m) , 7.75 (IH, d, J=9.3Hz) , 9.79(lH,s),
12.25(lH,s) . Example 92
5-Cyano-4, 7-dihydro-4- (3, 4-dihydro-2iJ-benzopyran-8-yl) -6-
(piperidin-4-yl) -2-H-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) -2-H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 2.
MS (El) :361(M+) .
XH-NMR (400MHz, DMSO-d6)δ (ppm) : 1.83-1.98 (4H,m) , 2.14 (2H, ), 2.74(2H,m), 2.90-3.00 (3H,m) , 4.22(2H, ), 3.40-3.70 (5H,m) , 4.16-4.27 (2H,m), 5.15(lH,s), 6.74 (lH, ), 6.83-6.89 (2H,m) , 7.22 (lH,s) , 9.54(lH,s) . Example 93
5-Cyano-4, 7-dihydro-4- (indan-4-yl) -6- (piperidin-4-yl) -2-H- 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- (indan-4-yl) - 2Jf-pyrazolo [3, 4-b] pyridine in the same manner as in Example 2. MS (El) :345(M+) .
1H-N R (400MHz, DMSO-d6)δ (ppm) : 1.80-1.99 (4H,m) , 2.14 (2H,m), 2.58 (lH,m), 2.82-2.95 ( 6H,m) , 3.30-3.50 (2H,m) , 4.97(lH,s),
6.90(lH,m), 7.04-7.09(2H,m) , 7.17(lH,s), 8.37(lH,m),
9.10(lH,m), 9.62(lH,s), 12.18 (lH,brs) .
Example 94
5-Cyano-4, 7-dihydro-4- (indan-4-yl) -6- (l-methylpiperidin-4- yl) -2-H-pyrazolo [3, 4-b]pyridine
The title compound was prepared from 5-cyano-4,7- dihydro-4- (indan-4-yl) -6- (piperidin-4-yl) -2ff-pyrazolo [3, 4- b] pyridine hydrochloride in the same manner as in Example 3,
1H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.56 (2H,m), 1.84-1.98 ( 6H,m) , 2.15(2H,m), 2.58(lH,m), 2.80-3.00 ( 6H,m) , 3.20-3.40 (2H,m) ,
4.95(lH,s), 6.90(lH,m), 7.05-7.07 (2H,m) , 7.14(lH,s),
9.54 (lH,brs) , 12.10 (lH,brs) .
Example 95
5-Cyano-4, 7-dihydro-4- (3, 4-dihydro-2_H-benzopyran-8-yl) -6- (l-methylpiperidin-4-yl) -2ff-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) -2iϊ-pyrazolo [3, 4-b] pyridine hydrochloride in the same manner as in Example 3.
^■H-NMR (400MHz, DMSO-d6)δ (ppm) : 1.90-2.00 (4H,m) , 2.24 (2H,m), 2.73-2.75(5H,m) , 2.94-3.08 (3H,m) , 3.40-3.48 (2H,m) , 4.17- 4.27 (2H, ), 5.15(lH,s), 6.74(lH,m), 6.84-6.89 (2H,m) , 7.22(lH,s), 9.58(lH,s), 9.80(lH,m) , 12.15(lH,s) . Example 96
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methanesulfonylpiperidin-2-yl) -2-H-pyrazolo [3, 4-b] pyridine
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 (El) : 425 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.20-2.07 (7H, m) , 2.95 and 2.98(3H, s), 2.98-3.17 (IH, m) , 3.63-3.68 (IH, m) , 5.40 and 5.52(1H, s), 7.24 and 7.27(lH, s) , 7.41-7.63 (2H, m) , 7.90- 7.93 (IH, 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- nαethylpiperidin-4-yl) -2-H-pyrazolo [3, 4-b] pyridine hydrochloride The title compound was prepared from 4- (2,1,3- benzoxadiazol-4-yl) -5-cyano-4, 7-di.hydro-6- (1- methylpiperidin-4-yl) -2iϊ-pyrazolo [3, 4-b] pyridine in the same manner as in Example 64. MS (El) : 361 (M+) . 1H- MR (400MHz, DMSO-d6) δ (ppm) : 1.86-1.90 (2H, m) , 2.24-
2.27(2H, m) , 2.48(3H, s) , 2.72-2.75 (2H, m) , 2.94-2.98 (2H, m) , 3.20-3.33(lH, br) , 3.44-3.47 (IH, m) , 5.40(1H, s) , 7.28(1H, s), 7.44(1H, d, J=6.6Hz), 7.59(1H, dd, J=9.0Hz and 6.6Hz), 7.93(1H, d, J=9.0Hz), 9.92 (IH, brs), 12.26(1H, brs). Example 98
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1,2- dihydro-l-methyl-2-oxo-pyridin-4-yl) -2H-pyrazolo [3, 4- b] pyridine
The title compound was prepared from 1, 2-dihydro-l- 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 (El) : 371 (M+) . αH- MR (400MHz, DMSO-d6) δ (ppm) : 3.46 (3H, s) , 5.42 (IH, s) , 6.34(1H, d, J=7.2Hz), 6.56(1H, s) , 7.33(1H, s) , 7.52(1H, d, J=7.2Hz), 7.61 (IH, dd, J=9.0Hz and 6.6Hz), 7.80 (IH, d, J=6.6Hz), 7.95(1H, d, J=9.0Hz), 10.33(1H, brs), 12.29(1H, brs) .
Example 99
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1,2, 5, 6-tetrahydropyridin-3-yl) -2-H-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 manner as in Examples 1 and 2. MS (El) : 345 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 2.42-2.44 (2H, m) , 3.11- 3.14(2H, ) , 3.84-3.87 (2H, ) , 4.39(1H, br) , 5.46(1H, s) , 6.36(1H, s), 7.30(1H, s) , 7.49(1H, d, J=6.6Hz), 7.56(1H, dd, J=9.0Hz and 6.6Hz), 7.94 (IH, d, J=9.0Hz), 9.39 (2H, br) , 10.06(1H, brs) . Example 100
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methyl-1, 4, 5, 6-tetrahydropyridin-3-yl) -2-H-pyrazolo [3, 4- 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 (El) : 359 (M+) .
1H-N R (400MHz, DMSO-d6) δ (ppm) : 2.18-2.20 (2H, m) , 2.43- 2.47(2H, m) , 3.02-3.11 (2H, m) , 5.43(1H, s) , 6.11(1H, s) , 7.26 (IH, s),7.43(lH, d, J=6.6Hz), 7.59 (IH, dd, J=9.0Hz and 6.6Hz), 7.92(1H, d, J=9.0Hz), 9.87(1H, brs), 12.16(1H, brs) . Example 101
4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- (methylamino ) ethyl ) -2-H-pyrazolo [ 3 , 4-b] pyridine 2 hydrochloride
The title compound was prepared from 2-methylglycine ethyl ester, 2, 1, 3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Examples 15 and 2. MS (El) : 321 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.56(3H, d, J=6.8Hz), 3.07(3H, s), 4.59-4.68 (3H, m) , 5.66(1H, s), 7.29(1H, d, J=6.6Hz), 7.44 (IH, s) , 7.52 (IH, dd, J=9. OHz and 6.6Hz), 7.87(1H, d, "J=9.0Hz) , 8.22(1H, br) , 8.44(1H, br) , 10.95(1H, brs) .
Example 102
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1, 2- dihydro-l-methyl-2-oxo-pyridin-4-yl) -2H-pyrazolo [3, 4- b] pyridine
The title compound was prepared from 1, 2-dihydro-l- methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2- bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. MS (El) : 433 (M+) .
XH-NMR (400MHz, DMSO-d6) δ (ppm) : 3.46 (3H, s) , 5.35 (IH, 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 (IH, brs) . Example 103
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (4-
(methylamino) cyclohexyl) -2-H-pyrazolo [3, 4-b] pyridine
2 hydrochloride
The title compound was prepared from 4- aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3- cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
MS (El) : 436 (M+) .
XH-NMR (400MHz, DMSO-d6) δ (ppm) : 1.39 (2H, m) , 1.80-1.90 (4H, m) , 2.15-2.16 (2H, m) , 2.84-2.86 (IH, m) , 3.14-3.16 (IH, m) ,
4.20(2H, br) , 5.46(1H, s) , 7.33(1H, s) , 7.56-7.57 (2H, m) ,
7.82(1H, d, J=7.3Hz), 8.98(2H, br) , 9.80(1H, brs).
Example 104
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1,2,5,6- tetrahydropyridin-3-yl) -2H-pyrazolo [3, 4-b] pyridine
2 hydrochloride The title compound was prepared from 1,2,5,6- tetrahydropyridine-3-carboxylic acid ethyl ester, 2-bromo- 3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 407 (M+) .
1H-NMR (400MHz, DMSO-ds) δ (ppm) : 2.43-2.44 (2H, ) , 3.13- 3.15(2H, m) , 3.70-3.72 (2H, br) , 3.86-3.88 (2H, m) , 5.54(1H, s), 6.41(1H, s), 7.36(1H, s) , 7.58(1H, dd, J=7.3Hz and 7.2Hz), 7.84(1H, d, J=7.3Hz), 7.86(1H, d, J=7.3Hz), 9.32(2H, br) , 10.03 (IH, brs) . Example 105
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (4- (dimethylamino) cyclohexyl) -2-H-pyrazolo [3, 4-b] pyridine The title compound was prepared from 4- (2-bromo-3- cyanophenyl) -5-cyano-4, 7-dihydro-6- (4-
(methylamino) cyclohexyl) -2-H-pyrazolo [3, 4-b] pyridine in the same manner as in Example 3. MS (El) : 450 (M+) .
^■H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.26-1.29 (2H, m) , 1.76- 1.93(6H, m) , 2.27(6H, s) , 2.34-2.36 (IH, m) , 2.63-2.66 (IH, m) , 5.45(1H, s) , 7.33(1H, s) , 7.56-7.60 (2H, m) , 7.82(1H, d,
J=7.3Hz), 9.74 (IH, brs), 12.27 (IH, s) .
Example 106
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1-methyl- 1,4,5, 6-tetrahydropyridin-3-yl) -2H-pyrazolo [3, 4-b]pyridine The title compound was prepared from 4- (2-bromo-3- cyanophenyl) -5-cyano-4, 7-dihydro-6- (1,4,5,6- tetrahydropyridin-3-yl) -2Jϊ-pyrazolo [3, 4-b] pyridine in the same manner as in Example 3. MS (El) : 420 (M+) .
^-H-NMR (400MHz, DMSO-d6) δ (ppm) : 2.21-2.22 (2H, m) , 2.28 (3H, s), 2.48-2.49(2H, m) , 3.08-3.12 (2H, m) , 5.49(1H, s) , 6.15(1H, s), 7.33(1H, s) , 7.56-7.61 (2H, m) , 7.84(1H, dd, J=7.3Hz and 7.2Hz), 9.87(1H, brs), 12.26(1H, brs) . Example 107
6- (exo-2-Azabicyclo [2, 2, 2] octan-6-yl) -4- (2,1,3- benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2.H-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 (El) :373(M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.53-1.55 (IH, m) , 1.75-
1.77(1H, m) , 1.89-2.06(4H, m) , 2.21-2.23 (IH, m) , 3.07- 3.10(2H, m) , 3.43-3.48 (4H, m) , 5.39-5.43 (IH, s) , 7.26-
7.28(1H, m) , 7.44-7. 7 (IH, m) , 7.57-7.61 (IH, ) , 7.93-
7.95(1H, m) , 8.87-9.03 (IH, br) , 9.46-9.52 (IH, br) , 9.73 and
9.80 (IH, 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-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 (El) : 373 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.67-1.73 (3H, m) , 2.03-
2.13(4H, m) , 3.04-3.06 (IH, m) , 3.34-3.57 (5H, m) , 5.49(1H, s),7.30(lH, s), 7.50-7.51(lH, m) , 7.58-7.60 (IH, 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) -2ff-pyrazolo [3, 4- 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 (El) : 387 (M+) .
XH-NMR (400MHz, DMSO-ds) δ (ppm) : 1.43-1.44 (IH, m) , 1.70- 1.90(5H, m) , 2.11-2.13(1H, m) , 2.38-2.46 (4H, m) , 3.00- 3.02(1H, m) , 3.32-3.36(2H, m) , 5.38 and 5.40(lH, s) , 7.25- 7.27(1H, m) , 7.38-7.42 (IH, m) , 7.56-7.61 (IH, 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) -2fl-pyrazolo [3, 4-b]pyridine-5-carboxylate 2 hydrobromide
A solution of 2, 1, 3-benzoxadiazole-4-aldehyde (3.0 g) , Meldrum' s acid (3.0 g) , ethyl 3-keto-3-(l- benzylcarbonylpiperidin-4-yl) propionate (6.8 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 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 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 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 crystals in acetic acid (10 mL) was added HBr-AcOH solution (10 mL) and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure to give colorless crystals. The crystal was purified by recrystalization from EtOH to give the title compound (630 mg) as colorless crystals. MS (El) : 394 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 0.77 (3H, t, J=7.3Hz), 1.80- 2.16(4H, m) , 2.90-2.93 (2H, m) , 3.40-3.43 (2H, m) , 3.80(2H, q, J=7.3Hz), 4.12-4.15(1H, m) , 4.50(2H, br) , 5.67(1H, s) , 7.17(1H, d, J=6.6Hz), 7.26(1H, s) , 7.51(1H, dd, J=9.0Hz and 6.6Hz), 7.79(1H, d, J=9.0Hz), 8.10(lH,br), 8.74(1H, br) , 9.38 (IH, 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- 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-2iϊ-pyrazolo [3, 4-b] pyridine in the same manner as in Example 3. MS (El) : 387 (M+) .
XH-N R (400MHz, DMSO-d6) δ (ppm) : 1.43-1.47 (2H, ) , 1.60- 1.64(2H, ) , 1.81-1.82 (IH, 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 (IH, m) , 5.43(1H, s) , 7.25(1H, s), 7.42-7.46 (IH, m) , 7.57- 7.60(1H, ) , 7.90-7.94(lH, m) , 10.79(1H, brs), 12.16(1H, brs) .
Example 112
Ethyl 4- (2, 1, 3-benzoxadiazol-4-yl) -4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2-H-pyrazolo [3, 4-b]pyridine-5- carboxylate 2 hydrochloride
The title compound was prepared from ethyl 4- (2,1,3- benzoxadiazol-4-yl) -4, 7-dihydro-6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine-5-carboxylate in the same manner as in Example 3. MS (El) : 408 (M+) .
^-NMR (400MHz, DMSO-d6) δ (ppm) : 0.75 (3H, t, J=7.3Hz), 1.55- 1.56(1H, m) , 1.71-1.73(1H, m) , 1.87-2.06 (4H, ) , 2.17(3H, s), 2.84-2.87 (2H, m),3.78(2H, q, J=7.3Hz), 3.93-3.96 (IH, ) , 5.68(1H, s), 7.12(1H, d, J=6.6Hz), 7.22(1H, s) , 7.49(1H, dd, J=9.0Hz and 6.6Hz), 7.77 (IH, d, J=9.0Hz), 9.32(1H, brs), 12.06(1H, brs) . Example 113
4- (2-Bromophenyl) -5-cyano-4, 7-dihydro-6- (piperidin-4-yl) - 2JH-pyrazolo [3, 4-b] pyridine hydrochloride
The title compound was prepared from ethyl nipecotate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 383 (M+) .
1H-NMR (400MHz, DMS0-d6) δ (ppm) : 1.85-1.93 (2H, m) , 2.14-
2.20(2H, m) , 2.94-2.98 (2H, m) , 3.32-3.36 (3H, m) , 5.36(1H, s), 7.16(1H, dd, J=7.3Hz and 7.2Hz), 7.23-7.27 (2H, m) ,
7.35 (IH, dd, J=7.3Hz and 7.2Hz), 7.59 (IH, d, J=7.3Hz),
8.41(1H, br) , 9.14(1H, br) , 9.73(1H, brs), 12.21(1H, brs).
Example 114
5-Cyano-4, 7-dihydro-4- (2-methoxyphenyl) -6- (piperidin-4-yl) - 2H-pyrazolo [3, 4-b] pyridine hydrochloride
The title compound was prepared from ethyl nipecotate,
2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (El) : 335 (M+) . 1H-NMR (400MHz, DMS0-d6) δ (ppm) : 1.87-1.95 (2H, m) , 2.14-
2.20(2H, m) , 2.94-3.03 (3H, m) , 3.32-3.36 (2H, m) , 3.82(3H, s), 5.21(1H, s), 6.88(1H, dd, J=7.3Hz and 7.2Hz), 6.99(1H, d, J=7.3Hz), 7.05 (IH, d, J=7.3Hz), 7.15-7.20 (2H, m) , 8.44(1H, br) , 9.17(1H, br) , 9.53(1H, brs), 12.11(1H, brs). Example 115
5-Cyano-4- (2, 3-dichlorophenyl) -4, 7-dihydro-6- (piperidin-4- yl) -2H-pyrazolo [3, 4-b] pyridine hydrochloride
The title compound was prepared from ethyl nipecotate, 2, 3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 373 (M+) . 1H-NMR (400MHz, DMSO-ds) δ (ppm) : 1.84-1.90 (2H, m) , 2.16- 2.20(2H, m) , 2.94-3.00 (3H, m) , 3.32-3.38 (2H, m) , 5.44(1H, s), 7.24-7.36(3H, ) , 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) -2-H-pyrazolo [3, 4-b]pyridine
The title compound was prepared from 4- (2-bromophenyl) - 5-cyano-4, 7-dihydro-6- (piperidin-4-yl) -2-H-pyrazolo [3, 4- b] pyridine in the same manner as in Example 3. MS (El) : 397 (M+) .
^■H-N R (400MHz, DMSO-d6) δ (ppm) : 1.56-1.63 (2H, m) , 1.85- 1.90(2H, m) , 2.01-2.06(2H, m) , 2.17(3H, s) , 2.62-2.65 (IH, m) , 2.87-2.89(2H, m) , 5.34(1H, s) , 7.14-7.26 (3H, m) , 7.36(1H, dd, J=7.3Hz and 7.2Hz), 7.60(1H, d, J=7.3Hz), 9.60(1H, brs), 12.16(1H, brs). Example 117
5-Cyano-4, 7-dihydro-4- (2-methoxyphenyl) -6- (1- methylpiperidin-4-yl) -2H~pyrazolo [3, 4-b] pyridine The title compound was prepared from 5-cyano-4,7- dihydro-4- (2-methoxyphenyl) -6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine in the same manner as in Example 3. MS (El) : 349 (M+) .
1H-NMR (400MHz, DMSO-ds) δ (ppm) : 1.56-1.66 (2H, m) , 1.86- 1.92 (2H, m) , 2.01-2.04 (2H, m) , 2.17(3H, s) , 2.64-2.67 (IH, 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 (IH, d, J=7.3Hz), 7.05(1H, d, J=7.3Hz), 7.16-7.19(2H, m) , 9.41(1H, brs), 12.01(1H, brs). Example 118 5-Cyano-4- (2, 3-dichlorophenyl) -4, 7-dihydro-6- (1- methylpiperidin-4-yl) ~2H-pyrazolo [3, 4-b]pyridine
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 in Example 3.
MS (El) : 387 (M+) . 1H-N R (400MHz, DMSO-d6) δ (ppm) : 0.57-1.65 (2H, m) , 1.85- 1.90(2H, m) , 2.01-2.06 (2H, m) , 2.17(3H, s) , 2.59-2.66 (IH, 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 (IH, 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, 2-fluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 323 (M+) .
^■H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.85-1.89 (2H, m) , 2.12-
2.20(2H, m) , 2.90-2.98 (3H, m) , 3.33-3.39 (2H, m) , 5.20(1H, s), 7.14-7.28 (5H, m) , 8.37(1H, br) , 9.09(1H, br) , 9.66(1H, brs) , 12.23 (IH, brs) .
Example 120
5-Cyano-4- (2, 3-difluorophenyl) -4, 7-dihydro-6- (piperidin-4- yl) -2ff-pyrazolo [3, 4-b] pyridine hydrochloride 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 (El) : 341 (M+) .
1H-N R (400MHz, DMSO-d6) δ (ppm) : 1.84-1.88 (2H, m) , 2.14- 2.19(2H, m) , 2.95-3.00 (3H, m) , 3.33-3.38 (2H, m) , 5.26(1H, s), 7.03(1H, d, J=7.3Hz), 7.18(1H, dd, J=7.3Hz and 7.2Hz),
7.26-7.31 (2H, m) , 8.80(2H, br) , 9.74(1H, brs), 12.29(1H, brs) .
Example 121 5-Cyano-4- (2, 6-difluorophenyl) -4, 7-dihydro-6- (piperidin-4- yl) -2H-pyrazolo [3, 4-b] pyridine hydrochloride
The title compound was prepared from ethyl nipecotate,
2, 6-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 341 (M+) .
XH-NMR (400MHz, DMSO-d6) δ (ppm) : 1.76-1.84 (2H, m) , 2.13- 2.18(2H, m) , 2.91-2.95 (3H, m) , 3.28-3.30 (2H, m) , 5.35(1H, s), 7.02-7.07 (2H, m) , 7.31-7.38 (2H, m) , 8.77(2H, br) , 9.68(1H, brs), 12.22(1H, brs). Example 122 5-Cyano-4, 7-dihydro-4- (2-methylthiophenyl) -6- (piperidin-4- yl) -2-H-pyrazolo [3, 4-b] pyridine 2 hydrochloride
The title compound was prepared from ethyl nipecotate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 351 (M+) .
XH-1S1MR (400MHz, DMSO-d6) δ (ppm) : 1.86-1.93 (2H, m) , 2.17- 2.23(2H, m) , 2.50(3H, s) , 2.95-3.00 (3H, ) , 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 (IH, brs) . Example 123
5-Cyano-4- (2, 6-dichlorophenyl) -4, 7-dihydro-6- (piperidin-4- yl) -2iJ-pyrazolo [3, 4-b] pyridine hydrochloride
The title compound was prepared from ethyl nipecotate, 2, 6-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 373 (M+) .
1H-NMR (400MHz, DMS0-d6) δ (ppm) : 1.80-1.84 (2H, m) , 2.12-
2.20(2H, m) , 2.90-2.98 (3H, m) , 3.30-3.33 (2H, m) , 5.92(1H, s), 7.19(1H, s), 7.29(1H, dd, J=7.3Hz and 7.2Hz), 7.38(1H, d, J=7.3Hz), 7.51 (IH, d, J=7.3Hz), 8.41 (IH, br) , 9.16(1H, br), 9.73(1H, brs), 12.18(1H, brs) .
Example 124
5-Cyano-4, 7-dihydro-6- (piperidin-4-yl) -4- (2- trifluoromethylphenyl) -2H-pyrazolo [3, 4-b] pyridine 2 hydrochloride
The title compound was prepared from ethyl nipecotate,
2-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2.
MS (El) : 373 (M+) . XH-NMR ( 400MHz , DMS0~d6) δ (ppm) : 1 . 83-1 . 90 ( 2H, m) , 2 . 18-
2 . 2 6 ( 2H, m) , 2 . 92-3 . 00 ( 3H, m) , 3 . 38-3 . 43 ( 2H, ) , 4 . 16 ( 2H, br) , 5.22(1H, s) , 7.06(1H, s) , 7.42-7.44 (2H, m) , 7.63- 7.69(2H, m) , 8.57(1H, br) , 9.30(1H, br) , 9.77(1H, br) . Example 125
5-Cyano-4, 7-dihydro-4- (2-fluorophenyl) -6- (1- methylpiperidin-4-yl) -2H-pyrazolo [3, 4-b]pyridine
The title compound was prepared from 5-cyano-4,7- dihydro-4- (2-fluorophenyl) -6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine hydrochloride in the same manner as in Example 3. MS (El) : 337 (M+) .
^-H- MR (400MHz, DMS0-d6) δ (ppm) : 1.55-1.59 (2H, m) , 1.83- 1.88(2H, m) , 1.96-2.00 (2H, m) , 2.15(3H, s) , 2.60-2.63 (IH, m) , 2.84-2.88 (2H, ) , 5.17(1H, s) , 7.13-7.24 (5H, m) , 9.60(1H, brs), 12.18(1H, brs). Example 126
5-Cyano-4- (2, 3-difluorophenyl) -4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2-H-pyrazolo [3, 4-b]pyridine
The title compound was prepared from 5-cyano-4- (2, 3- difluorophenyl) -4, 7-dihydro-6- (piperidin-4-yl) -2H- pyrazolo [3, 4—b] pyridine hydrochloride in the same manner as in Example 3. MS (El) : 355 (M+) .
1H-NMR (400MHz, DMS0-d6) δ (ppm) : 1.55-1.59 (2H, m) , 1.82-
1.8(2H, m) , 1.99-2.02 (2H, m) , 2.15(3H, s) , 2.57-2.60 (IH, m) , 2.84-2.88 (2H, m) , 5.23(1H, s) , 7.00(1H, dd, J=7.3Hz and
7.2Hz), 7.16(1H, d, J=7.3Hz), 7.27-7.30 (2H, ) , 9.66(1H, brs) , 12.24 (IH, brs) .
Example 127
5-Cyano-4- (2, 6-difluorophenyl) -4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2-H-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. MS (El) : 355 (M+) .
1H-NMR (400MHz, DMS0-d6) δ (ppm) : 1.49-1.53 (2H, m) , 1.82- 1.86(2H, ) , 1.96-2.01 (2H, m) , 2.15(3H, s) , 2.48-2.51 (IH, ) , 2.83-2.86(2H, m) , 5.31(1H, s) , 7.00-7.05 (2H, m) , 7.29- 7.31(2H, ) , 9.60(1H, brs), 12.15(1H, brs). Example 128 5-Cyano-4, 7-dihydro-4- (2-nitrophenyl) -6- (piperidin-4-yl) - 2iJ-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. MS (El) : 351 (M+) . l-NMR (400MHz, DMS0-d6) δ (ppm) : 1.84-1.93 (2H, ) , 2.17- 2.23(2H, m) , 2.94-3.00 (3H, m) , 3.35-3.38 (2H, ) , 4.42(2H, br) , 5.40(1H, s) , 7.30(1H, s) , 7.46-7.51 (2H, ) , 7.71(1H, dd, J=7.3Hz and 7.2Hz), 7.90 (IH, d, J=7.3Hz), 8.61 (IH, br) , 9.36(1H, br) , 9.87(1H, brs). Example 129
5-Cyano-4, 7-dihydro-4-phenyl-6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b]pyridine 2 hydrochloride
The title compound was prepared from ethyl nipecotate, benzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 305 (M+) .
^•H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.81-1.89 (2H, m) , 2.14- 2.20(2H, m) , 2.90-2.96 (3H, m) , 3.32-3.35 (2H, m) , 4.20(2H, br), 4.89(1H, s) , 7.17-7.22 (4H, m) , 7.28-7.31 (2H, m) , 8.58(1H, br), 9.32(1H, br) , 9.65(1H, brs). Example 130
5-Cyano-4, 7-dihydro-6- (l-methylpiperidin-4-yl) -4- (2- methylthiophenyl) -2-H-pyrazolo [3, 4-b]pyridine The title compound was prepared from 5-cyano-4,7- dihydro-4- (2-methylthiophenyl) -6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b]pyridine 2 hydrochloride in the same manner as in Example 3. MS (El) : 366 (M+) . ^-NMR (400MHz, DMSO-d6) δ (ppm) : 1.58-1.66 (2H, m) , 1.83- 1.89(2H, m) , 1.97-2.02 (2H, ) , 2.15(3H, s) , 2.50(3H, s) , 2.62-2.65(lH, m) , 2.84-2.87 (2H, m) , 5.32(1H, s) , 7.12- 7.30(5H, m) , 9.57 (IH, brs), 12.18(1H, brs). Example 131
5-Cyano-4- (2, 6-dichlorophenyl) -4, 7-dihydro-6- (1- methylpiperidm-4-yl) -2g-pyrazolo [3, 4-b] pyridine
The title compound was prepared from 5-cyano-4- (2, 6- dichlorophenyl) -4, 7-dihydro-6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine hydrochloride in the same manner as in Example 3. MS (El) : 387 (M+) .
1H-N R (400MHz, DMSO-d6) δ (ppm) : 1.52-1.56 (2H, m) , 1.83- 1.87(2H, m) , 1.99-2.06 (2H, m) , 2.15(3H, s) , 2.52-2.55 (IH, 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 (IH, d, J=7.3Hz), 9.67(1H, brs), 12.12(1H, brs). Example 132
5-Cyano-4, 7-dihydro-6- (l-methylpiperidin-4-yl) -4- (2- trifluoromethylphenyl) -2H-pyrazolo [3, 4-b] pyridine The title compound was prepared from 5-cyano-4,7- dihydro-6- (piperidin-4-yl) -4- (2-trifluoromethylphenyl) -2-H- pyrazolo [3, 4-b]pyridine 2 hydrochloride in the same manner as in Example 3. MS (El) : 387 (M+) .
1H-N R (400MHz, DMSO-d6) δ (ppm) : 1.57-1.62 (2H, ) , 1.83- 1.86(2H, m) , 1.97-2.03 (2H, m) , 2.16(3H, s) , 2.60-2.63 (IH, ) , 2.84-2.87 (2H, m) , 5.18(1H, s) , 7.05(1H, s) , 7.40- 7.42(2H, m) , 7.62-7.68 (2H, m) , 9.69(1H, brs), 12.23(1H, brs) .
Example 133 5-Cyano-4, 7-dihydro-6- (l-methylpiperidin-4-yl) -4- (2- nitrophenyl) -2-H-pyrazolo [3, 4-b]pyridine
The title compound was prepared from 5-cyano-4,7- dihydro-4- (2-nitrophenyl) -6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b]pyridine 2 hydrochloride in the same manner as in Example 3. MS (El) : 365 (M+) . XH-NMR (400MHz, DMSO-d6) δ (ppm) : 1.58-1.67 (2H, m) , 1.86- 1.90(2H, m) , 1.99-2.06(2H, ) , 2.16(3H, s) , 2.58-2.61 (IH, m) , 2.86-2.90(2H, m) , 5.36(1H, s) , 7.26(1H, s) , 7.42- 7.48(2H, ) , 7.69(1H, dd, J=7.3Hz and 7.2Hz), 7.88(1H, d, J=7.3Hz), 9.72 (IH, brs), 12.26(1H, brs) . Example 134
5-Cyano-4, 7-dihydro-4-phenyl-6- (l-methylpiperidin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine
The title compound was prepared from 5-cyano-4,7- dihydro-4-phenyl-6- (piperidin-4-yl) ~2H-pyrazolo [3,4- b] pyridine 2 hydrochloride in the same manner as in Example
3.
MS (El) : 319 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.54-1.57 (2H, ) , 1.81- 1.87(2H, m) ,1.97-2.03 (2H, m) , 2.15(3H, s) , 2.58-2.60 (IH, 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-2.H-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 (El) :322 (M+) . 1H-N R (400MHz, DMS0-d6) δ (ppm) : 0.93 (3H, t, J=7.3Hz), 1.63-
1.68(2H, m) , 2.34-2.45 (2H, m) , 5.16(1H, s) , 7.02(1H, d,
J=7.3Hz), 7.18 (IH, dd, J=7.3Hz and 7.2Hz), 7.28 (IH, d,
J=7.2Hz), 9.88 (IH, brs), 12.22 (IH, brs) .
Example 136 4- (2, 1, 3-Benzothiadiazol-4-yl) -5-cyano-4, 7-dihydro-6-
(piperidin-4-yl) -2-H-pyrazolo [3, 4-b]pyridine 2 hydrochloride 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 (El) : 363 (M+) .
^-NMR (400MHz, DMSO-d6) δ (ppm) : 1.89-1.98 (2H, m) , 2.22- 2.29(2H, m) , 2.98-3.05(3H, m) , 3.37-3.43 (2H, m) , 5.20(2H, br) , 5.72(1H, s) , 7.24(1H, s) , 7.48(1H, d, J=6.6Hz), 7.72(1H, dd, J=9.0Hz and 6.6Hz), 7.99(1H, d, J=9.0Hz), 8.68(1H, br) , 9.43(1H, br) , 9.86(1H, brs). Example 137
5-Cyano-4- (2, 2-difluoro-l, 3-benzodioxol-4-yl) -4, 7-dihydro- 6- (piperidin-4-yl) -2-H-pyrazolo [3, 4-b]pyridine 2 hydrochloride
The title compound was prepared from ethyl nipecotate, 2, 2-difluoro-l, 3-benzodioxol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 385 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.82-1.85 (2H, m) , 2.16-
2.22(2H, m) , 2.95-3.00 (3H, m) , 3.34-3.39 (2H, m) , 5.17(1H, s), 5.65(2H, br) , 7.05(1H, d, J=7.3Hz), 7.19(1H, dd,
J=7.3Hz and 7.2Hz), 7.29(1H, d, J=7.3Hz), 7.33(1H, s) ,
8.65(1H, br) , 9.43(1H, br) , 9.86(1H, brs).
Example 138
4- (2, 1, 3-Benzothiadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2-H-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. MS (El) : 377 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.64-1.73 (2H, m) , 1.91- 1.97 (2H, m) , 2.05-2.09 (2H, m) , 2.419(3H, s) , 2.70-2.72 (IH, m) , 2.90-2.93 (2H, m) , 5.71(1H, s) , 7.22(1H, s) , 7.45(1H, d, J=6.6Hz), 7.72 (IH, dd, J=9.0Hz and 6.6Hz) , 7.98 (IH, d, J=9. OHz) ,9.71 (IH, brs), 12.13(1H, brs). Example 139
5-Cyano-4- (2, 2-difluoro-l, 3-benzodioxol-4-yl) -4, 7-dihydro- 6- (l-methylpiperidin-4-yl) -2ff-pyrazolo [3, 4-b]pyridine The title compound was prepared from 5-cyano-4- (2, 2- difluoro-1, 3-benzodioxol-4-yl) -4, 7-dihydro-6- (piperidin-4- yl) -2-H-pyrazolo [3, 4-b] pyridine 2 hydrochloride in the same manner as in Example 3. MS (El) : 399 (M+) .
XH-NMR (400MHz, DMSO-d6) δ (ppm) : 1.5-1.58 (2H, m) , 1.86- 1.90(2H, m) , 1.99-2.03 (2H, m) , 2.16(3H, s) , 2.59-2.62 (IH, m) , 2.85-2.89(2H, m) , 5.15(1H, s) , 7.03(1H, d, J=7.3Hz),
7.17 (IH, dd, J=7.3Hz and 7.2Hz), 7.26-7.31 (2H, m) , 9.71 (IH, brs) , 12.26(1H, brs) . Example 140
5-Cyano-4- (2-cyanophenyl) -4, 7-dihydro-6- (piperidin-4-yl) - 2JH-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 (El) : 330 (M+) . ^-H-NMR (400MHz, DMSO~d6) δ (ppm) : 1.86-1.90 (2H, m) , 2.18-
2.22(2H, m) , 2.92-2.98 (3H, m) , 3.34-3.37(2H ,m) , 5.10(2H, br) , 5.25(1H, s) , 7.27(1H, s) , 7.43-7.47 (2H, m) , 7.68(1H, dd, J=7.3Hz and 7.2Hz), 7.82 (IH, d, J=7.3Hz), 8.61 (IH, br) , 9.41(1H, br) , 9.93(1H, brs). Example 141
5-Cyano-4- (2-cyanophenyl) -4, 7-dihydro-6- (1-methylpiperidin- 4-yl) -2iϊ-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 (El) : 344 (M+) .
1H-NMR (400MHz, DMSO-ds) δ (ppm) : 1.58-1.63 (2H, m) , 1.82-
1.87(2H, m) , 1.98-2.06(2H, m) , 2.16(3H, s) , 2.59-2.61 (IH, m) , 2.84-2.88 (2H, ) , 5.23(1H, s) , 7.25(1H, s) , 7.39-
7.46(2H, m) , 7.6(1H, dd, J=7.3Hz and 7.2Hz), 7.81(1H, d,
J=7.3Hz), 9.77(1H, brs), 12.26(1H, brs).
Example 142
5-Cyano-4, 7-dihydro-6- (piperidin-4-yl) -4- (pyridin-4-yl) -2H- pyrazolo [3, 4-b] pyridine 3 hydrochloride
The title compound was prepared from ethyl nipecotate, pyridine-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 306 (M+) .
XH-1SIMR (400MHz, DMSO-d6) δ (ppm) : 1.86-1.92 (2H, m) , 2.18- 2.25(2H, m) , 2.93-3.00 (3H, m) , 3.35-3.38 (2H, m) , 5.41(1H, s), 6.50(3H, br) , 7.42(1H, s) , 7.97(2H, d, J=6.8Hz), 8.90(1H, br), 8.93(2H, d, J=6.8Hz), 9.60(1H, br) , 10.10(1H, brs) . Example 143 5-Cyano-4, 7-dihydro-6- (piperidin-4-yl) -4- (pyridin-3-yl) -2-H- 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. MS (El) : 306 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.86-1.93 (2H, m) , 2.19- 2.25(2H, m) , 2.90-2.97 (3H, m) , 3.35-3.38 (2H, ) , 5.39(1H, s), 6.50(3H, br) , 7.41(1H, s) , 8.09(1H, dd, J=8.2Hz and 5.4Hz), 8.49(1H, d, J=8.2Hz), 8.72(1H, br) , 8.88(1H, d, J=5.4Hz), 8.92 (IH, s) , 9.57 (IH, br) , 10.02 (IH, brs) . Example 144
5-Cyano-4, 7-dihydro-6- (l-methylpiperidin-4-yl) -4- (pyridin- 4-yl) -2-H-pyrazolo [3, 4-b] pyridine
The title compound was prepared from 5-cyano-4,7- dihydro-6- (piperidin-4-yl) -4- (pyridin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine 3 hydrochloride in the same manner as in Example 3. MS (El) : 320 (M+) .
1H-N R (400MHz, DMSO-d6) δ (ppm) : 1.56-1.64 (2H, m) , 1.86- 1.90(2H, m) , 1.99-2.03 (2H, m) , 2.17(3H, s), 2.61-2.64 (IH, m) , 2.86-2.89(2H, m) , 4.96(1H, s) , 7.23(2H, d, J=6.8Hz),
7.31(1H, s), 8.50(2H, d, J=6.8Hz), 9.67(1H, brs), 12.25(1H, brs) .
Example 145 5-Cyano-4, 7-dihydro-6- (l-methylpiperidin-4-yl) -4- (pyridin-
3-yl) -2-H-pyrazolo [3, 4-b]pyridine The title compound was prepared from 5-cyano-4,7- dihydro-6- (piperidin-4-yl) -4- (pyridin-3-yl) -2-H- pyrazolo [3, 4-b] pyridine 3 hydrochloride in the same manner as in Example 3. MS (El) : 320 (M+) .
^■H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.57-1.60 (2H, m) , 1.84- 1.89(2H, ) , 1.99-2.05 (2H, m) , 2.17(3H, s) , 2.58-2.61 (IH, m) , 2.85-2.8(2H, ) , 4.98(1H, s) , 7.29(1H, s) , 7.35(1H, dd, J=8.2Hz and 5.4Hz), 7.55(1H, d, J=8.2Hz), 8.42-8.45 (2H, m) , 9.64 (IH, 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-2.H-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- brom.o~3-cyanobenzaldeh.yde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 435 (M+) . 1H-N R (400MHz, DMSO-d6) δ (ppm) : 1.52-1.54 (IH, 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-2.H-pyrazolo [3, 4-b] pyridine 2 hydrochloride
The title compound was prepared from endo-2- azabicyclo [2, 2, 2] octane-6-carboxylic acid ethyl ester, 2- bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1 and 2. MS (El) : 435 (M+) .
XH-NMR (400MHz, DMSO-d6) δ (ppm) : 1.67-1.69 (3H, m) , 2.02- 2.12(4H, m) , 3.02-3.05 (IH, m) , 3.31-3.35 (IH, m) , 3.45- 3.51(2H, m) , 4.04(2H, br) , 5.50(1H, s) , 7.34(1H, s) , 7.56 (IH, dd, J=7.3Hz and 7.2Hz), 7.82 (IH, 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) -2-H-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 hydrochloride in the same manner as in Example 3. MS (El) : 449 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.42-1.45 (IH, m) , 1.72- 1.88(5H, m) , 2.06-2.09 (IH, m) , 2. 6-2.51 (4H, m) , 3.04- 3.07(1H, m) , 3.45-3.48 (2H, ) , 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 (IH, brs) . Example 149
Ethyl 4- (2, 2-difluoro-l, 3-benzodioxol-4-yl) -4, 7-dihydro-6- propyl-2-H-pyrazolo [3, 4-b] pyridine-5-carboxylate 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 L) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (27 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.0 g) , and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give the title compound (190 mg) as colorless crystals. MS (El) :391 (M+) . 1H-NMR (400MHz, DMSO-d6) δ (ppm) : 0.90-0.97 (6H, m) , 1.58-
1.64(2H, ) , 2.60-2.64 (IH, m) , 2.83-2.86 (IH, 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 (El) : 455 (M+) . 1H-N R (400MHz, DMSO-d6) δ (ppm) : 0.84 (3H, t, J=7.3Hz), 1.78- 1.81(1H, m) , 1.98-2.14 (3H, m) , 2.87-2.90 (2H, m) , 3.40- 3.42(2H, m) , 3.78(2H, q, J=7.3Hz), 3.80-4.25 (3H, ) , 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) -2-H-pyrazolo [3, 4-b] pyridine-5- carboxylate
The title compound was prepared from ethyl 4- (2-bromo-3- cyanophenyl) -4, 7-dihydro-6- (piperidin-4-yl) -2-H- pyrazolo [3, 4-b] pyridine-5-carboxylate 2 hydrobromide in the same manner as in Example 3. MS (El) : 469 (M+) .
1H-NMR (400MHz, DMSO-ds) δ (ppm) : 0.85(3H, t, J=7.3Hz), 1.53- 1.55(1H, m) , 1.70-1.72(1H, m) , 1.87-2.06 (4H, m) , 2.16(3H, s), 2.84-2.88 (2H, m) , 3.78(2H, q, J=7.3Hz), 3.94-3.96 (IH, 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) -2-H-pyrazolo [3, 4-b] pyridine The title compound was prepared from l-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. MS (El) : 375 (M+) .
1H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.88-1.91 (IH, m) , 2.26- 2.33(2H, m) , 2.65-2.70 (IH, m) , 2.82(3H, m) , 3.17-3.20 (IH, m) , 3.31-3.36(2H, ) , 5.40(1H, s) , 7.29(1H, s) , 7.44(1H, d, J=6.6Hz), 7.58 (IH, dd, J=9.0Hz and 6.6Hz), 7.92 (IH, d, J=9.0Hz), 9.88 (IH, brs), 12.22 (IH, brs). Example 153
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1-methyl- 2-oxo-piperidin-4-yl) -2-H-pyrazolo [3, 4-b] pyridine
The title compound was prepared from l-methyl-2-oxo- piperidine-4-carboxylic acid ethyl ester, 2-bromo-3- cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1. MS (El) : 437 (M+) .
XH-NMR (400MHz, DMSO-ds) δ (ppm) : 1.88-1.92 (IH, m) , 2.25- 2.36(2H, m) , 2.69-2.74 (IH, 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-l, 3, 4-oxadiazol- 2-yl) -6-propyl-2H-pyrazolo [3, 4-b] pyridine
A solution of 2-chlorobenzaldehyde (21 g) , Me1drum' s acid (21 g) , 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 L) 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 IN NaOH solution (lOOmL) 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 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 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 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 (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 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 (El) : 356 (M+) .
^■H-NMR (400MHz, DMSO-d6) δ (ppm) : 1.00 (3H, t, J=7.3Hz), 1.67- 1.74(2H, m) , 2.31(3H, s) , 2.70-2.83 (2H, m) , 5.71(1H, s) ,
7.07-7.12 (3H, m) , 7.33-7.40 (2H, ) , 9.49(1H, brs), 12.04(1H, brs) . Example 155
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- (methylamino) ethyl) -2-H-pyrazolo [3, 4-b] pyridine 2 hydrochloride
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 (El) : 384 (M+) . ^-H-NMR (400MHZ, DMSO-d6) δ (ppm) : 1.49(3H, d, J=7.3Hz),
3.09(3H, s), 4.00(2H, br) , 4.60(1H, q, J=7.3Hz), 5.53(1H, s), 7.48-7.53 (2H, m) , 7.64(1H, s) , 7.82(1H, d, J=7.3Hz), 8.00-8.29(2H, br) , 10.97(1H, brs). Example 156 4- (2-Chlorophenyl) -4, 7-dihydro-5- (5-methyl-l, 2, 4-oxadiazol- 3-yl) -6-propyl-2.H-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 L) 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 IN NaOH solution (100 L) 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) . An Ammonia solution (3.0 g) and GDI (2.8 g) were added to the obtained colorless 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 heated for 2 hours, and the solvent was evaporated under reduced pressure. Hydroxyammonium (1.4 g) , IN NaOH (20 L) , dioxane (20 mL) and acetic acid (28 L) 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 obtained colorless crystals in chloroforom (20 L) 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 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) , and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give the title compound (500 mg) as colorless crystals. MS (El) :356(M+) .
1H-NMR (400MHz, DMSO-ds) δ (ppm) : 0.99(3H, s) , 1.62 (3H, t, J=7.3Hz), 1.66-1.73 (2H, m) , 2.13(3H, s) , 2.35-2.38 (2H, m) , 2.84-3.05(2H, m) , 5.73(1H, s) , 7.06-7.17 (3H, ) , 9.90(1H, brs), 12.11 (IH, brs). Example 157
4- (2, 1, 3-Benzoxadiazol-4-yl) -4, 7-dihydro-5- (5-methyl-l, 3, 4- oxadiazol-2-yl) -6-prόpyl-2.H-pyrazolo [3, 4-b] pyridine The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde in the same manner as in Example 154. MS (El) : 364 (M+) .
XH-NMR (400MHz, DMSO~d6) δ (ppm) : 1.01 (3H, t, J=7.3Hz), 1.69- 1.76(2H, m) , 2.31(3H, s) , 2.72-2.86 (2H, m) , 5.82(1H, s) , 7.18(1H, d, J=6.6Hz), 7.32(1H, s) , 7.48(1H, dd, J=9. OHz and 6.6Hz), 7.80(1H, d, J=9.0Hz), 9.65(1H, brs), 12.07(1H, brs). Example 158
4- (2-Bromo-3-cyanophenyl) -4, 7-dihydro-5- (5-methyl-l, 3, 4- oxadiazol-2-yl) -6-propyl-2-H-pyrazolo [3, 4-b] pyridine The title compound was prepared from 2-bromo-3- cyanobenzaldehyde in the same manner as in Example 154. MS (El) : 425 (M+) .
1H-NMR (400MHz, DMSO-d5) δ (ppm) : 1.00 (3H, t, J=7.3Hz), 1.66- 1.73(2H, ) , 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 (IH, brs) . Example 159
6- ( 1-Amino-1-methylethyl) -4- (2-chlorophenyl) -5-cyano-4, 7- dihydro-2-H-pyrazolo [3, 4-b] pyridine hydrochloride
The title compound was prepared from 2, 2-dimethylglycine ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
Figure imgf000101_0001
Figure imgf000101_0003
Example 5 Example 6
Figure imgf000101_0002
Figure imgf000101_0004
Figure imgf000101_0006
Example 11
Figure imgf000101_0005
Figure imgf000101_0007
Figure imgf000101_0008
Example 15 Example 16
Figure imgf000101_0010
Figure imgf000101_0009
Example 17 Example 18
Figure imgf000101_0011
Example 20
Figure imgf000102_0001
Example 25 Example 26 Example 27 Example 28
Figure imgf000102_0002
Figure imgf000102_0004
Figure imgf000102_0003
Example 37 Example 38
Figure imgf000102_0005
Example 40
Figure imgf000103_0001
Figure imgf000103_0002
Example 41 Example 43 Example 44
Figure imgf000103_0005
Figure imgf000103_0003
Figure imgf000103_0004
Figure imgf000103_0006
Example 53 Example 54 Example 55 Example 56
Figure imgf000103_0007
Figure imgf000103_0008
Example 57
Figure imgf000103_0010
Example 59
Figure imgf000103_0009
Figure imgf000104_0002
Example 61 Example 64
Figure imgf000104_0003
Example 65
Figure imgf000104_0004
Example 69
Figure imgf000104_0001
Example 72
Figure imgf000104_0005
Example 73 Example 74 Example 75 Example 76
Figure imgf000104_0006
Example 77 Example 78 Example 79
Figure imgf000104_0007
Figure imgf000105_0001
Example 81 Example 82 Example 83 Example 84
Figure imgf000105_0002
Example 85 Example 86 Example 87 Example 88
Figure imgf000105_0003
Example 89 Example 90 Example 91
Figure imgf000105_0004
Figure imgf000105_0005
Example 93 Example 94 Example 95
Figure imgf000106_0001
Example 96 Example 97 Example 98
Figure imgf000106_0003
Example 100 Example 101 Example 102
Figure imgf000106_0002
Figure imgf000106_0004
Example 105 Example 106 Example 107
Figure imgf000106_0005
Figure imgf000106_0006
Example 108 Example 109 Example 110 Example 111
Figure imgf000106_0007
Example 112 Example 113 Example 114 Example 115
Figure imgf000107_0001
Example 116 Example 117 Example 118 Example 119
Figure imgf000107_0002
Example 120 Example 121 Example 122 Example 123
Figure imgf000107_0003
Example 124 Example 125 Example 126 Example 127
Figure imgf000107_0004
Example 128 Example 129 Example 130 Example 131
Figure imgf000107_0005
Example 132 Example 133 Example 134 Example 135
Figure imgf000108_0001
Example 136 Example 137 Example 138 Example 139
Figure imgf000108_0003
Figure imgf000108_0002
Example 140 Example 141
Figure imgf000108_0004
Example 143
Figure imgf000108_0005
Example 144 Example 145 Example 146 Example 147
Figure imgf000108_0006
Example 148 Example 151
Example 1 9 Example 150
Figure imgf000108_0007
Example 152 Example 153 Example 154 Example 155
Figure imgf000109_0001
Example 156 Example 157 Example 158 Example 159
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 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 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 on glycogen synthase kinase-3 beta (GSK-3β) were evaluated and confirmed as follows.
Experimental Example 1 : GSK-3β-inhibitory activity
CREB phosphopeptide (4.6 n ol) , rabbit GSK-3β (0.5 unit), ATP (5 nmol), [γ-32P]ATP (12.3 kBq) and a test compound were reacted in a GSK-3β buffer solution (25 μL)
(20 mmol/L Tris-HCl (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 μL) was adsorbed on a P81 ion-exchange paper, and the paper was 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 IC5o values of 1 to 1000 nmol/L. For example, the IC50 values of the compounds are shown in the following Table 1.
CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser- Arg-Arg-Pro-Ser ( P) -Tyr-Arg .
Table 1
Figure imgf000111_0001
Experimental Example 2 : GSK-3β-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 with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β 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 using phosphorylated Tau-recognizing antibody
(phosphorylated site by GSK-3β) , and the inhibitory effect of the GSK-3β inhibitor on the neurons was evaluated. Experimental Example 3: Effect on amyloid β-induced cytotoxicity 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 with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor) , and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined, and the effect of the GSK-3β inhibitor on the amyloid β-induced cytotoxicity was evaluated.
Experimental Example : GSK-3β-inhibitory effect in gerbil brain ischemia model
A test compound (GSK-3β inhibitor) was 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 gerbil brain, and the level of phosphorylation of Tau protein was determined by Western blot using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β) , based on which the GSK-3β-inhibitory effect of the GSK-3β 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-3β) , 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 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, or as immunopotentiators,
This application is based on patent application No. 2002-230581 filed in Japan, the contents of which are hereby incorporated by reference.

Claims

1. A dihydropyrazolopyridine compound of the formula (I)
Figure imgf000114_0001
wherein
R° is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , phenylalkyl optionally having substituent (s) , or a group of the formula: -COOR8 (wherein R8 is hydrogen, alkyl, aryl optionally having substituent (s) or aralkyl optionally having substituent (s) ) ; R1 is hydrogen;
R2 is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent (s) , aromatic heterocyclic group or phenylalkyl; is
(1) alkyl or haloalkyl,
(2) cycloalkyl, (3) phenyl optionally having substituent (s) ,
(4) aromatic heterocyclic group,
(5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom (s) , or
(7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom (s) , which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent (s) , or a group selected from the groups represented by the following formulas (II) and (III) :
Figure imgf000115_0001
(II) (III) wherein R6 and R7 are each phenyl optionally having substituent (s) or an aromatic heterocyclic group, or R2 and R3 in conjunction form a ring optionally containing heteroatom (s) , wherein the ring may be fused with a benzene ring optionally having substituent (s) ; is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group optionally having substituent (s) , cyano or nitro; and
R5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) , a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CRaRb) nNR1:LR12 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, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R12 is hydrogen or alkyl, provided that when R°, R1 and R2 are each hydrogen, R4 is methoxycarbonyl and R5 is methyl, then R3 should not be phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R5 is alkyl, then R4 is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
2. The dihydropyrazolopyridine compound of claim 1, wherein
R4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group having substituent (s) , cyano or nitro, and R5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) , a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: - (CH2) nNR11R12 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R12 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
3. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R2 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
4. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R3 is phenyl optionally having 1 to 3 substituent (s) , naphthyl, 2, 1, 3-benzoxadiazol-4-yl or 3,4- dihydro-2H-benzopyran-8-yl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
5. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R4 is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
6. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R5 is a group of the formula: - (CH2) nNR1;LR12 wherein n is an integer of 1 to 4, R11 is hydrogen, alkyl or alkoxycarbonyl and R12 is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
7. The dihydropyrazolopyridine compound of claim 1 or 2, wherein R° is hydrogen or a group of the formula: -C0OR8 (wherein R8 is alkyl, aryl optionally having substituent (s) or aralkyl optionally having substituent (s) ) , or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
8. The dihydropyrazolopyridine compound of claim 1 or 2, which is selected from the group consisting of
(2) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (piperidin-4-yl) -2-H-pyrazolo [3, 4-b] pyridine,
(3) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2H-pyrazolo [3, 4-Jb] pyridine,
(11) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- methylmorpholin-2-yl) -2H-pyrazolo [3, 4-Jb] pyridine,
(14) 4- (2,1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- methyl-1, 2, 3, 6~tetrahydropyridin-4-yl) -2Jtf-pyrazolo [3, 4-Jb] - pyridine,
(23) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- (N,N-dimethylamino) cyclohexyl) -2iϊ-pyrazolo [3, 4-Jb] pyridine, (27) 6- (l-acetyl-1,2,3, 6-tetrahydropyridin-4-yl) -4- (2, 1, 3- benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2iJ-pyrazolo [3, 4-jb] - pyridine, (33) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (1- ethylpiperidin-4-yl) -2iϊ-pyrazolo [3, 4-b] pyridine,
(37) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (piperidin-4-yl) -2Jϊ-pyrazolo [3, 4-b] pyridine,
(38) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-4-yl) -2iJ-pyrazolo [3, 4-b] pyridine,
(41) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methylpiperidin-3-yl) -2iϊ-pyrazolo [3, 4-b] pyridine,
(46) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (4- meth lmorpholin-2-yl) -2Jϊ-pyrazolo [3, 4--b] yridine, (48) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -2JT-pyrazolo [3, 4-b] - pyridine,
(51) 6- (l-acetylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) - 5-cyano-4, 7-dihydro-2Jϊ-pyrazolo [3, 4-jb] pyridine, (52) 6- (l-benzoylpiperidin-4-yl) -4- (2-bromo-3-cyanophenyl) - 5-cyano-4, 7-dihydro-2H-pyrazolo [3, -b] pyridine,
(53) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (1- methanesulfonylpiperidin-4-yl) -2ff-pyrazolo [3, 4-b] pyridine,
(59) 4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (4- oxocyclohexan-1-yl) -2iϊ-pyrazolo [3, 4-b] pyridine,
(62) 4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (2- oxocyclohexan-1-yl) -2iϊ-pyrazolo [3, 4-b] pyridine,
( 63) 6-acetylmethyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7- dihydro-2Jf-pyrazolo [3, 4-jb] pyridine, (73) 5-cyano-4, 7-dihydro-4- (2, 3- (methylenedioxy) phenyl) -6- (piperidin-4-yl) -2ff-pyrazolo [3, -b] pyridine, (75) 4- (2,1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-2iϊ- pyrazolo [3, 4-b] pyridine- 6-carboxylic acid phenylamide, (78) 4- (2-chlorophenyl) -5-cyano-4, 7-dihydro-6- (4-phenyl- piperazin-l-yl)methyl-2H-pyrazolo [3, 4-Jb] pyridine,
(81) 6-acetyl-4- (2-bromo-3-cyanophenyl) -5-cyano-4, 7- dihydro-2iϊ-pyrazolo [3, 4-b] pyridine,
(82) 6-acetyl-4- (2, 1, 3-benzoxadiazol-4-yl) -5-cyano-4, 7- dihydro-2 -pyrazolo [3, 4-b]pyridine,
(84) 4- (2~bromo~3-cyanophenyl) -5- (pyridin-2-yl) -4, 7- dihydro-β-propyl-2 -pyrazolo [3, 4-b]pyridine,
(86) 4- (2-chlorophenyl) -5-cyano-4, 7-dihydro-6- (pyrrolidin- 3-yl) -2iϊ-pyrazolo [3, 4-b] pyridine, and
(87) 4- (2, 1, 3-benzoxadiazol-4-yl) -5- (pyridin-2-yl) -4, 7- dihydro-6-propyl-2f-pyrazolo [3, 4-b] pyridine, a tautomer thereof, an optically active form thereof, or a pharmaceutically acceptable salt thereof.
9. A medicament comprising a dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
11. A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of claim 1, an optically active form thereof and a pharmaceutically acceptable salt thereof.
12. The medicament of claim 9, which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.
13. The medicament of claim 9, which is used for prevention and/or treatment of a neurodegenerative disease.
14. The medicament of claim 13, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington' s disease and manic-depressive psychosis.
15. The medicament of claim 9, which is used for prevention and/or treatment of diabetes and diabetic complications.
16. The medicament of claim 9, which is used as an immunopotentiator .
17. The medicament of claim 9, which is used for prevention and/or treatment of alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell lukemia or virus-induced tumors.
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ZA200501842B (en) 2006-05-31
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