CN1675209A - Dihydropyrazolopyridine compounds - Google Patents

Dihydropyrazolopyridine compounds Download PDF

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CN1675209A
CN1675209A CNA038190362A CN03819036A CN1675209A CN 1675209 A CN1675209 A CN 1675209A CN A038190362 A CNA038190362 A CN A038190362A CN 03819036 A CN03819036 A CN 03819036A CN 1675209 A CN1675209 A CN 1675209A
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phenyl
dihydro
pyrazolo
pyridine
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小原利行
福永谦二
花野笃志
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Mitsubishi Pharma Corp
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    • 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
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    • 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
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Abstract

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

Description

The dihydro-pyrazolo pyridine compounds
Technical field
The present invention relates to medicinal new compound and application thereof, described new compound has glycogen synthase kinase-3 β (GSK-3 β) and suppresses active.
Background technology
Reported glycogen synthase kinase-3 β (GSK-3 β), a kind of protein kinase, relevant with the cause of the multiple disease of the following stated.
Type ii diabetes is the disease that glucose increases in the insulin activity step-down of wherein pancreatic beta cell and the blood.Therefore, it brings out complication such as diabetic nephropathy, retinal degeneration, heart trouble etc.GSK-3 β suppresses glycogen accumulated, reduced insulin replies and increases glucose in the blood in peripheral tissues effect by the Glycogensynthase phosphorylation is played.Have GSK-3 β and suppress active lithium in fact by the active glucose (Proc.Nat.Acad.Sci., 93,8455 (1996)) that reduces in the blood of GSK-3 β inhibition.Therefore, think to have GSK-3 β to suppress active medicine be the active drug that improves type ii diabetes and complication thereof.
Also do not illustrate the development mechanism of Alzheimer's dementia.Yet it is closely related to think that amyloid aggregation and neuroneme change with its development.As described below, GSK-3 β changes relevant with amyloid aggregation and neuroneme.(1) it combines with the mutant presenilin and increases the proteic generation of insoluble starch sample (Proc.Nat.Acad.Sci., 95,9637 (1998)).(2) it causes the proteic phosphorylation of Tau, causes neuroneme to change, and the neurone skeleton is weakened and inducing neural unit dead (Neurosci.Lett., 128,195 (1991)).Except that above-mentioned, (3) have been reported GSK-3 β and have been participated in the generation that reduces the required vagusstoff of maintenance cytoactive by phosphorylation passivation pyruvic oxidase directly, thereby make neuronal death.
In addition, also proposed for the effectiveness of AIDS encephalopathic as the nerve degeneration disease that is different from Alzheimer's dementia.Tat is as the protein that is produced by the HIV virus that causes AIDS, and it strengthens the GSK-3 'beta ' activity in the neurone, inducing neural unit dead (J.Neurochem., 73,578 (1999)).From the above, think that the GSK-3 beta inhibitor is the medicine that is used for effectively improving the nerve degeneration disease that comprises Alzheimer's dementia.
Have anti-active lithium of manic depression and valproic acid and have GSK-3 β inhibition active (J.Neurochem., 72,1327 (1999)).Not clear for the relation that anti-manic depressed activity and GSK-3 β suppress between the activity, but think that the inhibition activity to glutamate toxicity is the partly cause (Proc.Nat.Acad.Sci., 95,2642 (1998)) that keeps neuronal activity.Based on above-mentioned, think that the GSK-3 beta inhibitor is the active drug that improves manic depressive psychosis.
NF-AT is a kind of transcription factor, and it is transferred neuroprotein (calcineurin) dephosphorylation to increase immunne response (Science, 275,1930 (1997)) by calcium.GSK-3 β plays the effect that suppresses immunologic function by making the NF-AT phosphorylation on the contrary.Therefore, think that the GSK-3 beta inhibitor is the active drug that is used for immunopotentiation.
Incidentally, JP-A-3-272189 (relating to the invention of improving one's methods of synthetic mevalonolactone (mevalolacton) intermediate), JP-A-2-275878 (relate to and be used for hyperlipoproteinemia and atherosclerosis therapy agent) and JP-A-1-272584 (therapeutical agent that relates to hyperlipoproteinemia) disclose wherein, and the 6-position is pyrazolo [3, the 4-b] pyridine compounds of methyl, sec.-propyl or cyclopropyl.These documents do not have open or propose any effect of these compounds to GSK-3 β or central nervous system.
The specification sheets of JP-A-59-65089, JP-A-59-118786, JP-A-60-56979, JP-A-60-197685 etc. discloses the 6-methyl-4-substituted-phenyl-4 that is used for the treatment of cardiovascular disorder, 7-dihydro-pyrazolo [3,4-b] pyridine-5-formic acid ester compound, and prepare them by similar method.Reaction A shown in the inventor has repeated hereinafter according to method described in the JP-A-59-65089, but fail to obtain the compound shown in the embodiment 14 described herein (formula hereinafter (IV)).They have confirmed only to produce pyrazolo [1, the 5-a] pyrimidine derivatives shown in the formula V.Measured IR, NMR and the fusing point of formula V compound, found identical with IR, NMR and the fusing point described in the described specification sheets that discloses text.Therefore conclude and in these documents, disclose wrong structural formula.In other words, can not be according to the synthetic 6-methyl of the described method of these documents-4-substituted-phenyl-4,7-dihydro-pyrazolo [3,4-b] pyridine-5-manthanoate.
Compound shown in the above-mentioned formula (IV) can be according to J.Chem.Soc., Perkin Trans.1, the method described in 947 (1996) is synthetic, and this publication discloses 4-(2-chloro-phenyl-)-6-methyl-4, the 7-dihydro-1 h-pyrazole is [3,4-b] pyridine-5-methyl-formiate etc. also.
Disclosure of the Invention
The purpose of this invention is to provide and have selectivity and strong anti-glycogen synthase kinase-3 β (GSK-3 β) suppresses active new compound, and medicine that comprises them and the pharmaceutical composition that comprises them are provided in addition.
To achieve these goals, the inventor has carried out deep research, found that 4, and 7-dihydro-pyrazolo [3,4-b] pyridine derivate has optionally active with strong GSK-3 β inhibition, has finished the present invention based on this.That is to say, the present invention relates to medicine, it dihydro-pyrazolo pyridine compounds, its optical isomer, its pharmacologically acceptable salt or its hydrate that comprises following formula (I) expression with the active also useful as drug of GSK-3 β inhibition is as activeconstituents.
The invention provides following content.
[1] the dihydro-pyrazolo pyridine compounds shown in the formula (I), or its optical activity form, or its pharmacologically acceptable salt:
Figure A0381903600112
Wherein
R 0Be hydrogen; alkyl; aralkyl; acyl group; cycloalkyl; formyl radical; haloalkyl; aminoalkyl group; alkoxyalkyl; phenoxyalkyl; hydroxyalkyl; aminocarboxyl; the alkylthio carbonyl; carboxyalkyl; the cycloalkyloxy alkyl; alkyl sulphinyl; alkyl sulphonyl; phenyl sulfonyl; the phenyl sulfinyl; mercaptoalkyl; alkylthio alkyl; the acyloxy ethanoyl; the acyloxy alkyl; randomly has substituent phenyl; randomly has substituent aromatic heterocycle group; randomly has substituent phenylalkyl; or formula-COOR 8Shown group (R wherein 8For hydrogen, alkyl, randomly have substituent aryl or randomly have substituent aralkyl);
R 1Be hydrogen;
R 2Be hydrogen, alkyl, aralkyl, acyl group, cycloalkyl, hydroxyl, thiol, halogen, amino, formyl radical, carboxyl, cyano group, nitro, alkylthio, haloalkyl, aminoalkyl group, amido, alkoxyl group, cycloalkyloxy, phenoxy group, the phenyl alkoxyl group, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxy carbonyl, aminocarboxyl, the alkylthio carbonyl, carboxyalkyl, the cycloalkyloxy alkyl, thiophenyl, alkyl sulphinyl, alkyl sulphonyl, phenyl sulfonyl, mercaptoalkyl, alkylthio alkyl, randomly has substituent phenyl, aromatic heterocycle group or phenylalkyl;
R 3For
(1) alkyl or haloalkyl,
(2) cycloalkyl,
(3) randomly have substituent phenyl,
(4) aromatic heterocycle group,
(5) derived from the group of phenyl ring, described phenyl ring and saturated or undersaturated 5 or 6 yuan carbocyclic fused,
(6) derived from the group of phenyl ring, described phenyl ring condenses with comprising 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, or
(7) derived from the group that comprises 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, described carbocyclic ring and phenyl ring condense,
Wherein (2) to (7) listed group can have one or more substituting groups, or
The group that is selected from following formula (II) and (III) represents:
Figure A0381903600131
R wherein 6And R 7Respectively doing for oneself randomly has substituent phenyl or aromatic heterocycle group,
Or R 2And R 3Randomly comprise heteroatomic ring in conjunction with forming, wherein said ring can with randomly have substituent phenyl ring and condense;
R 4For
Alkoxy carbonyl,
Alkyl-carbonyl,
Alkyl sulphonyl,
Alkyl sulphinyl,
The phenyl sulfinyl,
Phenyl sulfonyl,
The dialkyl group phosphinyl,
The dialkyl phosphine acyl group,
Randomly have substituent phenyl,
Randomly have substituent aromatic heterocycle group,
Cyano group, or
Nitro; And
R 5For
Alkyl,
The phenyl amino alkyl,
Acyl group,
The acyl group alkyl,
Aminocarboxyl,
Aromatic yl aminocarbonyl,
Randomly have substituent 4 to 7 yuan of saturated or unsaturated heterocycles,
Have substituent 3 to 7 yuan of saturated carbon rings,
4 to 7 yuan of saturated or unsaturated cyclosubstituted alkyl (described ring can randomly have substituting group) of involved 1 or 2 nitrogen-atoms, or
Suc as formula-(CR aR b) nNR 11R 12Shown group, wherein n is 1 to 4 integer, R aBe hydrogen or alkyl, R bBe hydrogen or alkyl, R 11Be hydrogen, alkyl, alkyl sulphonyl, phenyl sulfonyl, phenylalkyl alkylsulfonyl, alkyl sulphinyl, phenyl sulfinyl, phenylalkyl sulfinyl, alkoxy carbonyl, phenyloxycarbonyl, phenyl alkoxy carbonyl, alkyl-carbonyl, phenylcarbonyl group or phenylalkyl carbonyl, and R 12Be hydrogen or alkyl,
Condition is to work as R 0, R 1And R 2Hydrogen, R respectively do for oneself 4Be methoxycarbonyl and R 5During for methyl, R then 3Should not phenyl, 2-chloro-phenyl-, 3-nitrophenyl, 4-carboxyl phenyl or 4-methoxycarbonyl phenyl, and work as R 5During for alkyl, R then 4Not alkoxy carbonyl, alkyl sulphonyl, alkyl sulphinyl, phenyl sulfinyl, phenyl sulfonyl, dialkyl group phosphinyl, dialkyl phosphine acyl group, cyano group or nitro.
[2] the dihydro-pyrazolo pyridine compounds of above-mentioned [1], or its optical activity form, or its pharmacologically acceptable salt, wherein R 4Be alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl, alkyl sulphinyl, phenyl sulfinyl, phenyl sulfonyl, dialkyl group phosphinyl; the dialkyl phosphine acyl group, randomly have substituent phenyl, have substituent aromatic heterocycle group, cyano group or nitro, and
R 5For alkyl, phenyl amino alkyl, acyl group, acyl group alkyl, aminocarboxyl, aromatic yl aminocarbonyl, randomly have substituent 4 to 7 yuan of saturated or unsaturated heterocycles, have 4 to 7 yuan of saturated or unsaturated cyclosubstituted alkyl (described ring randomly has substituting group) of substituent 3 to 7 yuan of saturated carbon rings, involved 1 or 2 nitrogen-atoms, or suc as formula-(CH 2) nNR 11R 12Shown group, wherein n is 1 to 4 integer, R 11Be hydrogen, alkyl, alkyl sulphonyl, phenyl sulfonyl, phenylalkyl alkylsulfonyl, alkyl sulphinyl, phenyl sulfinyl, phenylalkyl sulfinyl, alkoxy carbonyl, phenyloxycarbonyl, phenyl alkoxy carbonyl, alkyl-carbonyl, phenylcarbonyl group or phenylalkyl carbonyl, and R 12Be hydrogen or alkyl.
[3] the dihydro-pyrazolo pyridine compounds of above-mentioned [1] or [2], or its optical activity form, or its pharmacologically acceptable salt, wherein R 2Be hydrogen or alkyl.
[4] the dihydro-pyrazolo pyridine compounds of above-mentioned [1] or [2], or its optical activity form, or its pharmacologically acceptable salt, wherein R 3Be phenyl (it randomly has 1 to 3 substituting group), naphthyl, 2,1,3-Ben Bing oxadiazole-4-base or 3,4-dihydro-2H-chromene-8-base.
[5] the dihydro-pyrazolo pyridine compounds of above-mentioned [1] or [2], or its optical activity form, or its pharmacologically acceptable salt, wherein R 4For alkoxy carbonyl, alkyl-carbonyl with 2 to 5 carbon atoms with 2 to 5 carbon atoms, have the alkyl sulphonyl of 1 to 4 carbon atom or have the alkyl sulphinyl of 1 to 4 carbon atom.
[6] the dihydro-pyrazolo pyridine compounds of above-mentioned [1] or [2], or its optical activity form, or its pharmacologically acceptable salt, wherein R 5For suc as formula-(CH 2) nNR 11R 12Shown group, wherein n is 1 to 4 integer, R 11Be hydrogen, alkyl or alkoxy carbonyl, and R 12Be hydrogen or alkyl.
[7] the dihydro-pyrazolo pyridine compounds of above-mentioned [1] or [2], or its optical activity form, or its pharmacologically acceptable salt, wherein R 0For hydrogen or suc as formula-COOR 8Shown group: (R wherein 8For alkyl, randomly have a substituent aryl or randomly have substituent aralkyl.
[8] the dihydro-pyrazolo pyridine compounds of above-mentioned [1] or [2], it is selected from following compound, its tautomer, its optical activity form or its pharmacologically acceptable salt:
(2) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(3) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(11) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine,
(14) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(23) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-(N, N-dimethylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine,
(27) 6-(1-ethanoyl-1,2,3,6-tetrahydropyridine-4-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(33) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-ethyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(37) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(38) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(41) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-3-yl)-2H-pyrazolo [3,4-b] pyridine,
(46) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine,
(48) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(51) 6-(1-ethanoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(52) 6-(1-benzoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(53) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methylsulfonyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(59) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine,
(62) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(2-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine,
(63) 6-ethanoyl methyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(73) 5-cyano group-4,7-dihydro-4-(2,3-(methylene-dioxy) phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(75) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-6-phenyl amino carbonyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(78) 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(4-phenylpiperazine-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine,
(81) 6-ethanoyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(82) 6-ethanoyl-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(84) 4-(2-bromo-3-cyano-phenyl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine,
(86) 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(tetramethyleneimine-3-yl)-2H-pyrazolo [3,4-b] pyridine and
(87) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine.
[9] comprise the medicine of dihydro-pyrazolo pyridine compounds, its optical activity form or its pharmacologically acceptable salt of above-mentioned [1] or [2].
[10] comprise the pharmaceutical composition of dihydro-pyrazolo pyridine compounds, its optical activity form or its pharmacologically acceptable salt and the pharmaceutically acceptable additive of above-mentioned [1] or [2].
[11] comprise the glycogen synthase kinase-3 beta inhibitor of the compound of the dihydro-pyrazolo pyridine compounds, its optical activity form and the pharmacologically acceptable salt thereof that are selected from above-mentioned [1].
[12] medicine of above-mentioned [9], it is used to prevent and/or treat by the too high disease that causes of glycogen synthase kinase-3 'beta ' activity.
[13] medicine of above-mentioned [9], it is used to prevent and/or treat the nerve degeneration disease.
[14] medicine of above-mentioned [13], wherein said disease is selected from Alzheimer, the ischemic cerebral vascular disorder, Down's syndrome, the cerebral ischemia that brain amyloid blood vessel disease causes, stein-leventhal syndrome, subacute sclerosing panencephalitis Parkinson neurological dysfunction, Parkinson's neurological dysfunction after the encephalitis, boxer's encephalopathic (boxer ' s encephalopathy), Guam (Guam) type Parkinson chronic brain syndrome, thunder dimension corpusculum disease (Lewy bodydisease), Pick's disease (Pick ' s disease), cortex Basal ganglia sex change (corticobasaldegeneration), volume temporal lobe type dementia, the AIDS encephalopathic, Huntington's disease and manic depressive psychosis.
[15] medicine of above-mentioned [9], it is used to prevent and/or treat diabetes and diabetic complication.
[16] medicine of above-mentioned [9], it is as immunostimulant.
[17] medicine of above-mentioned [9], it is used to prevent and/or treat alopecia, mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T cell or B cell leukemia or viral-induced tumour.
Detailed Description Of The Invention
Formula (I) is represented based on the following formula (I-a) of pyrazoles ring hydrogen atom position and the existence of tautomer (I-b).The present invention includes formula (I-a) and (I-b) shown in every kind of isomer, and these mixture of isomers.
Be described in more detail below the compound shown in this specification sheets Chinese style (I).
" alkyl " is meant the hydrocarbon chain of the straight or branched with 1 to 8 carbon atom, it comprises methyl, ethyl, propyl group, butyl, amyl group, hexyl or its constitutional isomer, as sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, tert-pentyl etc., preferably has the alkyl of 1 to 4 carbon atom.R 2Alkyl be preferably alkyl with 1 to 4 carbon atom.R 5Alkyl be preferably alkyl with 2 to 8 carbon atoms." alkyl with 2 to 8 carbon atoms " specifically comprises ethyl, propyl group, butyl, amyl group, hexyl, heptyl and octyl group or its constitutional isomer, as sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, tert-pentyl etc.The alkyl that more preferably has 2 to 4 carbon atoms, preferred especially propyl group.
" acyl group " is meant C 2-C 14Acyl group, it comprises that " alkyl-carbonyl " with 2 to 8 carbon atoms is as ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, valeryl, caproyl, oenanthyl etc., for R 4The acyl group that preferably has 2 to 5 carbon atoms, " C 7-C 12Aryl carbonyl " as benzoyl, naphthoyl etc.; " C 7-C 12Aromatic alkyl carbonyl " as benzyloxycarbonyl group, 2-phenylethyl carbonyl, 3-phenyl propyl carbonyl etc., or the like.Phenyl ring and naphthalene nucleus can have 1 to 5 substituting group, and are not specifically limited for the position of substitution.
" acyl group alkyl " is by above-mentioned C 1-C 8Alkyl and above-mentioned C 2-C 14The acyl group alkyl that acyl group is formed, it comprises for example ethanoyl methyl, propionyl methyl, butyryl radicals methyl, isobutyryl methyl, pentanoyl methyl, valeryl methyl, 2-ethanoyl ethyl, 2-propionyl ethyl, 3-ethanoyl propyl group etc.
" cycloalkyl " is meant the cyclic hydrocarbon of 3 to 8 carbon atoms.Cycloalkyl specifically comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc., preferably has the cycloalkyl of 3 to 6 carbon atoms.Cycloalkyl can have 1 to 5 substituting group, and is not specifically limited for the position of substitution.
" halo " expression fluorine, chlorine, bromine or iodine.
" amino " is meant to have above-mentioned C 1-C 8The primary amine of alkyl, secondary amine or uncle's ammonia, it comprises for example amino, single or two C 1-C 8Amino that alkyl replaces such as methylamino, dimethylamino, ethylamino, diethylamino, propyl group amino, dipropyl amino, butyl amino, dibutylamino etc.
" alkylthio " is the alkylthio with straight or branched of 1 to 6 carbon atom, it comprises for example methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl, own sulfenyl and constitutional isomer thereof, as sec.-propyl sulfenyl, isobutyl-sulfenyl, sec-butyl sulfenyl, tertiary butyl sulfenyl, isopentyl sulfenyl, neo-pentyl sulfenyl, tert-pentyl sulfenyl etc., preferably has the alkylthio of 1 to 3 carbon atom.
" thiophenyl " is meant randomly have 1 to 5 substituent thiophenyl on phenyl, and is not specifically limited for the position of substitution.
" haloalkyl " is by the above-mentioned C of 1 to 5 halogen replacement 1-C 8Alkyl, its expression methyl fluoride, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls etc.
" aminoalkyl group " is for having the C of primary amino 1-C 8Alkyl, it comprises for example amino methyl, 2-amino-ethyl, 3-aminopropyl, the amino butyl of 4-etc., preferably comprises the aminoalkyl group with 1 to 4 carbon atom.
" acyl amino " is for having above-mentioned C 2-C 14The acyl amino of acyl group, it represents for example kharophen, propionamido, butyrylamino, valeryl amino, pivalyl amino, benzoyl-amido, phenylacetyl amino, hydrocinnamoyl amino, benzene butyryl radicals amino etc.
" alkoxyl group " is for having above-mentioned C 1-C 8The alkoxyl group of alkyl, it comprises for example methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy and constitutional isomer thereof, as isopropoxy, isobutoxy, sec-butoxy, tert.-butoxy, isopentyloxy, neopentyl oxygen, uncle's pentyloxy etc., preferably has the alkoxyl group of 1 to 4 carbon atom.
" cycloalkyloxy " is for having above-mentioned C 3-C 8The cycloalkyloxy of cycloalkyl, it comprises and for example encircles propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc., preferably comprises the cycloalkyloxy of the cycloalkyl with 3 to 6 carbon atoms.
" phenoxy group " is meant randomly have 1 to 5 substituent phenoxy group on phenyl, and is not specifically limited for the position of substitution.
" phenyl alkoxyl group " is for having above-mentioned C 1-C 8The phenyl alkoxyl group of alkoxyl group, it comprises for example benzyloxy, 1-phenyl ethoxy, 2-phenyl ethoxy, 3-phenyl propoxy-, 4-phenyl butoxy, 1-methyl isophthalic acid-phenyl ethoxy, 1-methyl-2-phenyl ethoxy, 1-phenyl propoxy-, 2-phenyl propoxy-, 1-methyl isophthalic acid-phenyl propoxy-, 1-methyl-2-phenyl propoxy-, 1-methyl-3-phenyl propoxy-etc., preferably comprises the phenyl alkoxyl group of the alkoxyl group with 1 to 4 carbon atom.The phenyl alkoxyl group randomly has 1 to 5 substituting group on phenyl, and is not specifically limited for the position of substitution.
" aminoalkoxy " is by above-mentioned amino and C 1-C 8The aminoalkoxy that alkoxyl group is formed, it comprises for example amino methoxyl group, methylamino methoxyl group, dimethylamino ylmethoxy, 2-(dimethylamino) oxyethyl group, 3-(dimethylamino) propoxy-, 4-(dimethylamino) butoxy etc., preferably by the amino aminoalkoxy of forming with the alkoxyl group with 1 to 4 carbon atom of the uncle who comprises the alkyl with 1 to 4 carbon atom.
" alkoxyalkyl " is by above-mentioned C 1-C 8Alkoxyl group and C 1-C 8The alkoxyalkyl that alkyl is formed, it comprises for example methoxymethyl, ethoxyl methyl, 2-methoxy ethyl, propoxy-methyl, isopropoxy methyl etc., preferably the alkoxyalkyl of being made up of alkoxyl group with 1 to 4 carbon atom and the alkyl with 1 to 4 carbon atom.
" phenoxyalkyl " is by above-mentioned phenoxy group and C 1-C 8The phenoxyalkyl that alkyl is formed, it comprises for example phenoxymethyl, 2-phenoxy group ethyl, 3-phenoxy propyl etc., preferably comprises the phenoxyalkyl of the alkyl with 1 to 4 carbon atom.Phenoxyalkyl randomly has substituting group on phenyl, and is not specifically limited for the position that replaces.
" hydroxyalkyl " is for having above-mentioned C 1-C 8The hydroxyalkyl of alkyl, it comprises for example methylol, 2-hydroxyethyl, 3-hydroxypropyl etc., preferably comprises the hydroxyalkyl of the alkyl with 1 to 4 carbon atom.
" alkoxy carbonyl " is for having above-mentioned C 1-C 8The alkoxy carbonyl of alkoxyl group, it comprises for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, pentyloxy carbonyl, hexyloxy carbonyl and constitutional isomer thereof, as isopropoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, isopentyloxy carbonyl, neopentyl oxygen carbonyl, tert-pentyloxy carbonyl etc., preferred wherein alkoxyl group partly has the alkoxy carbonyl of 1 to 4 carbon atom.R 4Alkoxy carbonyl be preferably alkoxy carbonyl with 2 to 5 carbon atoms.
" phenyloxycarbonyl " for randomly to have 1 to 5 substituent phenyloxycarbonyl on phenyl, and be not specifically limited for the position of substitution.
" aminocarboxyl " is for having the list of comprising or two C 1-C 8The aminocarboxyl of the above-mentioned amino of the amino that alkyl replaces, it comprises for example aminocarboxyl, methylamino carbonyl, dimethylamino carbonyl, ethylamino carbonyl, diethylamino carbonyl, propyl group aminocarboxyl, dipropyl aminocarboxyl etc.
" alkylthio carbonyl " is for having above-mentioned C 1-C 6The alkylthio carbonyl of alkylthio, it comprises for example methylthio group carbonyl, ethylmercapto group carbonyl, rosickyite base carbonyl, butylthio carbonyl and constitutional isomer thereof, as iprotiazem base carbonyl, isobutyl sulfenyl carbonyl, secondary butylthio carbonyl, uncle's butylthio carbonyl etc., preferred wherein moieties has the alkylthio carbonyl of 1 to 3 carbon atom.
" carboxyalkyl " is for having above-mentioned C 1-C 8The carboxyalkyl of alkyl, it comprises for example carboxymethyl, propyloic, carboxylic propyl group etc., preferably comprises the carboxyalkyl of the alkyl with 1 to 4 carbon atom.
" cycloalkyloxy alkyl " is by above-mentioned C 3-C 8Cycloalkyloxy and C 1-C 8The cycloalkyloxy alkyl that alkyl is formed, it comprises and for example encircles propoxy-methyl, ring propoxy-ethyl, cyclobutoxy group methyl, cyclopentyloxy methyl, cyclohexyloxy methyl etc., preferably by the cycloalkyloxy with 3 to 6 carbon atoms with have the cycloalkyloxy alkyl that the alkyl of 1 to 4 carbon atom is formed.The cycloalkyloxy alkyl randomly has 1 to 3 substituting group on cycloalkyl, and is not specifically limited for the position of substitution.
" alkyl sulphinyl " is for having above-mentioned C 1-C 8The alkyl sulphinyl of alkyl, it comprises for example methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl, sec.-propyl sulfinyl etc., preferably comprises the alkyl sulphinyl of 1 to 5 carbon atom alkyl.Preferred R 4Alkyl sulphinyl be alkyl sulphinyl with 1 to 4 carbon atom.
" phenyl sulfinyl " is meant randomly have 1 to 5 substituent phenyl sulfinyl on phenyl, and is not specifically limited for the position of substitution.
" alkyl sulphonyl " is for having above-mentioned C 1-C 8The alkyl sulphonyl of alkyl, it comprises for example methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl etc., preferably comprises the alkyl sulphonyl of 1 to 5 carbon atom alkyl.Preferred R 4Alkyl sulphonyl be alkyl sulphonyl with 1 to 4 carbon atom.
" phenyl sulfonyl " is meant randomly have 1 to 5 substituent phenyl sulfonyl on phenyl, and is not specifically limited for the position of substitution.
" mercaptoalkyl " is for having above-mentioned C 1-C 8The mercaptoalkyl of alkyl, it comprises for example mercapto methyl, mercaptoethyl, sulfydryl propyl group etc., preferably comprises the mercaptoalkyl of 1 to 4 carbon atom alkyl.
" alkylthio alkyl " is by above-mentioned C 1-C 6Alkylthio and C 1-C 8The alkylthio alkyl that alkyl is formed, it comprises for example methylthiomethyl, methylmercaptoethyl, methylthio group propyl group, ethylmercapto group methyl, ethylmercapto group ethyl, ethylsuleenyl propyl etc., and preferred alkylthio alkyl is made up of alkylthio with 1 to 3 carbon atom and the alkyl with 1 to 4 carbon atom.
" aryl " for having the aryl of 6 to 14 carbon atoms, it comprises for example phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl etc.They can have 1 to 5 substituting group, and are not specifically limited for the position of substitution.
" aralkyl " is above-mentioned C wherein 1-C 8Alkyl is by above-mentioned C 6-C 14The aralkyl that aryl replaces, it comprises benzyl, 2-phenylethyl, 3-phenyl propyl, 1-menaphthyl, 2-menaphthyl etc.These can have 1 to 5 substituting group on aryl moiety, and are not specifically limited for the position of substitution.
" acyloxy ethanoyl " is for having above-mentioned C 2-C 14The acyloxy ethanoyl of acyl group, it comprises for example acetoxyl group ethanoyl, propionyloxy ethanoyl, butyryl acyloxy ethanoyl, benzoyloxy ethanoyl etc.
" acyloxy alkyl " is for having above-mentioned C 2-C 14Acyl group and C 1-C 8The acyloxy alkyl of alkyl, it comprises for example acetoxy-methyl, propionyloxy methyl, butyryl acyloxy methyl, benzoyloxy methyl, 2-acetoxyl group ethyl, 2-propionyloxy ethyl, 2-butyryl acyloxy ethyl, 2-benzoyloxy ethyl etc.
The substituting group that " randomly has substituent phenyl " is for example the following stated " substituting group ", and wherein substituent number is generally 1 to 5, preferred 1 to 3.Especially preferably have 1 or 2 substituent phenyl, and be not specifically limited for the position of substitution.
" aromatic heterocycle group " is for for example comprising 1 to 3 heteroatomic 5 or 6 membered aromatic heterocycle group that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it comprises that for example thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxadiazole base are (as 1,3,4-oxadiazole base 1,2,4-oxadiazole base etc.) etc.Aromatic heterocycle group can have 1 to 6 substituting group, and is not specifically limited for the position of substitution.
" randomly have substituent saturated or unsaturated 4 to 7 yuan of heterocycles " and comprise following group etc.:
Figure A0381903600231
R wherein 9Be hydrogen independently of one another; alkyl; acyl group; aralkyl; cycloalkyl; formyl radical; haloalkyl; aminoalkyl group; phenylalkyl; alkoxyalkyl; phenoxyalkyl; amidino groups; hydroxyalkyl; aminocarboxyl; the alkylthio carbonyl; carboxyalkyl; alkoxy carbonyl; phenyloxycarbonyl; alkyl sulphinyl; alkyl sulphonyl; phenyl sulfonyl; mercaptoalkyl; alkylthio alkyl; the acyloxy ethanoyl; the acyloxy alkyl; randomly has substituent aryl; randomly have substituent aromatic heterocycle group or randomly have substituent phenylalkyl.
" have substituent 3 to 7 yuan of saturated carbon rings " and comprise following group etc.:
R wherein 10For alkyl, acyl group, aralkyl, cycloalkyl, formyl radical, haloalkyl, aminoalkyl group, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarboxyl, alkylthio carbonyl, carboxyalkyl, alkyl sulphinyl, alkyl sulphonyl, phenyl sulfonyl, mercaptoalkyl, alkylthio alkyl, acyloxy ethanoyl, acyloxy alkyl, randomly have substituent aryl, randomly have substituent aromatic heterocycle group or randomly have substituent phenylalkyl and a R 10 'Be hydrogen; alkyl; acyl group; aralkyl; cycloalkyl; formyl radical; haloalkyl; aminoalkyl group; alkoxyalkyl; phenylalkyl; phenoxyalkyl; amino; hydroxyalkyl; aminocarboxyl; the alkylthio carbonyl; carboxyalkyl; alkyl sulphinyl; alkyl sulphonyl; phenyl sulfonyl; mercaptoalkyl; alkylthio alkyl; the acyloxy ethanoyl; the acyloxy alkyl; randomly has substituent aryl; randomly has substituent aromatic heterocycle group; or randomly has a substituent phenylalkyl.
Substituting group in " randomly having substituent aromatic heterocycle group " those " substituting groups " for mentioning below for example, wherein substituent number is generally 1 to 6, and is not specifically limited for the position that replaces.
" phenylalkyl " is by phenyl and above-mentioned C 1-C 8The phenylalkyl that alkyl is formed, it comprises for example benzyl, 2-phenylethyl, 3-phenyl propyl, 4-phenyl butyl, 1-phenylethyl, 1-methyl-2-phenylethyl, 1-phenyl propyl, 2-phenyl propyl, 1-methyl isophthalic acid-phenyl propyl, 1-methyl-2-phenyl propyl, 1-methyl-3-phenyl propyl etc., preferably the phenylalkyl of being made up of phenyl and the alkyl with 1 to 4 carbon atom.
Substituent kind in " randomly having substituent phenylalkyl " and number are identical with in above-mentioned " aromatic heterocycle group " those, and are not specifically limited for the position of substitution.
" dialkyl group phosphinyl " is for having above-mentioned C 1-C 8The dialkyl group phosphinyl of alkyl, it comprises for example dimethyl oxygen phosphino-, diethyl phosphinyl, dipropyl phosphinyl etc., preferably comprises the dialkyl group phosphinyl of 1 to 4 carbon atom alkyl.
" dialkyl phosphine acyl group " is for having above-mentioned C 1-C 8The dialkyl phosphine acyl group of alkyl, it comprises for example dimethyl phosphine acyl group, diethyl phosphonyl, dipropyl phosphono etc., preferably comprises the dialkyl phosphine acyl group of 1 to 4 carbon atom alkyl.
In this manual, " substituting group " comprises alkyl, acyl group, cycloalkyl, phenyl, aromatic heterocycle group, phenylalkyl, hydroxyl, carboxyl, thiol, halogen, amino, formyl radical, formamyl, cyano group, nitro, alkylthio, haloalkyl, aminoalkyl group, acyl amino, alkoxyl group, cycloalkyloxy, phenoxy group, phenyl alkoxyl group, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxy carbonyl, alkyl sulphinyl, aminocarboxyl, alkylthio carbonyl etc.
" randomly comprise heteroatomic ring " for randomly comprising 1 to 3 heteroatomic 5 or 6 yuan of carbocyclic ring that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, the ring of special preferred package sulfur atom-containing.This ring can be replaced by one or more above-mentioned substituting groups or oxo group.Be not specifically limited for the position of substitution.This ring is by the R in the formula (I) 2And R 3Connected carbon atom forms together.By forming this ring, in the compound shown in the formula (I), form volution.Above-mentioned ring can condense with phenyl ring, and described phenyl ring randomly has substituting group and is not specifically limited for the position of substitution.This ring for example comprises 2,3-dihydrobenzo [b] thiophene, 2,3-dihydrobenzo [b] thiophene-1-oxide compound etc.
" derived from the group of phenyl ring, the saturated or unsaturated carbocyclic of described phenyl ring and 5 or 6 yuan condenses " expression is derived from naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-naphthane, 2, the group of 3-indane etc.This wherein, preferred naphthyl such as naphthalene-1-base etc. and 2,3-indanyl are as 2,3-indane-4-base etc.This group can have 1 to 4 substituting group, and is not specifically limited for the position of substitution.
" derived from the group of phenyl ring, described phenyl ring with comprise 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic and condense " comprises following group etc.:
Figure A0381903600261
This wherein, preferred 2,1,3-Ben Bing oxadiazole, dihydrobenzo [b] furans, methylenedioxyphenyl and 3,4-dihydro-2H-chromene, preferred especially 2,1,3-Ben Bing oxadiazole-4-base, 2,3-dihydrobenzo [b] furans-7-base, 2,3-(methylene-dioxy) phenyl and 3,4-dihydro-2H-chromene-8-base.This group can have 1 to 3 substituting group, and is not specifically limited for substituent position.
" derived from the group that comprises 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, described carbocyclic ring and phenyl ring condense " comprises following group etc.:
Figure A0381903600262
This group can have 1 to 5 substituting group, and is not specifically limited for the position of substitution.
" alkyl-carbonyl alkyl " is for example C 1-C 4-alkyl-carbonyl-C 1-C 4Alkyl, it comprises for example methyl carbonyl methyl, ethyl carbonyl methyl, carbonyl propyl ylmethyl, butyl carbonyl methyl etc.
" aromatic yl aminocarbonyl " is C 6-C 10Aryl-aminocarboxyl, it comprises for example phenyl amino carbonyl, naphthyl aminocarboxyl etc.Aromatic yl aminocarbonyl randomly has 1 to 3 substituting group on aryl, and is not specifically limited for the position of substitution.
" aryl alkyl amino carbonyl " is C 7-C 14Aralkyl-aminocarboxyl, it comprises for example benzylamino carbonyl etc.The aryl alkyl amino carbonyl randomly has 1 to 3 substituting group on aryl, and is not specifically limited for the position of substitution.
" saturated or unsaturated 4 to 7 yuan of cyclosubstituted alkyl of involved 1 or 2 nitrogen-atoms, described 4 to 7 yuan of rings randomly have a substituting group " are meant the C that is replaced by " saturated or unsaturated 4 to the 7 yuan of rings that comprise 1 or 2 nitrogen-atoms " 1-C 8Alkyl, described saturated or unsaturated 4 to 7 yuan of rings such as pyrroles, pyrroline, pyrazoles, pyridine, piperidines, piperazine, high piperazine (homopiperazine) or morpholine etc., and it randomly has substituting group such as C 1-C 4Alkyl, C 6-C 10Aryl (as phenyl, naphthyl etc.), " saturated or unsaturated 4 to 7 yuan of cyclosubstituted alkyl of involved 1 or 2 nitrogen-atoms, described ring randomly has a substituting group " for example comprise (4-phenylpiperazine-1-yl) methyl, 2-(4-phenylpiperazine-1-yl) ethyl, 3-(4-phenylpiperazine-1-yl) propyl group, (4-(naphthalene-1-yl) piperazine-1-yl) methyl, 2-(4-(naphthalene-1-yl) piperazine-1-yl) ethyl, (the high piperazine of 4-methyl-1-yl) methyl etc.
" phenyl amino alkyl " is phenyl amino-C 1-C 4Alkyl, it comprises for example phenyl amino methyl, 2-phenyl amino ethyl, 3-phenyl amino propyl group, 4-phenyl amino butyl etc.The phenyl amino alkyl randomly has 1 to 3 substituting group on phenyl, and is not specifically limited for the position of substitution.
" phenylalkyl carbonyl " is phenyl-C 1-C 4Alkyl-carbonyl, it comprises for example benzyloxycarbonyl group, 2-phenylethyl carbonyl, 3-phenyl propyl carbonyl, 4-phenyl butyl carbonyl etc.The phenylalkyl carbonyl randomly has 1 to 3 substituting group on phenyl, and is not specifically limited for the position of substitution.
R 11In " alkyl " be C 1-C 4Alkyl, it comprises for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl etc.
R 11In " alkyl sulphonyl " be C 1-C 4Alkyl-alkylsulfonyl, it comprises for example methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base etc.
R 11In " phenyl sulfonyl " on phenyl, randomly to have 1 to 3 substituent phenyl sulfonyl, and be not specifically limited for the position of substitution.
R 11In " phenylalkyl alkylsulfonyl " be phenyl-C 1-C 4Alkyl-alkylsulfonyl, it comprises for example benzyl alkylsulfonyl, 2-phenylethyl alkylsulfonyl, 3-phenyl propyl alkylsulfonyl, 4-phenyl butyl alkylsulfonyl etc.The phenylalkyl alkylsulfonyl randomly has 1 to 3 substituting group on phenyl, and is not specifically limited for the position of substitution.
R 11In " alkyl sulphinyl " be C 1-C 4Alkyl-sulfinyl, it comprises for example methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl etc.
R 11In " phenyl sulfinyl " on phenyl, randomly to have 1 to 3 substituent phenyl sulfinyl, and be not specifically limited for the position of substitution.
R 11In " phenylalkyl sulfinyl " be phenyl-C 1-C 4Alkyl-sulfinyl, it comprises for example benzyl sulfinyl, 2-phenylethyl sulfinyl, 3-phenyl propyl sulfinyl, 4-phenyl butyl sulfinyl etc.The phenylalkyl sulfinyl randomly has 1 to 3 substituting group on phenyl, and is not specifically limited for the position of substitution.
R 11In " alkoxy carbonyl " be C 1-C 4Alkoxy carbonyl, it comprises for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.
R 11In " phenyl alkoxy carbonyl " be phenyl-C 1-C 4It comprises for example benzyloxycarbonyl, 2-phenyl ethoxy carbonyl, 3-phenyl propoxycarbonyl, 4-phenyl butoxy carbonyl etc. alkoxy carbonyl.The phenyl alkoxy carbonyl randomly has 1 to 3 substituting group on phenyl, and is not specifically limited for the position of substitution.
R 11In " alkyl-carbonyl " be C 1-C 4Alkyl-carbonyl, it comprises for example ethanoyl, propionyl, butyl carbonyl etc.
R 11In " phenylcarbonyl group " on phenyl, randomly to have 1 to 3 substituent phenylcarbonyl group, and be not specifically limited for the position of substitution.
R 11In " phenylalkyl carbonyl " be phenyl-C 1-C 4Alkyl-carbonyl, it comprises for example benzyloxycarbonyl group, 2-phenylethyl carbonyl, 3-phenyl propyl carbonyl, 4-phenyl butyl carbonyl etc.The phenylalkyl carbonyl randomly has 1 to 3 substituting group on phenyl, and is not specifically limited for the position of substitution.
R 11In " phenyloxycarbonyl " be meant on phenyl, randomly to have 1 to 3 substituent phenyloxycarbonyl, and be not specifically limited for the position of substitution.
R 12In " alkyl " be C 1-C 4Alkyl, it comprises for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl etc.
Can use pharmaceutically acceptable acid to be converted into acid salt, and the present invention also comprise this acid salt by the compound of formula of the present invention (I) expression.This acid salt for example comprises the salt that forms with mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid etc.; The salt that forms with organic acid such as formic acid, acetate, trifluoroacetic acid, propionic acid, oxalic acid, propanedioic acid, Succinic Acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, citric acid, tartrate, methylsulfonic acid, Phenylsulfonic acid, tosic acid, L-glutamic acid etc.When having unsymmetrical carbon, can there be its optical isomer and racemoid thereof, all these comprises in the present invention.
For compound of the present invention (I), as shown below, can be according to J.Chem.Soc., Perkin Trans.1, the synthetic wherein R of method that describes in 947 (1996) etc. 0Compound for hydrogen.
First preparation method
R wherein 2, R 3, R 4And R 5As above definition.
In the presence of ammonium acetate, make the plum forests moral human relations acid (2 shown in the formula (VI), 2-dimethyl-1,3-dioxane-4,6-diketone) and carbonyl derivative shown in the formula (VII) and the reaction of the carbonyl derivative shown in the formula (VIII), obtain the amide derivatives shown in the formula (IX).Be reflected at reaction to carrying out under inert carboxylic acid solvent's the existence.As solvent, use formic acid, acetate, propionic acid, butyric acid, valeric acid etc. usually.Be reflected under the arbitrary temp and carry out, for example from 0 ℃ to 200 ℃, preferably from 60 ℃ to 100 ℃.
R wherein 2, R 3, R 4And R 5As above definition.
In the presence of dimethyl formamide and phosphoryl chloride, make the amide derivatives reaction shown in the formula (IX) that obtains, obtain the formyl radical derivative shown in the formula (X).Be reflected at reaction to carrying out under the existence of inert solvent.As solvent, use ether, tetrahydrofuran (THF), dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, methylene dichloride, dimethyl formamide, methyl-sulphoxide etc. usually.Be reflected under the arbitrary temp and carry out, for example from 0 ℃ to 200 ℃, preferably from 0 ℃ to 60 ℃.
R wherein 1, R 2, R 3, R 4And R 5As above definition.
Can prepare compound of the present invention (I) by in the presence of hydrazine, making formula (X) the formyl radical derivatives reaction that obtains.Be reflected at reaction to carrying out under the existence of inert solvent.As solvent, use ether, tetrahydrofuran (THF), dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, methylene dichloride, dimethyl formamide, methyl-sulphoxide, pyridine, alcohol etc. usually.Be reflected under the arbitrary temp and carry out, for example from 0 ℃ to 200 ℃, preferably from 60 ℃ to 100 ℃.
Can be as the carbonyl derivative shown in the formula (VII) of raw material according to J.Org.Chem., 46,783 (1981), Eur.J.Med.Chem., 31,3 (1996) and TetrahedronLett., method described in 24,5023 (1983) is synthetic.Carbonyl derivative shown in the formula (VIII) can be according to Synthesis, and 290 (1993) described methods are synthetic.
Second preparation method
R wherein 1, R 2, R 3, R 4And R 5As above definition.
Can be by making the carbonyl derivative prepared in reaction compound of the present invention (I) shown in carbonyl derivative shown in amino-pyrazol shown in the formula (XI) and the formula (VII) and the formula (VIII).Be reflected at reaction to carrying out under the existence of inert solvent.As solvent, use ether, tetrahydrofuran (THF), dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, methylene dichloride, dimethyl formamide, methyl-sulphoxide, alcohol etc. usually.Be reflected under the arbitrary temp and carry out, for example from 0 ℃ to 200 ℃, preferably from 60 ℃ to 100 ℃.
For compound of the present invention (I), can following synthetic wherein R 0For being different from the substituent compound of hydrogen.
The 3rd preparation method
R wherein 0, R 1, R 2, R 3, R 4And R 5As above definition, X represents halogen, and condition is R 0Not hydrogen.
Can be by making the prepared in reaction compound of the present invention (I) in the presence of alkali of the halogenide shown in dihydro-pyrazolo pyridine derivate shown in the formula (XI) and the formula (XII).Suitable alkali comprises for example triethylamine, di-isopropyl ethyl ammonia, 4-dimethylaminopyridine etc.Be reflected at reaction to carrying out under the existence of inert solvent.As solvent, use not hydroxyl-bearing solvent such as tetrahydrofuran (THF), ethyl acetate, benzene, toluene, chloroform, methylene dichloride, dimethyl formamide, methylimidazole alkane ketone etc. usually.Be reflected under the arbitrary temp and carry out, for example from-10 ℃ to 200 ℃, preferably from 0 ℃ to 100 ℃.
The 4th preparation method
R wherein 0, R 1, R 2, R 3, R 4And R 5As above definition, condition is R 0Not hydrogen.
Can be by making acid anhydride shown in dihydro-pyrazolo pyridine derivate shown in the formula (XI) and the formula (XIII) such as diacetyl oxide prepared in reaction compound of the present invention (I) in the presence of alkali.Suitable alkali comprises for example triethylamine, pyridine, 4-dimethylaminopyridine etc.Be reflected at reaction to carrying out under the existence of inert solvent.As solvent, use not hydroxyl-bearing solvent usually, as tetrahydrofuran (THF), ethyl acetate, benzene, toluene, chloroform, methylene dichloride, dimethyl formamide, methylimidazole alkane ketone, pyridine etc.Be reflected under the arbitrary temp and carry out, for example from-10 ℃ to 200 ℃, preferably from 0 ℃ to 100 ℃.
It should be appreciated by those skilled in the art that and to change above-mentioned preparation method according to required compound.
So the compound of the present invention (I) of preparation can be used as the separated and purifying of free compound or its salt.Chemical process by routine as extraction, concentrate, evaporation, crystallization, filtration, recrystallization, plurality of color spectrometry etc. separate and purifying.When the purified product that so obtains is racemoid, fractional recrystallization that can be by for example adopting optical activity acid or make it separate required optically active compound by the post of filling with the optics active carrier.The present invention also comprises optically active compound.The compound of the present invention that obtains by aforesaid method has weak inhibition activity to kinases such as CaM kinases II, map kinase, casein kinase, PKA, PKC and the ROCK that is different from GSK-3 β, but GSK-3 β is had strong inhibition activity.Therefore, compound of the present invention has optionally, and GSK-3 β suppresses active, and can be used as and have the little medicine of side effect, be used for diabetes, diabetic complication, nerve degeneration disease (Alzheimer, the ischemic cerebral vascular disorder, Down's syndrome, because the cerebral ischemia that brain amyloid blood vessel disease causes, stein-leventhal syndrome, subacute sclerosing panencephalitis Parkinson neurological dysfunction, Parkinson's neurological dysfunction after the encephalitis, boxer's encephalopathic, Guam type Parkinson chronic brain syndrome, thunder dimension corpusculum disease, Pick's disease, the sex change of cortex Basal ganglia, volume temporal lobe type dementia, the AIDS encephalopathic, Huntington's disease, with manic depressive psychosis etc.), alopecia, mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T cell or B cell leukemia, with several viral-induced tumours.In addition, compound of the present invention can be used as immunostimulant.
Use carrier, vehicle and other additive preparation that is generally used for preparation to comprise compound or its salt of the present invention as formulations of active ingredients.Formulation carrier and vehicle can be solid or liquid, and it comprises for example lactose, Magnesium Stearate, starch such as W-Gum, talcum, gel, agar, pectin, Sudan Gum-arabic, sweet oil, sesame oil, theobroma oil, ethylene glycol and other normally used material.Administration can be the oral administration of tablet, pill, capsule, granule, powder agent, solution etc.; Or parenteral drug administration by injection (intravenous injection, intramuscularly etc.), suppository, through skin medicament etc.Suitably determine dosage though can consider symptom, age and the sex etc. of administration object according to every kind of situation, it typically is grownup 1-1 every day, 000mg, preferred every day, 50-200mg arrived the several times oral administration once a day; Or be grownup 1-500mg every day, arrive the several times intravenous administration once a day; Or 1 to 24 hour every day intravenous administration continuously.
Embodiment
Hereinafter, describe the present invention in detail based on embodiment, example of formulations and test example.Scope of the present invention is not limited to these embodiment.
Embodiment 1
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl-piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
In the THF of 4-piperidine ethyl formate (10.0g) (200mL) solution, adding triethylamine (7.8g), 4-dimethylaminopyridine (0.8g) and two dimethyl dicarbonate butyl esters (15.3g) under 0 ℃, and stirring the mixture one hour.With the ethyl acetate extraction mixture and remove solvent under reduced pressure, obtain N-Boc-piperidines 4-ethyl formate (16.3g), be colorless oil.In the THF of acetonitrile (3.2g) (300mL) solution, adding n-Butyl Lithium (44mmol) under-78 ℃, and stirring three hours.Add N-Boc-piperidines 4-ethyl formate (16.3g) then, and stirred the mixture one hour.Behind hcl acidifying, use the ethyl acetate extraction compound, remove under reduced pressure solvent and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (5: 1)) purifying resistates, obtain 1-(N-Boc-piperidin-4-yl)-2-cyano group ethane-1-ketone (11.6g), be colorless oil.With 2,1, acetonitrile (10mL) vlil of 3-Ben Bing oxadiazole-4-aldehyde (1.0g), 3-amino-pyrazol (0.6g) and 2-(N-Boc-piperidin-4-yl)-1-cyano group ethane-2-ketone (1.7g) is spent the night.With the reaction mixture cool to room temperature, and the crystal of filtration collecting precipitation, obtain title compound (2.0g), be clear crystal.
MP：226℃。
Ultimate analysis, calculated value: C 23H 25N 7O 3: C, 61.73; H, 5.63; N, 21.97.
Discovery value: C, 61.45; H, 5.82; N, 21.61.
MS(EI)：447(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.42 (9H, m), 1.59-1.62 (2H, m), 1.89-1.92 (2H, m), and 2.62-2.86 (3H, m), 4.05-4.08 (2H, m), 5.40 (1H, s), 7.26 (1H, s), 7.41 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.81 (1H, brs), 12.24 (1H, brs).
Embodiment 2
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
Under 0 ℃, with 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridines (1.7g) join in the trifluoroacetic acid (20mL), and stir the mixture one hour.Remove solvent under reduced pressure.After with the sodium bicarbonate alkalization, use the ethyl acetate extraction mixture.Remove solvent under reduced pressure and wash resistates, filter the crystal of collecting precipitation, obtain title compound (0.83g), be yellow crystals with acetonitrile.
MP：216℃。
MS(EI)：348(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.78-1.81 (2H, m), 2.07-2.11 (2H, m), 2.80-2.86 (3H, m), and 3.27-3.30 (3H, m), 5.39 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.86 (1H, brs), 12.24 (1H, brs).
Embodiment 3
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4 Evil-b] pyridine
At room temperature, to 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] add 37% formaldehyde (0.18g), sodium cyanoborohydride (0.19g) and acetate (0.36g) in MeOH (200mL) solution of pyridine (0.7g), and stir the mixture and spend the night.After with the sodium bicarbonate alkalization, use the ethyl acetate extraction mixture.Remove solvent under reduced pressure and wash resistates, filter the crystal of collecting precipitation, obtain title compound (0.32g), be yellow crystals with acetonitrile.
MP：＞270℃。
MS(EI)：361(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.57-1.60 (2H, m), 1.82-1.88 (2H, m), 2.01-2.06 (2H, m), 2.15 (3H, s), 2.58-2.61 (1H, m), 2.85-2.88 (2H, m), 5.40 (1H, s), 7.26 (1H, s), 7.40 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.91 (1H, d, J=9.0Hz), 9.76 (1H, brs), 12.17 (1H, brs).
Embodiment 4
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl-piperidines-3-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from nipecotic acid ethyl ester, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：229℃。
Ultimate analysis, calculated value: C 23H 25N 7O 3: C, 61.73; H, 5.63; N, 21.97.
Discovery value: C, 61.56; H, 5.66; N, 21.67.
MS(EI)：447(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.32-1.40 (2H, m), 1.39 (9H, s), 1.69-1.78 (2H, m), and 2.69-2.76 (2H, m), 3.16-3.19 (1H, m), 3.92-3.95 (2H, m), 5.42 (1H, s), 7.28 (1H, s), 7.42 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.87 (1H, brs), 12.21 (1H, brs).
Embodiment 5
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidines-3-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl piperidines-3-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：202℃。
Ultimate analysis, calculated value: C 18H 17N 7O:C, 62.24; H, 4.93; N, 28.23.
Discovery value: C, 61.97; H, 5.13; N, 27.89.
MS(EI)：347(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.42-1.45 (1H, m), 1.72-1.88 (3H, m), 2.66-2.84 (5H, m), and 2.94-3.02 (1H, m), 5.38 (1H, s), 7.26 (1H, s), 7.39 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.91 (1H, d, J=9.0Hz), 10.39 (1H, brs), 12.17 (1H, brs).
Embodiment 6
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-3-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidines-3-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：228℃。
MS(EI)：361(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.53-1.76 (4H, m), 2.21 (3H, s), 2.47-2.55 (4H, m), and 2.93-2.96 (1H, m), 5.38 (1H, s), 7.27 (1H, s), 7.40 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 10.16 (1H, brs), 12.20 (1H, brs).
Embodiment 7
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl-piperidines-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from Pipecolic Acid ethyl ester, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：447(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.27 and 1.32 (9H, s), 1.42-1.97 (6H, m), 3.30-3.33 (1H, m), 3.53-3.61 (1H, m), 4.47-4.50 (1H, m), 5.37 and 5.39 (1H, s), 7.26 and 7.29 (1H, s), 7.38-7.44 (1H, m), 7.54-7.60 (1H, m), 7.90-7.93 (1H, m), 9.63 and 9.73 (1H, brs), 12.16 (1H, brs).
Embodiment 8
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidines-2-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl piperidines-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：347(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.27-1.88 (6H, m), 3.12-3.16 (1H, m), 4.12-4.15 (1H, m), 4.48-4.58 (1H, m), 5.64 and 5.66 (1H, s), 7.22-7.28 (1H, m), 7.45-7.52 (2H, m), 7.87-7.90 (1H, m), 8.26 (1H, br), 10.92 and 10.94 (1H, brs), 12.35 (1H, brs).
Embodiment 9
4-(2,1,3-benzene and oxadiazole-4-yl)-6-(4-tert-butoxycarbonyl morpholine-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from morpholine-2-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：449(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.36 and 1.40 (9H, s), 2.95-3.06 (2H, m), 3.50-3.52 (1H, m), 3.75-3.95 (3H, m), 4.34-4.40 (1H, m), 5.44 and 5.48 (1H, s), 7.26 and 7.30 (1H, s), 7.42-7.45 (1H, m), 7.57-7.62 (1H, m), 7.93-7.96 (1H, m), 9.84 and 9.92 (1H, brs), 12.23 (1H, brs).
Embodiment 10
4-(2,1,3-benzene and oxadiazole-4-yl)-5-cyano group-4, and 7-dihydro-6-(morpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, (4-tert-butoxycarbonyl morpholine-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound from 4-(2,1,3-benzene and oxadiazole-4-yl)-6-.
MS(EI)：349(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.64-2.95 (4H, m), 3.53 (1H, br), 3.55-3.57 (1H, m), 3.82-3.85 (1H, m), 4.41-4.45 (1H, m), 5.43 and 5.44 (1H, s), 7.24 and 7.28 (1H, s), 7.38-7.41 (1H, m), 7.56-7.61 (1H, m), 7.91-7.94 (1H, m), 9.74 and 9.76 (1H, brs), 12.19 (1H, brs).
Embodiment 11
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-benzene and oxadiazole-4-yl)-5-cyano group-4, (morpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound to 7-dihydro-6-.
MP：143℃。
MS(EI)：363(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.21 (3H, s), 2.19-2.30 (2H, m), 2.60-2.69 (2H, m), and 3.60-3.62 (1H, m), 3.88-3.92 (1H, m), 4.48-4.50 (1H, m), 5.44 (1H, s), 7.28 (1H, s), 7.39 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.80 (1H, brs), 12.20 (1H, brs).
Embodiment 12
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 1,2,3,6-tetrahydropyridine-4-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：222℃。
MS(EI)：445(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.41 (9H, s), 2.35-2.39 (2H, m), 3.46-3.48 (2H, m), 3.90-3.92 (2H, m), 5.43 (1H, s), 6.06-6.09 (1H, m), 7.28 (1H, s), 7.45 (1H, d, J=6.6Hz), 7.60 (1H, dd, J=9.0Hz and 6.6Hz), 7.93 (1H, d, J=9.0Hz), 9.94 (1H, brs), 12.19 (1H, brs).
Embodiment 13
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：180℃。
MS(EI)：345(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.26-2.32 (2H, m), 2.87-2.90 (2H, m), 3.30-3.36 (3H, m), 5.42 (1H, s), 6.09-6.10 (1H, m), 7.30 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.60 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.87 (1H, brs), 12.18 (1H, brs).
Embodiment 14
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：218℃。
MS(EI)：359(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.24 (3H, s), 2.35-2.42 (2H, m), 2.91-2.93 (2H, m), 3.31-3.33 (2H, m), 5.42 (1H, s), 6.04-6.05 (1H, m), 7.27 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.87 (1H, brs), 12.17 (1H, brs).
Embodiment 15
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(2-(N-tert-butoxycarbonyl-N-methyl-amino) ethyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Under 0 ℃, stirred the mixture four hours to the THF of 3-alanine carbethoxy hydrochloride (19g) (600mL) solution adding triethylamine (44mL), dimethyl aminopyridine (1.5g) and two dimethyl dicarbonate butyl esters (30g) and at 40 ℃.With the ethyl acetate extraction mixture and remove solvent under reduced pressure, obtain N-Boc-3-alanine ethyl ester (16.7g), be colorless oil.In the THF of N-Boc-3-alanine ethyl ester (5.0g) (50mL) solution, adding t-BuOK (2.8g) and methyl iodide (4.9g) under 0 ℃ and at room temperature stirring the mixture one hour.With the ethyl acetate extraction mixture and remove solvent under reduced pressure, obtain 3-(N-Boc-N-methylamino) ethyl propionate (4.3g), be colorless oil.Then, with the method identical with embodiment 1, from 3-(N-Boc-N-methylamino) ethyl propionate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：240℃。
Ultimate analysis, calculated value: C 21H 23N 7O 3: C, 59.85; H, 5.50; N, 23.26.
Discovery value: C, 59.69; H, 5.45; N, 23.22.
MS(EI)：421(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.26 and 2.32 (9H, s), 2.62-2.63 (2H, m), 2.81 (3H, s), and 3.48-3.55 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.40 (1H, d, J=6.6Hz), 7.57 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 10.07 (1H, brs), 12.15 (1H, brs).
Embodiment 16
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(2-(N-methylamino) ethyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(2-(N-tert-butoxycarbonyl-N-methylamino) ethyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：174℃。
MS(EI)：321(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.29 (3H, s), 2.50-2.78 (4H, m), 3.31 (3H, br), 5.39 (1H, s), 7.24 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.91 (1H, d, J=9.0Hz).
Embodiment 17
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(2-(N-tert-butoxycarbonyl amino) ethyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 3-alanine carbethoxy hydrochloride, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：231℃。
Ultimate analysis, calculated value: C 20H 21N 7O 3: C, 58.96; H, 5.20; N, 24.06.
Discovery value: C, 58.81; H, 5.19; N, 23.82.
MS(EI)：407(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.33 (9H, s), 2.55-2.60 (2H, m), 3.23-3.33 (2H, m), 5.41 (1H, s), 6.81 (1H, brs), 7.25 (1H, s), 7.44 (1H, d, J=6.6Hz), 7.57 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.94 (1H, brs), 12.14 (1H, brs).
Embodiment 18
6-(2-amino-ethyl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(2-(N-tert-butoxycarbonyl amino) ethyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：307(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.50-2.54 (2H, m), 2.88 (2H, t, J=7.3Hz), 3.35 (4H, br), 5.40 (1H, s), 7.25 (1H, s), 7.44 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz).
Embodiment 19
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(2-(N, N-dimethylamino) ethyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(2-(N-methylamino) ethyl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：215℃。
MS(EI)：335(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.19 (6H, s), 2.45-2.62 (4H, m), 5.41 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 10.04 (1H, brs), 12.16 (1H, brs).
Embodiment 20
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-((N-tert-butoxycarbonyl-N-methyl-amino) methyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 15, from glycine ethyl ester hydrochloride, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：207℃。
Ultimate analysis, calculated value: C 20H 21N 7O 3: C, 58.96; H, 5.20; N, 24.06.
Discovery value: C, 58.80; H, 5.12; N, 24.38.
MS(EI)：407(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.33 and 1.39 (9H, s), 2.81 (3H, s), 4.13-4.20 (2H, m), 5.42 (1H, s), 7.29 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.94 (1H, d, J=9.0Hz), 9.33 (1H, brs), 12.15 (1H, brs).
Embodiment 21
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-((N-methylamino) methyl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate
Under 0 ℃ with 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-((N-tert-butoxycarbonyl-N-methylamino) methyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (0.6g) joins in the trifluoroacetic acid (10mL), and stirred the mixture one hour.Remove solvent under reduced pressure and make resistates, filter the crystal of collecting precipitation, obtain title compound (0.1g), be yellow crystals from alcohol crystal.
MP：174℃。
MS(EI)：307(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 3.10 (3H, s), 4.51-4.68 (2H, m), 7.24 (1H, d, J=6.6Hz), 7.45 (1H, s), 7.52 (1H, dd, J=9.0Hz and 6.6Hz), 7.89 (1H, d, J=9.0Hz), 8.08-8.20 (2H, br), 10.81 (1H, brs), 12.41 (1H, brs).
Embodiment 22
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-(N-methylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 15 and then according to the method for embodiment 2, from 4-aminocyclohexane ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：375(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.32-1.35 (2H, m), 1.81-2.12 (6H, m), 2.57 (3H, s), and 2.65-2.69 (1H, m), 2.81-2.85 (1H, m), 5.39 (1H, s), 7.28 (1H, s), 7.41 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 8.54 (1H, br), 9.79 (1H, brs), 12.22 (1H, brs).
Embodiment 23
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-(N, N-dimethylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-(N-methylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：241℃。
MS(EI)：389(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.15-2.02 (9H, m), 2.15 and 2.21 (6H, s), 2.62-2.76 (1H, m), 5.38 and 5.43 (1H, s), 7.26 (1H, s), 7.38-7.44 (1H, m), 7.56-7.62 (1H, m), 7.90-7.96 (1H, m), 9.74 (1H, brs), 12.18 (1H, brs).
Embodiment 24
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-Phenylpiperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
At room temperature to the CH of 4-piperidine ethyl formate (8.9g) 2Cl 2(500mL) add triphenyl bismuth (25g) and venus crystals (II) in the solution (10.3g), stir the mixture and spend the night.Use CH after filtering 2Cl 2The extraction mixture.Remove under reduced pressure solvent and by silica gel column chromatography (eluent: normal hexane-ethyl acetate (10: 1)) purifying resistates, obtain 1-Phenylpiperidine-4-ethyl formate (8.6g), be clear crystal.In the THF of acetonitrile (1.9g) (200mL) solution, adding n-Butyl Lithium (41mmol) under-78 ℃.Add 1-Phenylpiperidine-4-ethyl formate (8.6g) then and stirred the mixture one hour.After with hcl acidifying, use the ethyl acetate extraction mixture.Remove under reduced pressure solvent and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (10: 1)) purifying resistates, obtain 1-(1-Phenylpiperidine-4-yl)-2-cyano group ethane-1-ketone (2.0g), be clear crystal.With 2,1, acetonitrile (10mL) vlil of 3-Ben Bing oxadiazole-4-aldehyde (0.3g), 3-amino-pyrazol (0.2g) and 1-(1-Phenylpiperidine-4-yl)-2-cyano group ethane-1-ketone (0.5g) is spent the night.With the reaction mixture cool to room temperature, and the crystal of filtration collecting precipitation, obtain title compound (0.6g), be clear crystal.
MS(FAB)：424(M ++1)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.73-1.76 (2H, m), 2.14-2.18 (2H, m), 2.62-2.66 (2H, m), 2.81-2.84 (1H, m), 3.80-3.84 (2H, m), 5.41 (1H, s), (6.75 1H, dd, J=7.3Hz and 7.2Hz), and 6.94-6.96 (2H, m), 7.18-7.27 (3H, m), 7.42 (1H, d, J=6.6Hz), (7.59 1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.81 (1H, brs), 12.17 (1H, brs).
Embodiment 25
6-(1-ethanoyl piperidin-4-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
In the THF of 4-piperidine ethyl formate (8.0g) (100mL) solution, adding triethylamine (5.7g), dimethyl aminopyridine (0.6g) and Acetyl Chloride 98Min. (4.4g) under 0 ℃, and stirring the mixture one hour.With the ethyl acetate extraction mixture and remove solvent under reduced pressure, obtain 1-ethanoyl piperidine-4-ethyl formate (10g), be colorless oil.In the THF of acetonitrile (2.5g) (300mL) solution, adding n-Butyl Lithium (57mmol) under-78 ℃.Add 1-ethanoyl piperidine-4-ethyl formate (10g) then, and stirred the mixture one hour.After hcl acidifying, use the ethyl acetate extraction mixture.Remove under reduced pressure solvent and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (10: 1)) purifying resistates, obtain 1-(1-ethanoyl piperidin-4-yl)-2-cyano group ethane-1-ketone (7.5g), be colorless oil.With 2,1, acetonitrile (10mL) vlil of 3-Ben Bing oxadiazole-4-aldehyde (0.3g), 3-amino-pyrazol (0.17g) and 1-(1-ethanoyl piperidin-4-yl)-2-cyano group ethane-1-ketone (0.4g) is spent the night.With the reaction mixture cool to room temperature, and the crystal of filtration collecting precipitation, obtain title compound (0.49g), be yellow crystals.
MP：248℃。
MS(FAB)：340(M ++1)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.62-1.64 (2H, m), 1.82-1.84 (1H, m), 2.00-2.02 (4H, m), 2.49-2.50 (1H, m), 2.94-3.07 (2H, m), 3.89-3.92 (1H, m), 4.48-4.51 (1H, m), 5.40 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J=6.6Hz), (7.59 1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.81 (1H, brs), 12.18 (1H, brs).
Embodiment 26
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-benzoyl piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from Benzoyl chloride, 4-piperidine ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：228℃。
MS(FAB)：452(M ++1)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.59-1.76(2H，m)，2.04-2.08(2H，m)，2.76-2.80(1H，m)，3.01-3.09(2H，m)，3.58-3.60(1H，m)，4.60-4.63(1H，m)，5.41(1H，s)，7.28(1H，s)，7.43-7.46(6H，m)，7.56-7.59(1H，m)，7.92(1H，d，J＝9.0Hz)，9.90(1H，brs)，12.21(1H，brs)。
Embodiment 27
6-(1-ethanoyl-1,2,3,6-tetrahydropyridine-4-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from Acetyl Chloride 98Min., 1,2,3,6-tetrahydropyridine-4-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：237℃。
MS(EI)：387(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.00 and 2.04 (3H, s), 2.46-2.49 (2H, m), 3.55-3.58 (2H, m), 4.00-4.06 (2H, m), 5.44 (1H, s), 6.10 (1H, s), 7.29 (1H, s), 7.45 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.93 (1H, d, J=9.0Hz), 9.94 (1H, brs), 12.17 (1H, brs).
Embodiment 28
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-(ethoxy carbonyl) piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from Vinyl chloroformate, 4-piperidine ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：419(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.19 (3H, t, J=7.3Hz), 1.61-1.63 (2H, m), 1.90-1.94 (2H, m), 2.84-2.88 (3H, m), 4.02-4.07 (4H, m), 5.40 (1H, s), 7.26 (1H, s), 7.41 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.80 (1H, brs), 12.17 (1H, brs).
Embodiment 29
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methylsulfonyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from methylsulfonyl chloride, 4-piperidine ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：243℃。
MS(EI)：425(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.73-1.76 (2H, m), 2.04-2.08 (2H, m), 2.74-2.78 (3H, m), 2.88 (3H, s), 3.66-3.69 (2H, m), 5.41 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.93 (1H, d, J=9.0Hz), 9.84 (1H, brs), 12.20 (1H, brs).
Embodiment 30
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-(N, N-dimethylamino carbonyl) piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from 1-chloro-N, dinethylformamide, 4-piperidine ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：418(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.61-1.63 (2H, m), 2.00-2.06 (2H, m), 2.65-2.67 (2H, m), 2.75 (6H, s), 2.81-2.85 (1H, m), 3.64-3.67 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.41 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.86 (1H, brs), 12.18 (1H, brs).
Embodiment 31
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-amidino groups piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
At room temperature to 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] add diisopropyl ethyl amine (4.2g) and 1H-pyrazoles-1-amidine hydrochloride (0.96g) in MeOH (30mL) solution of pyridine (1.5g), and stir the mixture and spend the night.Filter the crystal of collecting precipitation, obtain title compound (1.0g), be yellow crystals.
MP：＞270℃。
MS(EI)：389(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.53-1.56 (2H, m), 1.86-1.91 (2H, m), 2.47-2.50 (2H, m), and 2.71-2.77 (1H, m), 3.00-3.03 (2H, m), 3.32-3.36 (3H, br), 5.39 (1H, s), 7.26 (1H, s), 7.39 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.91 (1H, d, J=9.0Hz), 9.79 (1H, brs), 12.21 (1H, brs).
Embodiment 32
6-(1-ethanoyl piperidines-3-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from Acetyl Chloride 98Min., nipecotic acid ethyl ester, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：219℃。
Ultimate analysis, calculated value: C 20H 19N 7O 2: C, 61.69; H, 4.92; N, 25.18.
Discovery value: C, 61.36; H, 4.90; N, 25.12.
MS(EI)：389(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.25-1.49 (1H, m), 1.74-1.78 (2H, m), 2.00 (3H, s), and 2.01-2.04 (1H, m), 2.49-2.98 (3H, m), 3.78-3.81 (1H, m), 4.37-4.40 (1H, m), 5.29 and 5.42 (1H, s), 7.28 (1H, s), 7.41-7.48 (1H, m), 7.58-7.62 (1H, m), 7.92-7.95 (1H, m), 9.90 (1H, brs), 12.21 (1H, brs).
Embodiment 33
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-ethyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine and acetaldehyde prepare title compound.
MP：231℃。
MS(EI)：375(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.99 (3H, t, J=7.3Hz), 1.60-1.63 (2H, m), 1.85-1.88 (2H, m), and 2.00-2.04 (2H, m), 2.31-2.34 (2H, m), 2.64-2.66 (1H, m), 2.97-3.00 (2H, m), 5.39 (1H, s), 7.26 (1H, s), 7.40 (1H, d, J=6.6Hz), (7.58 1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.75 (1H, brs), 12.18 (1H, brs).
Embodiment 34
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-propyl group piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine and propionic aldehyde prepare title compound.
MP：246℃。
Ultimate analysis, calculated value: C 21H 23N 7O:C, 64.76; H, 5.95; N, 25.18.
Discovery value: C, 64.23; H, 5.87; N, 24.86.
MS(EI)：389(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.84 (3H, t, J=7.3Hz), 1.40-1.45 (2H, m), 1.59-1.62 (2H, m), and 1.82-1.86 (2H, m), 2.00-2.05 (2H, m), 2.21 (2H, t, J=7.3Hz), 2.62-2.65 (1H, m), 2.94-2.97 (2H, m), 5.39 (1H, s), 7.26 (1H, s), 7.40 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.91 (1H, d, J=9.0Hz), 9.77 (1H, brs), 12.18 (1H, brs).
Embodiment 35
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-sec.-propyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine and acetone prepare title compound.
MP：260℃。
MS(EI)：389(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.22 (6H, d, J=7.3Hz), 1.82-3.42 (10H, m), 5.40 (1H, s), 7.27 (1H, s), 7.42 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.66 (1H, brs), 12.22 (1H, brs).
Embodiment 36
4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 4-piperidine ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：＞270℃。
Ultimate analysis, calculated value: C 24H 25BrN 6O 2: C, 56.59; H, 4.95; N, 16.50.
Discovery value: C, 56.47; H, 4.87; N, 16.52.
MS(EI)：509(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.41(9H，s)，1.59-1.66(2H，m)，1.85-1.90(2H，m)，2.65-2.82(3H，m)，4.05-4.07(2H，m)，5.47(1H，s)，7.33(1H，s)，7.56-7.60(2H，m)，7.84(1H，d，J＝7.3Hz)，9.81(1H，brs)，12.26(1H，brs)。
Embodiment 37
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：＞270℃。
MS(EI)：409(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.53-1.56(2H，m)，1.83-1.87(2H，m)，2.46-2.50(3H，m)，2.71-2.74(1H，m)，3.00-3.04(1H，m)，5.45(1H，s)，7.32(1H，s)，7.56-7.58(2H，m)，7.81(1H，d，J＝7.3Hz)，9.74(1H，brs)，12.26(1H，brs)。
Embodiment 38
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：＞270℃。
MS(EI)：423(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.65-1.71(2H，m)，2.02-2.08(3H，m)，2.29(3H，s)，2.48-2.52(1H，m)，1.66-1.69(1H，m)，2.95-2.98(2H，m)，5.50(1H，s)，7.34(1H，s)，7.55-7.57(2H，m)，7.83(1H，d，J＝7.3Hz)，9.83(1H，brs)，12.32(1H，brs)。
Embodiment 39
4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidines-3-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from nipecotic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：238℃。
Ultimate analysis, calculated value: C 24H 25BrN 6O 2: C, 56.56; H, 4.95; N, 16.50.
Discovery value: C, 56.49; H, 4.85; N, 16.50.
MS(EI)：509(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.37 and 1.39 (9H, s), 1.68-2.06 (4H, m), 2.65-2.75 (2H, m), 3.30-3.32 (1H, m), 3.94-3.97 (2H, m), 5.47 and 5.49 (1H, s), 7.34 (1H, s), 7.58-7.61 (2H, m), 7.82-7.86 (1H, m), 9.89 (1H, brs), 12.31 (1H, brs).
Embodiment 40
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidines-3-yl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate
With the method identical with embodiment 21, from 4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidines-3-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：225℃。
Ultimate analysis, calculated value: C 19H 17BrN 6CF 3COOH:C, 48.20; H, 3.47; N, 16.06.
Discovery value: C, 47.98; H, 3.52; N, 15.97.
MS(EI)：409(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.68-1.98(4H，m)，2.65-2.68(1H，m)，3.21-3.33(4H，m)，5.50(1H，s)，7.35(1H，s)，7.55-7.66(2H，m)，7.84-7.87(1H，m)，8.54(1H，br)，8.96(1H，br)，9.96(1H，brs)，12.36(1H，br)。
Embodiment 41
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-3-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidines-3-yl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate prepares title compound.
MP：174℃。
MS(EI)：423(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.54-1.78(4H，m)，2.18-2.20(1H，m)，2.20(3H，s)，2.55-2.58(2H，m)，2.94-2.96(1H，m)，3.31-3.34(1H，m)，5.47(1H，s)，7.33(1H，s)，7.57-7.58(2H，m)，7.84(1H，d，J＝7.3Hz)，10.06(1H，brs)，12.29(1H，brs)。
Embodiment 42
4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidines-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from Pipecolic Acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：509(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.3 5 (9H, s), 1.34-1.90 (6H, m), 3.48-3.52 (2H, m), 4.42-4.48 (1H, m), 5.43 and 5.46 (1H, s), 7.36-7.39 (1H, m), and 7.53-7.57 (2H, m), 7.80-7.83 (1H, m), 9.68 and 9.82 (1H, brs), 12.26 (1H, brs).
Embodiment 43
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidines-2-yl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate
With the method identical with embodiment 21, from 4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidines-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：232℃。
MS(EI)：409(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.27-1.98(5H，m)，2.47-2.51(2H，m)，3.12-3.18(1H，m)，4.7-4.10(1H，m)，4.50-4.57(1H，m)，7.40-7.63(3H，m)，7.79-7.82(2H，m)，8.06(1H，br)，10.93(1H，brs)，12.41(1H，brs)。
Embodiment 44
4-(2-bromo-3-cyano-phenyl)-6-(4-tert-butoxycarbonyl morpholine-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from morpholine-2-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazoles.
MP：219℃。
MS(EI)：511(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.40 (9H, s), 2.97-3.10 (2H, m), 3.47-3.53 (1H, m), 3.77-3.94 (3H, m), 4.37-4.39 (1H, m), 5.52 and 5.54 (1H, s), 7.34-7.36 (1H, m), 7.58-7.65 (2H, m), 7.94-7.96 (1H, m), 9.87 and 9.92 (1H, brs), 12.33 (1H, brs).
Embodiment 45
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4, and 7-dihydro-6-(morpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate
With the method identical with embodiment 21, (4-tert-butoxycarbonyl morpholine-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound from 4-(2-bromo-3-cyano-phenyl)-6-.
MP：236℃。
MS(EI)：411(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：3.02-3.05(1H，m)，3.24-3.33(3H，m)，3.80-3.84(1H，m)，4.08-4.11(1H，m)，4.82-4.85(1H，m)，5.55(1H，s)，7.36(1H，s)，7.55-7.62(2H，m)，7.84-7.87(1H，m)，9.14(2H，br)，10.04-10.09(1H，brs)，12.40(1H，brs)。
Embodiment 46
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4, (morpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate prepares title compound to 7-dihydro-6-.
MP：180℃。
MS(EI)：425(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.18-2.20 (1H, m), 2.20 and 2.21 (3H, s), 2.26-2.29 (1H, m), and 2.58-2.62 (1H, m), 2.75-2.78 (1H, m), 3.58-3.62 (1H, m), 3.88-3.91 (1H, m), 4.48-4.50 (1H, m), 5.51 (1H, s), 7.35 (1H, s), 7.56-7.61 (2H, m), 7.84-7.86 (1H, m), 9.81 and 9.84 (1H, brs), 12.31 (1H, brs).
Embodiment 47
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1,2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine
Then according to the method for embodiment 2, from 1,2,3,6-tetrahydropyridine-4-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol prepare title compound with the method identical with embodiment 1.
MP：226℃。
MS(EI)：407(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：2.36-2.40(2H，m)，2.95-2.98(2H，m)，3.56-3.60(3H，m)，5.51(1H，s)，6.15(1H，s)，7.34(1H，s)，7.56-7.60(2H，m)，7.84(1H，d，J＝7.3Hz)，9.93(1H，brs)，12.32(1H，brs)。
Embodiment 48
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1,2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：233℃。
MS(EI)：421(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：2.31(3H，s)，2.56-2.67(4H，m)，3.00-3.03(2H，m)，5.50(1H，s)，6.10(1H，s)，7.34(1H，s)，7.58-7.60(2H，m)，7.83(1H，d，J＝7.3Hz)，9.91(1H，brs)，12.29(1H，brs)。
Embodiment 49
4-(2-bromo-3-cyano-phenyl)-6-((N-tert-butoxycarbonyl-N-methyl-amino) methyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 15 prepares title compound from glycine ethyl ester hydrochloride, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：469(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.39(9H，s)，2.85(3H，s)，4.15-4.18(2H，m)，5.49(1H，s)，7.37(1H，s)，7.56-7.57(2H，m)，7.83(1H，d，J＝7.3Hz)，9.78-9.93(1H，br)，12.31(1H，brs)。
Embodiment 50
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-((N-methyl-amino) methyl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate
With the method identical with embodiment 21, from 4-(2-bromo-3-cyano group-phenyl)-6-((N-tert-butoxycarbonyl-N-methylamino) methyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：258℃。
MS(EI)：369(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：3.10(3H，s)，4.46-4.66(2H，m)，5.50(1H，s)，7.47-7.48(2H，m)，7.65(1H，s)，7.80-7.81(2H，m)，8.09(1H，br)，10.81(1H，brs)，12.38(1H，brs)。
Embodiment 51
6-(1-ethanoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 25 prepares title compound from Acetyl Chloride 98Min., 4-piperidine ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：＞280℃。
MS(EI)：451(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.63-1.82(3H，m)，1.98-2.00(1H，m)，2.00(3H，s)，2.49-2.51(1H，m)，2.94-3.10(2H，m)，3.89-3.91(1H，m)，4.48-4.50(1H，m)，5.47(1H，s)，7.34(1H，s)，7.56-7.58(2H，m)，7.84(1H，d，J＝7.3Hz)，9.81(1H，brs)，12.27(1H，brs)。
Embodiment 52
6-(1-benzoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 25 prepares title compound from Benzoyl chloride, 4-piperidine ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：＞280℃。
MS(FAB)：514(M ++1)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.64-2.04(4H，m)，2.76-2.80(1H，m)，3.05-3.10(2H，m)，3.60-3.63(1H，m)，4.62-4.65(1H，m)，5.48(1H，s)，7.34-7.58(8H，m)，7.84(1H，d，J＝7.3Hz)，9.90(1H，brs)，12.31(1H，brs)。
Embodiment 53
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methylsulfonyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 25 prepares title compound from methylsulfonyl chloride, 4-piperidine ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：＞280℃。
MS(EI)：487(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.75-2.07(4H，m)，2.76-2.79(2H，m)，2.89(3H，s)，3.66-3.69(2H，m)，5.48(1H，s)，7.34(1H，s)，7.56-7.58(2H，m)，7.84(1H，d，J＝7.3Hz)，9.84(1H，brs)，12.30(1H，brs)。
Embodiment 54
6-(1-tert-butoxycarbonyl piperidin-4-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 4-piperidine ethyl formate, 2-chlorobenzaldehyde and 3-amino-pyrazol.
MP：＞280℃。
Ultimate analysis, calculated value: C 23H 26ClN 5O 2: C, 62.79; H, 5.96; N, 15.92.
Discovery value: C, 62.81; H, 5.87; N, 16.01.
MS(EI)：439(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.41(9H，s)，1.58-1.67(2H，m)，1.86-1.91(2H，m)，2.84-2.90(3H，m)，4.06-4.09(2H，m)，5.35(1H，s)，7.21-7.33(4H，m)，7.42(1H，d，J＝7.3Hz)，9.69(1H，brs)，12.18(1H，brs)。
Embodiment 55
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 6-(1-tert-butoxycarbonyl piperidin-4-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：221℃。
MS(EI)：339(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.84-1.92(2H，m)，2.10-2.16(2H，m)，2.96-3.00(3H，m)，3.30-3.40(2H，m)，5.36(1H，s)，7.22-7.33(4H，m)，7.42(1H，d，J＝7.2Hz)，8.56(1H，br)，9.76(1H，brs)，12.26(1H，brs)。
Embodiment 56
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine trifluoroacetate prepares title compound.
MP：＞270℃。
Ultimate analysis, calculated value: C 19H 20ClN 5C, 64.49; H, 5.70; N, 19.79.
Discovery value: C, 64.71; H, 5.68; N, 19.59.
MS(EI)：353(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.56-1.65(2H，m)，1.84-1.90(2H，m)，2.02-2.06(2H，m)，2.16(3H，s)，2.60-2.65(1H，m)，2.85-2.88(2H，m)，5.34(1H，s)，7.21-7.33(4H，m)，7.41(1H，d，J＝7.3Hz)，9.63(1H，brs)，12.17(1H，brs)。
Embodiment 57
2-ethanoyl-6-(1-ethanoyl piperidin-4-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
At room temperature, add diacetyl oxide (0.42mL) in pyridine (1.2mL) solution of 7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridines (1.0g), and stirred the mixture two hours to 4-(2-chloro-phenyl-)-5-cyano group-4.The reduction vaporization mixture is also washed resistates with methyl alcohol, filters the crystal of collecting precipitation, obtains title compound (0.6g), is clear crystal.
MS(EI)：423(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.58-1.70(2H，m)，1.91-1.96(1H，m)，1.99-2.00(1H，m)，2.02(3H，s)，2.51(3H，s)，2.55-2.58(1H，m)，3.11-3.18(2H，m)，3.91-3.94(1H，m)，4.49-4.52(1H，m)，5.37(1H，s)，7.32-7.37(3H，m)，7.48(1H，d，J＝7.3Hz)，7.84(1H，s)，10.24(1H，brs)。
Embodiment 58
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(2-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine
At room temperature in toluene (200mL) solution of 2-pimelinketone ethyl formate (25g), add ethylene glycol (10.1g) and tosic acid (2.8g), used Dean-Rodney Stark (Dean-Stark) device reflux mixture five hours.With the reaction mixture cool to room temperature, remove under reduced pressure solvent and with silica gel column chromatography (eluent: normal hexane: ethyl acetate (10: 1)) purifying resistates, obtain 1,4-dioxo spiro [4,5] decane-6-ethyl formate (31g) is colorless oil.In the THF of acetonitrile (7.2g) (700mL) solution, adding n-Butyl Lithium (160mmol) under-78 ℃.Add 1 then, 4-dioxo spiro [4,5] decane-6-ethyl formate (31g), and stirred the mixture one hour.After hcl acidifying, use the ethyl acetate extraction mixture.Also (eluent: normal hexane: ethyl acetate (10: 1)) purifying resistates, obtaining 1-cyano group-2-(1,4-dioxo spiro [4,5] decane-6-yl) ethane-2-ketone (14.5g) is colorless oil with silica gel column chromatography to remove solvent under reduced pressure.With 2,1, acetonitrile (10mL) vlil of 3-Ben Bing oxadiazole-4-aldehyde (0.8g), 3-amino-pyrazol (0.5g) and 1-cyano group-2-(1,4-dioxo spiro [4,5] decane-6-yl) ethane-2-ketone (1.2g) is spent the night.With the reaction mixture cool to room temperature, and the crystal of filtration collecting precipitation, 4-(2,1 obtained, 3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,4-dioxo spiro [4,5] decane-6-yl)-and 2H-pyrazolo [3,4-b] pyridines (1.3g), be clear crystal.
At room temperature to 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,4-dioxo spiro [4,5] decane-6-yl)-add the dioxane solution (6.0mL) of 4N HCl in methyl alcohol (30mL) solution of 2H-pyrazolo [3,4-b] pyridines (1.0g), and 60 ℃ of heated mixt two hours.After the sodium bicarbonate alkalization, use the chloroform extraction mixture.Remove solvent under reduced pressure, and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying resistates, obtain title compound (20mg), be clear crystal.
MP：＞270℃。
MS(EI)：360(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.74-1.80 (5H, m), 2.60-2.65 (3H, m), 3.31-3.35 (1H, m), 5.98 (1H, s), 6.92 (1H, d, J=6.6Hz), 7.39 (1H, s), 7.47 (1H, dd, J=9.0Hz and 6.6Hz), 7.84 (1H, d, J=9.0Hz), 9.33 (1H, brs), 12.15 (1H, brs).
Embodiment 59
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 58, from 4-pimelinketone ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(FAB)：361(M ++1)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.96-2.12(3H，m)，2.22-2.30(3H，m)，2.48-2.51(1H，m)，3.27-3.31(2H，m)，5.42(1H，s)，7.26(1H，s)，7.38-7.46(1H，m)，7.57-7.61(1H，m)，7.88-7.95(1H，m)，9.76(1H，brs)，12.16(1H，br)。
Embodiment 60
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(2-oxo-cyclopentane-1-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 58, from 2-cyclopentanone ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(FAB)：347(M ++1)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.60-1.63 (2H, m), 1.86-2.05 (2H, m), 2.31-2.34 (2H, m), 3.43-3.46 (1H, m), 5.47 (1H, s), 7.25 and 7.30 (1H, s), 7.39-7.46 (1H, m), 7.56-7.60 (1H, m), 7.91-7.94 (1H, m), 9.90 (1H, brs), 12.20 (1H, brs).
Embodiment 61
6-ethanoyl methyl-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 58, from methyl aceto acetate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MP：200℃。
MS(FAB)：321(M ++1)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.22 (3H, s), 3.63-3.66 (2H, m), 5.48 (1H, s), 7.30 (1H, s), 7.47 (1H, d, J=6.6Hz), 7.61 (1H, dd, J=9.0Hz and 6.6Hz), 7.94 (1H, d, J=9.0Hz), 10.00 (1H, brs), 12.21 (1H, brs).
Embodiment 62
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(2-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 58 prepares title compound from 2-pimelinketone ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：273℃。
MS(EI)：422(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.72-1.81(5H，m)，2.59-2.65(3H，m)，3.30-3.32(1H，m)，5.91(1H，s)，7.05(1H，d，J＝7.3Hz)，7.40-7.43(2H，m)，7.52(1H，s)，7.74(1H，d，J＝7.3Hz)，9.33(1H，brs)，12.24(1H，brs)。
Embodiment 63
6-ethanoyl methyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 58 prepares title compound from methyl aceto acetate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MP：230℃。
MS(EI)：382(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.23 (3H, s), 3.60-3.67 (2H, m), 5.50 (1H, s), 7.39 (1H, s), 7.60 (1H, dd, J=7.3Hz and 7.2Hz), 7.70 (1H, d, J=7.3Hz), 7.83 (1H, d, J=7.3Hz), 9.97 (1H, brs), 12.29 (1H, brs).
Embodiment 64
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(1-tert-butoxycarbonyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridines (2.0g) join in the dioxane solution (20mL) of 4N-HCl, and stirred the mixture one hour under 0 ℃.Remove solvent under reduced pressure, and wash resistates, filter the crystal of collecting precipitation, obtain title compound (1.2g), be yellow crystals with ethanol.
MS(EI)：339(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.83-1.90(2H，m)，2.07-2.15(2H，m)，2.94-2.97(3H，m)，3.34-3.37(2H，m)，5.36(1H，s)，7.22-7.33(4H，m)，7.42(1H，d，J＝7.3Hz)，8.41(1H，br)，9.17(1H，br)，9.77(1H，brs)，12.27(1H，brs)。
Embodiment 65
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 64, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：＞270℃。
Ultimate analysis, calculated value: C 18H 17N 7OHCl:C, 56.09; H, 5.20; N, 24.10.
Discovery value: C, 55.80; H, 5.00; N, 23.80.
MS(EI)：347(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.82-1.85 (2H, m), 2.14-2.20 (2H, m), 2.93-2.99 (3H, m), 3.34-3.36 (2H, m), 5.40 (1H, s), 7.27 (1H, s), 7.43 (1H, d, J=6.6Hz), (7.58 1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 8.44 (1H, br), 9.21 (1H, br), 9.87 (1H, brs), 12.25 (1H, brs).
Embodiment 66
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 64, from 4-(2-bromo-3-cyano-phenyl)-6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：＞270℃。
MS(EI)：409(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.84-1.92 (2H, m), 2.07-2.10 (2H, m), 2.92-2.98 (5H, m), 5.48 (1H, s), 7.34 (1H, s), 7.57-7.59 (2H, m), (7.84 1H, dd, J=7.3Hz and 7.2Hz), 8.30 (1H, br), 9.04 (1H, br), 9.90 (1H, brs), 12.35 (1H, br).
Embodiment 67
4-(2-bromo-3-cyano-phenyl)-5-cyano group-6-(1-tert-butoxycarbonyl tetramethyleneimine-2-yl)-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 1-tert-butoxycarbonyl tetramethyleneimine-2-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：495(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.47(9H，s)，1.82-1.97(4H，m)，2.31(1H，m)，3.50(1H，m)，4.53(1H，m)，5.47(1H，s)，7.51-7.91(4H，m)，9.83(1H，m)，12.26(1H，s)。
Embodiment 68
4-(2-bromo-3-cyano-phenyl)-5-cyano group-6-(tetramethyleneimine-2-yl)-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-6-(1-tert-butoxycarbonyl tetramethyleneimine-2-yl)-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：＞240℃。
MS(EI)：395(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.39-1.55 (1H, m), 1.97 (2H, m), 2.30 (1H, m), 3.32 (2H, m), 4.10-4.28 (1H, m), 5.41 (1H, s), 6.52 (1H, s), 7.34-7.47 (2H, m), 7.70 (1H, dd, J=8.3Hz and 9.0Hz), 11.89 (1H, brs).
Embodiment 69
4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl tetramethyleneimine-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 1-tert-butoxycarbonyl tetramethyleneimine-2-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：433(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.40 (9H, s), 1.78-1.89 (4H, m), 2.11-2.31 (1H, m), 3.72 (1H, m), 4.53 (1H, m), 5.40 (1H, s), 7.26 (1H, s), 7.30-7.40 (1H, m), 7.58 (1H, dd, J=6.4Hz and 9.6Hz), 7.91 (1H, d, J=9.6Hz), 9.86 (1H, s), 12.16 (1H, s).
Embodiment 70
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(tetramethyleneimine-2-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-6-(1-tert-butoxycarbonyl tetramethyleneimine-2-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MP：＞240℃。
MS(EI)：333(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.41-1.46 (1H, m), 1.97-2.14 (4H, m), 3.72 (1H, m), 4.11-4.32 (1H, m), 5.52 (1H, s), 7.00 (1H, s), 7.26 (1H, s), 7.30-7.42 (1H, m), (7.58 1H, dd, J=6.4Hz and 9.6Hz), 7.91 (1H, d, J=9.3Hz), 11.87 (1H, s).
Embodiment 71
6-(1-tert-butoxycarbonyl tetramethyleneimine-2-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 1-tert-butoxycarbonyl tetramethyleneimine-2-ethyl formate, 2-chlorobenzaldehyde and 3-amino-pyrazol.
MS(EI)：425(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.36(9H，s)，1.86(4H，m)，2.32(1H，m)，3.54(1H，m)，4.57(1H，m)，5.38(1H，s)，7.23-7.27(4H，m)，7.42(1H，d，J＝7.6Hz)，9.68(1H，s)，12.17(1H，s)。
Embodiment 72
6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(2,3-(methylene-dioxy) phenyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 1-tert-butoxycarbonyl piperidine-4-ethyl formate, 2,3-(methylene-dioxy) phenyl aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：449(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.39(1H，m)，1.97-2.13(2H，m)，2.00(2H，m)，2.78-3.15(2H，m)，3.31(1H，m)，3.96(2H，s)，5.03(1H，d，J＝9.5Hz)，6.00-6.02(1H，m)，6.64(1H，d，J＝2.9Hz)，6.78(1H，d，J＝1.7Hz)，7.29(1H，s)，9.46(1H，s)，12.18(1H，s)。
Embodiment 73
5-cyano group-4,7-dihydro-4-(2,3-(methylene-dioxy) phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 2, from 6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(2,3-(methylene-dioxy) phenyl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：390(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.27-1.88(5H，m)，2.49-2.96(5H，m)，5.02(1H，s)，6.00-6.02(2H，m)，6.66(1H，m)，6.76(2H，m)，7.27(1H，s)，9.98(1H，s)，12.14(1H，s)。
Embodiment 74
4-(2-chloro-phenyl-)-5-cyano group-6-phenyl amino carbonyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from N-phenyl ethyl oxamide, 2-chlorobenzaldehyde and 3-amino-pyrazol.
MS(EI)：375(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 5.50 (1H, s), 7.13 (1H, dd, J=7.1Hz and 7.6Hz), 7.25-7.46 (7H, m), 7.66 (2H, dd, J=8.3Hz), 10.4 (1H, s), 10.76 (1H, s), 12.3 (1H, s).
Embodiment 75
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-6-phenyl amino carbonyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from N-phenyl ethyl oxamide, 2,1,3-benzene and oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：383(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 5.59 (1H, s), 7.11-7.15 (1H, dd, J=7.3Hz and 7.6Hz), 7.33-7.36 (3H, m), 7.51 (1H, d, J=6.6Hz), 7.63-7.68 (3H, m), 7.96 (1H, d, J=9.0Hz), 10.52 (1H, s), 10.76 (1H, s), 12.3 (1H, s).
Embodiment 76
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-[4-(naphthalene-1-yl) piperazine-1-yl] methyl-2H-pyrazolo [3,4-b] pyridine tri hydrochloride
With with embodiment 1 in identical method prepare 4-(2-chloro-phenyl-)-5-cyano group-6-(t-butyldimethylsilyl oxygen base) methyl-4 from t-butyldimethylsilyl ethoxyacetic acid ethyl ester, 2-chlorobenzaldehyde and 3-amino-pyrazol, 7-dihydro-2H-pyrazolo [3,4-b] pyridine.To 4-(2-chloro-phenyl-)-5-cyano group-6-(t-butyldimethylsilyl oxygen base) methyl-4,7-dihydro-2H-pyrazolo [3,4-b] add the THF solution (49.9mL) of the tetrabutyl ammonium fluoride of 1.0M in tetrahydrofuran (THF) (200mL) solution of pyridine (20g), and at room temperature stirred the mixture 1 hour.In reaction mixture, add ethyl acetate (800mL), and wash the mixture that obtains, and use anhydrous magnesium sulfate drying with saturated sodium-chloride water solution.Steaming desolventizes, and makes the resistates that obtains from the ethyl acetate crystallization, obtains 4-(2-chloro-phenyl-)-5-cyano group-6-methylol-4, and 7-dihydro-2H-pyrazolo [3,4-b] pyridines (12.7g) are white solid.Ice-cooled following to 4-(2-chloro-phenyl-)-5-cyano group-6 methylol-4,7-dihydro-2H-pyrazolo [3,4-b] add methylene dichloride (100mL) solution of triphenyl phosphine (12.2g) in methylene dichloride (340mL) solution of pyridine (12.7g) and carbon tetrabromide (15.4g), and at room temperature stirred the mixture 13 hours.The concentrating under reduced pressure reaction mixture, and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: the 1)) resistates that obtains of purifying obtains 4-(2-chloro-phenyl-)-5-cyano group-6-brooethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine (3.84g), be light yellow solid.In the DMF of sodium hydride (60mg) (10mL) suspension, add 1-(naphthalene-1-yl) piperazine (334mg) and under ice-cooled, stirred the mixture 30 minutes.In this reaction mixture, add 4-(2-chloro-phenyl-)-5-cyano group-6-brooethyl-4 down ice-cooled, the solution of 7-dihydro-2H-pyrazolo [3,4-b] pyridines (500mg), and under ice-cooled, stirred the mixture 6 hours.In reaction mixture, add entry, and use the ethyl acetate extraction mixture.Extraction liquid washes and uses anhydrous magnesium sulfate drying with saturated sodium-chloride water solution.Steaming desolventizes, with silica gel column chromatography (eluent: the resistates that obtains of purifying ethyl acetate-methyl alcohol (1: 1)).Handle the oily matter that obtains with hydrogenchloride-methyl alcohol, obtain title compound (370mg), be white crystal.
MP:203-205 ℃ (decomposition)
MS(EI)：481(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：3.31-3.70(8H，m)，4.33(2H，m)，4.85(3H，m)，5.54(1H，s)，7.19(1H，d，J＝7.3Hz)，7.29-7.54(8H，m)，7.67(1H，d，J＝8.1Hz)，7.92(1H，d，J＝7.1Hz)，8.15(1H，d，J＝7.3Hz)，10.35(1H，s)，11.28(1H，brs)。
Embodiment 77
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(the high piperazine of 4-methyl-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine dihydrochloride
With the method identical with embodiment 76, from 4-(2-chloro-phenyl-)-5-cyano group-6-brooethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine and the high piperazine of N-methyl prepare title compound.
MP:204-206 ℃ (decomposition).
MS(EI)：382(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：2.22(2H，m)，2.78(3H，s)，3.24-4.11(12H，m)，5.48(1H，s)，7.14-7.35(4H，m)，7.45(1H，d，J＝8.0Hz)，10.17(1H，brs)，11.51(1H，brs)。
Embodiment 78
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(4-phenylpiperazine-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine tri hydrochloride
With the method identical with embodiment 76, from 4-(2-chloro-phenyl-)-5-cyano group-6-brooethyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine and 1-phenylpiperazine prepare title compound.
MP:217-220 ℃ (decomposition).
MS(EI)：430(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：3.20-4.00(9H，m)，4.27(2H，m)，5.51(1H，s)，6.86(1H，t，J＝7.1Hz)，7.01(2H，d，J＝8.0Hz)，7.24-7.39(6H，m)，7.45(1H，d，J＝9.9Hz)，9.50(1H，brs)，10.37(1H，s)，11.40(1H，brs)。
Embodiment 79
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-phthalimide-based methyl-2H-pyrazolo [3,4-b] pyridine
, add potassium phthalimide (445mg) in DMF (10mL) solution of 7-dihydro-2H-pyrazolo [3,4-b] pyridines (0.8g), and under ice-cooled, stirred the mixture 4 hours down to 4-(2-chloro-phenyl-)-5-cyano group-6-brooethyl-4 ice-cooled.In reaction mixture, add entry, and use the ethyl acetate extraction mixture.Extraction liquid washes and uses anhydrous magnesium sulfate drying with saturated sodium-chloride water solution.Steaming desolventize and with silica gel column chromatography (eluent: purifying resistates ethyl acetate-normal hexane (2: 1)), obtain title compound (285mg), be white crystal.
MP：＞250℃。
MS(EI)：416(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：4.66(2H，d，J＝2.4Hz)，5.40(1H，s)，7.24-7.45(5H，m)，7.82-7.94(4H，m)，10.04(1H，s)，12.23(1H，s)。
Embodiment 80
6-ethanoyl-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
From 2,2-dimethoxy methyl propionate, 2-chlorobenzaldehyde and 3-amino-pyrazol prepare 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(1, the 1-dimethoxy-ethyl)-2H-pyrazolo [3,4-b] pyridine with the method identical with embodiment 1.Ice-cooled following to 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(1, the 1-dimethoxy-ethyl)-add trifluoroacetic acid (10mL) in methylene dichloride (10mL) solution of 2H-pyrazolo [3,4-b] pyridines (1.0g) and under ice-cooled, stirred the mixture 1 hour.Steaming desolventizes and makes the resistates that obtains from the ethyl acetate crystallization, obtains title compound (370mg), is white crystal.
MP:225-228 ℃ (decomposition).
MS(EI)：298(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：2.56(3H，s)，5.49(1H，s)，7.25-7.36(4H，m)，7.45(1H，d，J＝7.8Hz)，10.12(1H，s)，12.50(1H，brs)。
Embodiment 81
6-ethanoyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 2-bromo-3-cyanobenzaldehyde, 3-amino-pyrazol and 2,2-dimethoxy methyl propionate prepares title compound.
MP：＞230℃。
MS(EI)：368(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.42 (3H, s), 5.54 (1H, s), 7.32 (1H, brs), 7.50-7.59 (2H, m), 7.80 (1H, dd, J=1.7Hz and 7.3Hz), 10.19 (1H, s), 12.39 (1H, brs).
Embodiment 82
6-ethanoyl-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 2,1,3-Ben Bing oxadiazole-4-aldehyde, 3-amino-pyrazol and 2,2-dimethoxy methyl propionate prepares title compound.
MP:230 ℃ (decomposition).
MS(EI)：306(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.55 (3H, s), 5.54 (1H, s), 7.33 (1H, s), 7.49 (1H, d, J=6.6Hz), 7.61 (1H, dd, J=6.6Hz and 8.6Hz), 7.96 (1H, d, J=9.2Hz), 10.27 (1H, s), 12.36 (1H, brs).
Embodiment 83
6-(1-benzyl-2-oxo-pyrrolidine-4-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 2-chlorobenzaldehyde, 3-amino-pyrazol and, 1-benzyl-2-oxo-pyrrolidine-4-methyl-formiate prepares title compound.
MP：＞230℃。
Ultimate analysis, calculated value: C 24H 20ClN 5O:C, 67.05; H, 4.69; N, 16.29.
Discovery value: C, 66.86; H, 4.56; N, 16.31.
MS(EI)：429(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.60 (1H, dd, J=9.5Hz and 16.4Hz), 2.81 (1H, dd, J=10.5Hz and 16.4Hz), 3.39 (1H, m), 3.47 (1H, m), 4.42 (2H, m), 5.36 (1H, s), 7.23-7.43 (10H, m), 10.04 (1H, s), 12.21 (1H, s).
Embodiment 84
4-(2-bromo-3-cyano-phenyl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine
In the THF of 2-picoline (10g) (75mL) solution, adding n-Butyl Lithium (113mmol) under-40 ℃.Add methyl-butyrate (15.8mL) then and stirred the mixture water quencher mixture 1 hour.Use the ethyl acetate extraction mixture.Remove under reduced pressure solvent and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying resistates, obtain 2-(2-oxo amyl group) pyridine (4.8g), be yellow oil.With acetate (7mL) vlil of 2-bromo-3-cyanobenzaldehyde (1.5g), plum forests moral human relations acid (1.0g), 2-(2-oxo amyl group) pyridine (1.2g) and ammonium acetate (0.6g) 11 hours.With the reaction mixture cool to room temperature, remove solvent under reduced pressure, and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying resistates, make the resistates that obtains from the ethyl acetate crystallization, obtain clear crystal (520mg).At the solution of the ice-cooled crystal (520mg) that down in chloroform (5mL) solution of dimethyl formamide (384mg), adds phosphoryl chloride (805mg) and obtain and stir the mixture and spend the night.Under ice-cooled, add sodium acetate (3.4g) aqueous solution and also stirred the mixture 1 hour.With the ethyl acetate extraction mixture and remove solvent under reduced pressure, obtain oily matter.(eluent: the oily matter that obtains of purifying chloroform-methanol (9: 1)) obtains yellow solid (530mg) with silica gel column chromatography.In solid pyridine (10mL) solution that obtains, add hydrazine (120mg), and under heating, stirred the mixture 4 hours.With the reaction mixture cool to room temperature, and remove solvent under reduced pressure, obtain oily matter.In the oily matter that obtains, add entry, and use the ethyl acetate extraction mixture.Wash extraction liquid with saturated sodium-chloride water solution, and use anhydrous magnesium sulfate drying.Steaming desolventizes and makes the resistates that obtains from the ethyl acetate crystallization, obtains title compound (145mg), is light yellow crystallization.
MP:205-208 ℃ (decomposition).
Ultimate analysis, calculated value: C 21H 18BrN 5: C, 60.01; H, 4.32; N, 16.66.
Discovery value: C, 59.83; H, 4.42; N, 16.26.
MS(EI)：420(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.83 (3H, t, J=7.6Hz), 1.62 (2H, m), 2.24 (1H, m), 2.33 (1H, m), 5.93 (1H, s), 6.98 (1H, dd, J=4.9Hz and 7.3Hz), 7.05 (1H, d, J=7.8Hz), 7.28 (1H, m), 7.39 (1H, m), and 7.51-7.60 (3H, m), 8.36 (1H, d, J=3.6Hz), 8.52 (1H, s), 11.84 (1H, s).
Embodiment 85
6-(1-tert-butoxycarbonyl tetramethyleneimine-3-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
At the ice-cooled borine-THF (84mL) that in the THF (50mL) of 1-benzyl-2-oxo-pyrrolidine-4-methyl-formiate (10.9g) solution, adds 1.0M down, and mixture was refluxed 1 hour.Drip the hydrochloric acid methanol of 30mL, refluxing then made excessive borine and boron complex decompose in 1 hour, after removal of solvent under reduced pressure, adds another part 30mL hydrochloric acid methanol, and mixture was refluxed 1 hour again.Solvent removed in vacuo and handle resistates once more with saturated sodium bicarbonate aqueous solution, and use anhydrous magnesium sulfate drying.Steaming desolventize and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying resistates, obtain 1-benzyl-3-pyrrolidinecarboxylic acid methyl esters (4.8g), be light yellow oil.With the methyl alcohol (50mL) of 1-benzyl-3-pyrrolidinecarboxylic acid methyl esters (4.8mg), 5% palladium carbon (300mg) and ammonium formiate (2.8g)-water (5mL) suspension returning 2 hours.By diatomite (Celite) filter reaction mixture, and concentrating under reduced pressure filtrate.With silica gel column chromatography (eluent: purifying resistates chloroform-methanol (9: 1)), obtain 3-pyrrolidinecarboxylic acid methyl esters, be yellow oil.In methylene dichloride (20mL) solution of 3-pyrrolidinecarboxylic acid methyl esters (1.7g), adding dimethyl aminopyridine (161mg) and two dimethyl dicarbonate butyl esters (3.4g) under 0 ℃ and stirring the mixture 13 hours.The reduction vaporization mixture, and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (2: the 1)) resistates that obtains of purifying, obtain 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylic acid methyl esters, be colorless oil.Under-78 ℃, add n-Butyl Lithium (12.4mmol) to the THF of acetonitrile (554mg) (30mL) solution ester.Add THF (10mL) solution of 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylic acid methyl esters (2.6g) then, stirred the mixture 10 hours, and water quencher reaction.The reduction vaporization mixture, and with silica gel column chromatography (eluent: normal hexane-ethyl acetate (2: 1)) purifying resistates, obtain 1-(1-tert-butoxycarbonyl tetramethyleneimine-3-yl)-2-cyano group ethane-1-ketone (2.35g), be colorless oil.With acetonitrile (10mL) vlil of 2-chloro-phenyl-aldehyde (1.4g), 3-amino-pyrazol (819mg) and 1-(1-tert-butoxycarbonyl tetramethyleneimine-3-yl)-2-cyano group ethane-1-ketone (2.35g) 1.5 hours.With the reaction mixture cool to room temperature, and the crystal of filtration collecting precipitation, obtain title compound (2.18g), be clear crystal.
Ultimate analysis, calculated value: C 22H 24ClN 5O 2: C, 62.04; H, 5.68; N, 16.44.
Discovery value: C, 61.94; H, 5.69; N, 16.45.
MS(EI)：425(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.14(9H，s)，2.07(1H，m)，2.32(1H，m)，3.29-3.58(5H，m)，5.37(1H，s)，7.22-7.34(4H，m)，7.42(1H，d，J＝8.3Hz)，9.78(1H，s)，12.20(1H，s)。
Embodiment 86
4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(tetramethyleneimine-3-yl)-2H-pyrazolo [3,4-b] pyridine
At room temperature with 6-(1-tert-butoxycarbonyl tetramethyleneimine-3-yl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridines (706mg) join in the dioxane solution (5mL) of 4N-HCl, and stir the mixture 2 hours.Solvent evaporated under reduced pressure is also washed resistates with ethanol-ethyl acetate, filters the crystal of collecting precipitation, obtains title compound (460mg), is clear crystal.
MP:210-215 ℃ (decomposition).
MS(EI)：325(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：2.24(2H，m)，3.15(1H，m)，3.26-3.55(3H，m)，3.64(1H，m)，5.34(1H，s)，5.40(1H，brs)，7.23-7.32(4H，m)，7.43(1H，d，J＝7.3Hz)，9.38(1H，brs)，9.51(1H，brs)，9.97(1H，s)。
Embodiment 87
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 84, from 2,1,3-Ben Bing oxadiazole-4-aldehyde, plum forests moral human relations acid, 2-(2-oxo amyl group) pyridine and ammonium acetate prepare title compound.
MS(EI)：358(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：0.84(3H，t，J＝7.3Hz)，1.64(2H，m)，2.27(1H，m)，2.35(1H，m)，5.96(1H，s)，6.95(1H，m)，7.11-7.18(3H，m)，7.40(1H，m)，7.51(1H，m)，7.69(1H，d，J＝9.3Hz)，8.35(1H，m)，8.54(1H，s)，11.78(1H，brs)。
Embodiment 88
6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(2,3-indane-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 4-piperidine ethyl formate, 2,3-indane-4-formaldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：445(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.41(9H，s)，1.56-1.59(2H，m)，1.88-1.06(4H，m)，2.58-2.83(7H，m)，4.06(2H，m)，4.96(1H，s)，6.90(1H，m)，7.04-7.07(2H，m)，7.14(1H，s)，9.55(1H，s)，12.08(1H，s)。
Embodiment 89
6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(2,3-dihydrobenzo [b] furans-7-yl)-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 4-piperidine ethyl formate, 7-(2,3-dihydrobenzo [b] furans) formaldehyde and 3-amino-pyrazol.
MS(EI)：445(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.42(9H，s)，1.57-1.66(2H，m)，1.88(4H，m)，2.73-2.90(3H，m)，3.17(2H，m)，4.09(2H，m)，4.54(2H，m)，5.01(1H，s)，6.76(1H，m)，6.84(1H，d，J＝7.1Hz)，7.05(1H，d，J＝6.6Hz)，7.22(1H，s)，9.52(1H，s)，12.06(1H，s)。
Embodiment 90
6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(3,4-dihydro-2H-chromene-8-yl)-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 4-piperidine ethyl formate, 8-(3,4-dihydro-2H-chromene) formaldehyde and 3-amino-pyrazol.
MS(EI)：461(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.42(9H，s)，1.58-1.69(2H，m)，1.80-2.00(4H，m)，2.73-2.95(5H，m)，4.09(2H，m)，4.22(2H，m)，5.14(1H，s)，6.74(1H，m)，6.84-6.89(2H，m)，7.21(1H，s)，9.48(1H，s)，12.03(1H，s)。
Embodiment 91
6-(1-tert-butoxycarbonyl piperidin-4-yl)-4-(2-chloro-3-trifluoromethyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 4-piperidine ethyl formate, 2-chloro-3-trifluoromethylated benzaldehyde and 3-amino-pyrazol.
MS(EI)：461(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.41(9H，s)，1.62(2H，m)，1.89(2H，m)，2.60-2.90(3H，m)，4.10(2H，m)，5.54(1H，s)，7.32(1H，s)，7.52-7.56(2H，m)，7.75(1H，d，J＝9.3Hz)，9.79(1H，s)，12.25(1H，s)。
Embodiment 92
5-cyano group-4,7-dihydro-4-(3,4-dihydro-2H-chromene-8-yl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 2, from 6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(3,4-dihydro-2H-chromene-8-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：361(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.83-1.98(4H，m)，2.14(2H，m)，2.74(2H，m)，2.90-3.00(3H，m)，4.22(2H，m)，3.40-3.70(5H，m)，4.16-4.27(2H，m)，5.15(1H，s)，6.74(1H，m)，6.83-6.89(2H，m)，7.22(1H，s)，9.54(1H，s)。
Embodiment 93
5-cyano group-4,7-dihydro-4-(2,3-indane-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 2, from 6-(1-tert-butoxycarbonyl piperidin-4-yl)-5-cyano group-4,7-dihydro-4-(2,3-indane-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：345(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.80-1.99(4H，m)，2.14(2H，m)，2.58(1H，m)，2.82-2.95(6H，m)，3.30-3.50(2H，m)，4.97(1H，s)，6.90(1H，m)，7.04-7.09(2H，m)，7.17(1H，s)，8.37(1H，m)，9.10(1H，m)，9.62(1H，s)，12.18(1H，brs)。
Embodiment 94
5-cyano group-4,7-dihydro-4-(2,3-indane-4-yl)-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-(2,3-indane-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.56(2H，m)，1.84-1.98(6H，m)，2.15(2H，m)，2.58(1H，m)，2.80-3.00(6H，m)，3.20-3.40(2H，m)，4.95(1H，s)，6.90(1H，m)，7.05-7.07(2H，m)，7.14(1H，s)，9.54(1H，brs)，12.10(1H，brs)。
Embodiment 95
5-cyano group-4,7-dihydro-4-(3,4-dihydro-2H-chromene-8-yl)-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-(3,4-dihydro-2H-chromene-8-yl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.90-2.00(4H，m)，2.24(2H，m)，2.73-2.75(5H，m)，2.94-3.08(3H，m)，3.40-3.48(2H，m)，4.17-4.27(2H，m)，5.15(1H，s)，6.74(1H，m)，6.84-6.89(2H，m)，7.22(1H，s)，9.58(1H，s)，9.80(1H，m)，12.15(1H，s)。
Embodiment 96
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methylsulfonyl piperidines-2-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 25, from methylsulfonyl chloride, Pipecolic Acid ethyl ester, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：425(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.20-2.07 (7H, m), 2.95 and 2.98 (3H, s), 2.98-3.17 (1H, m), 3.63-3.68 (1H, m), 5.40 and 5.52 (1H, s), 7.24 and 7.27 (1H, s), and 7.41-7.63 (2H, m), 7.90-7.93 (1H, m), 9.80 and 9.82 (1H, brs), 12.16 (1H, brs).
Embodiment 97
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 64, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：361(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.86-1.90 (2H, m), 2.24-2.27 (2H, m), 2.48 (3H, s), 2.72-2.75 (2H, m), 2.94-2.98 (2H, m), 3.20-3.33 (1H, br), 3.44-3.47 (1H, m), 5.40 (1H, s), 7.28 (1H, s), 7.44 (1H, d, J=6.6Hz), (7.59 1H, dd, J=9.0Hz and 6.6Hz), 7.93 (1H, d, J=9.0Hz), 9.92 (1H, brs), 12.26 (1H, brs).
Embodiment 98
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,2-dihydro-1-methyl-2-oxo pyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 1,2-dihydro-1-methyl-2-oxo pyridine-4-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：371(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 3.46 (3H, s), 5.42 (1H, s), 6.34 (1H, d, J=7.2Hz), 6.56 (1H, s), 7.33 (1H, s), 7.52 (1H, d, J=7.2Hz), 7.61 (1H, dd, J=9.0Hz and 6.6Hz), 7.80 (1H, d, J=6.6Hz), 7.95 (1H, d, J=9.0Hz), 10.33 (1H, brs), 12.29 (1H, brs).
Embodiment 99
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,2,5,6-tetrahydropyridine-3-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 1 and embodiment 2, from 1,2,3,4-tetrahydropyridine-3-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：345(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.42-2.44 (2H, m), 3.11-3.14 (2H, m), 3.84-3.87 (2H, m), 4.39 (1H, br), 5.46 (1H, s), 6.36 (1H, s), 7.30 (1H, s), 7.49 (1H, d, J=6.6Hz), 7.56 (1H, dd, J=9.0Hz and 6.6Hz), 7.94 (1H, d, J=9.0Hz), 9.39 (2H, br), 10.06 (1H, brs).
Embodiment 100
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 4,5,6-tetrahydropyridine-3-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1,4,5,6-tetrahydropyridine-3-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：359(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.18-2.20 (2H, m), 2.43-2.47 (2H, m), 3.02-3.11 (2H, m), 5.43 (1H, s), 6.11 (1H, s), 7.26 (1H, s), 7.43 (1H, d, J=6.6Hz), 7.59 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.87 (1H, brs), 12.16 (1H, brs).
Embodiment 101
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-(methylamino) ethyl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 15 and embodiment 2, from 2-methylglycine ethyl ester, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：321(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.56 (3H, d, J=6.8Hz), 3.07 (3H, s), 4.59-4.68 (3H, m), 5.66 (1H, s), 7.29 (1H, d, J=6.6Hz), 7.44 (1H, s), (7.52 1H, dd, J=9.0Hz and 6.6Hz), 7.87 (1H, d, J=9.0Hz), 8.22 (1H, br), 8.44 (1H, br), 10.95 (1H, brs).
Embodiment 102
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1,2-dihydro-1-methyl-2-oxo pyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 1,2-dihydro-1-methyl-2-oxo pyridine-4-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：433(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 3.46 (3H, s), 5.35 (1H, s), 6.37 (1H, d, J=7.2Hz), 6.61 (1H, s), 7.38 (1H, s), 7.60 (1H, dd, J=7.3Hz and 7.2Hz), 7.72-7.86 (3H, m), 10.31 (1H, brs), 12.37 (1H, brs).
Embodiment 103
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-(methylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 15 and embodiment 2 prepares title compound from 4-aminocyclohexane ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：436(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.39(2H，m)，1.80-1.90(4H，m)，2.15-2.16(2H，m)，2.84-2.86(1H，m)，3.14-3.16(1H，m)，4.20(2H，br)，5.46(1H，s)，7.33(1H，s)，7.56-7.57(2H，m)，7.82(1H，d，J＝7.3Hz)，8.98(2H，br)，9.80(1H，brs)。
Embodiment 104
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1,2,5,6-tetrahydropyridine-3-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 1 and embodiment 2, from 1,2,5,6-tetrahydropyridine-3-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：407(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.43-2.44 (2H, m), 3.13-3.15 (2H, m), 3.70-3.72 (2H, br), 3.86-3.88 (2H, m), 5.54 (1H, s), 6.41 (1H, s), 7.36 (1H, s), 7.58 (1H, dd, J=7.3Hz and 7.2Hz), 7.84 (1H, d, J=7.3Hz), 7.86 (1H, d, J=7.3Hz), 9.32 (2H, br), 10.03 (1H, brs).
Embodiment 105
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-(dimethylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-(methylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：450(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.26-1.29(2H，m)，1.76-1.93(6H，m)，2.27(6H，s)，2.34-2.36(1H，m)，2.63-2.66(1H，m)，5.45(1H，s)，7.33(1H，s)，7.56-7.60(2H，m)，7.82(1H，d，J＝7.3Hz)，9.74(1H，brs)，12.27(1H，s)。
Embodiment 106
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 4,5,6-tetrahydropyridine-3-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1,4,5,6-tetrahydropyridine-3-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：420(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 2.21-2.22 (2H, m), 2.28 (3H, s), 2.48-2.49 (2H, m), 3.08-3.12 (2H, m), 5.49 (1H, s), 6.15 (1H, s), 7.33 (1H, s), 7.56-7.61 (2H, m), (7.84 1H, dd, J=7.3Hz and 7.2Hz), 9.87 (1H, brs), 12.26 (1H, brs).
Embodiment 107
6-(external form-2-azabicyclo [2,2,2] octane-6-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 1 and embodiment 2, from external form-2-azabicyclo [2,2,2] octane-6-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：373(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.53-1.55 (1H, m), 1.75-1.77 (1H, m), 1.89-2.06 (4H, m), and 2.21-2.23 (1H, m), 3.07-3.10 (2H, m), 3.43-3.48 (4H, m), 5.39-5.43 (1H, s), 7.26-7.28 (1H, m), and 7.44-7.47 (1H, m), 7.57-7.61 (1H, m), 7.93-7.95 (1H, m), 8.87-9.03 (1H, br), 9.46-9.52 (1H, br), 9.73 and 9.80 (1H, brs).
Embodiment 108
6-(interior type-2-azabicyclo [2,2,2] octane-6-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 1 and embodiment 2, from interior type-2-azabicyclo [2,2,2] octane-6-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：373(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.67-1.73(3H，m)，2.03-2.13(4H，m)，3.04-3.06(1H，m)，3.34-3.57(5H，m)，5.49(1H，s)，7.30(1H，s)，7.50-7.51(1H，m)，7.58-7.60(1H，m)，7.92-7.94(1H，m)，8.07(1H，br)，9.79(1H，br)，9.89(1H，br)。
Embodiment 109
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(external form-2-methyl-2-azabicyclo [2,2,2] octane-6-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 6-(external form-2-azabicyclo [2,2,2] octane-6-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：387(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.43-1.44 (1H, m), 1.70-1.90 (5H, m), 2.11-2.13 (1H, m), and 2.38-2.46 (4H, m), 3.00-3.02 (1H, m), 3.32-3.36 (2H, m), 5.38 and 5.40 (1H, s), 7.25-7.27 (1H, m), 7.38-7.42 (1H, m), 7.56-7.61 (1H, m), 7.90-7.93 (1H, m), 9.73 (1H, br), 12.23 (1H, br).
Embodiment 110
4-(2,1,3-Ben Bing oxadiazole-4-yl)-4,7-dihydro-5-ethoxy carbonyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrobromates
Make 2,1, acetate (20mL) solution of 3-Ben Bing oxadiazole-4-aldehyde (3.0g), plum forests moral human relations acid (3.0g), 3-ketone-3-(1-benzyloxycarbonyl group piperidin-4-yl) ethyl propionate (6.8g) and ammonium acetate (1.8g) stirred 12 hours under refluxing.With the reaction mixture cool to room temperature, remove solvent under reduced pressure, obtain clear crystal (4.7g).At chloroform (10mL) solution of the ice-cooled clear crystal (4.7g) that down in chloroform (10mL) solution of dimethyl formamide (2.7g), adds phosphoryl chloride (3.4mL) and obtain, and stir the mixture and spend the night.Under ice-cooled, add sodium acetate (37.8g) aqueous solution, and stirred the mixture one hour.Use the chloroform extraction reaction mixture, and remove solvent under reduced pressure, obtain oily matter.(eluent: the oily matter that normal hexane-ethyl acetate (8: 2)) purifying obtains obtains clear crystal with silica gel column chromatography.In pyridine (20mL) solution of the clear crystal that obtains, add hydrazine (1.4g), and under heating, stirred the mixture 3 hours.With the reaction mixture cool to room temperature, remove solvent under reduced pressure, obtain oily matter.With silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying oily matter, obtain title compound (840mg), be clear crystal.In acetate (10mL) solution of the clear crystal that obtains, add HBr-AcOH solution (10mL), and stirred the mixture 3 hours.Remove solvent under reduced pressure, obtain clear crystal.Crystal from the EtOH recrystallization, is obtained title compound (630mg), be clear crystal.
MS(EI)：394(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.77 (3H, t, J=7.3Hz), 1.80-2.16 (4H, m), 2.90-2.93 (2H, m), 3.40-3.43 (2H, m), 3.80 (2H, q, J=7.3Hz), 4.12-4.15 (1H, m), 4.50 (2H, br), 5.67 (1H, s), 7.17 (1H, d, J=6.6Hz), 7.26 (1H, s), 7.51 (1H, dd, J=9.0Hz and 6.6Hz), 7.79 (1H, d, J=9.0Hz), 8.10 (1H, br), 8.74 (1H, br), 9.38 (1H, brs).
Embodiment 111
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(interior type-2-methyl-2-azabicyclo [2,2,2] octane-6-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 6-(interior type-2-azabicyclo [2,2,2] octane-6-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：387(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.43-1.47(2H，m)，1.60-1.64(2H，m)，1.81-1.82(1H，m)，1.79-2.06(2H，m)，2.24-2.26(1H，m)，2.36(3H，s)，2.76-2.80(2H，m)，3.19-3.22(1H，m)，5.43(1H，s)，7.25(1H，s)，7.42-7.46(1H，m)，7.57-7.60(1H，m)，7.90-7.94(1H，m)，10.79(1H，brs)，12.16(1H，brs)。
Embodiment 112
4-(2,1,3-Ben Bing oxadiazole-4-yl)-4,7-dihydro-5-ethoxy carbonyl-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 3, from 4-(2,1,3-Ben Bing oxadiazole-4-yl)-4,7-dihydro-5-ethoxy carbonyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：408(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.75 (3H, t, J=7.3Hz), 1.55-1.56 (1H, m), 1.71-1.73 (1H, m), 1.87-2.06 (4H, m), 2.17 (3H, s), 2.84-2.87 (2H, m), 3.78 (2H, q, J=7.3Hz), 3.93-3.96 (1H, m), 5.68 (1H, s), 7.12 (1H, d, J=6.6Hz), 7.22 (1H, s), 7.49 (1H, dd, J=9.0Hz and 6.6Hz), 7.77 (1H, d, J=9.0Hz), 9.32 (1H, brs), 12.06 (1H, brs).
Embodiment 113
4-(2-bromophenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-bromobenzaldehyde and 3-amino-pyrazol.
MS(EI)：383(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.85-1.93 (2H, m), 2.14-2.20 (2H, m), 2.94-2.98 (2H, m), 3.32-3.36 (3H, m), 5.36 (1H, s), (7.16 1H, dd, J=7.3Hz and 7.2Hz), and 7.23-7.27 (2H, m), (7.35 1H, dd, J=7.3Hz and 7.2Hz), 7.59 (1H, d, J=7.3Hz), 8.41 (1H, br), 9.14 (1H, br), 9.73 (1H, brs), 12.21 (1H, brs).
Embodiment 114
5-cyano group-4,7-dihydro-4-(2-p-methoxy-phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-methoxybenzaldehyde and 3-amino-pyrazol.
MS(EI)：335(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.87-1.95 (2H, m), 2.14-2.20 (2H, m), 2.94-3.03 (3H, m), 3.32-3.36 (2H, m), 3.82 (3H, s), 5.21 (1H, s), 6.88 (1H, dd, J=7.3Hz and 7.2Hz), 6.99 (1H, d, J=7.3Hz), 7.05 (1H, d, J=7.3Hz), 7.15-7.20 (2H, m), 8.44 (1H, br), 9.17 (1H, br), 9.53 (1H, brs), 12.11 (1H, brs).
Embodiment 115
5-cyano group-4-(2, the 3-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2,3 dichloro benzaldehyde and 3-amino-pyrazol.
MS(EI)：373(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.84-1.90(2H，m)，2.16-2.20(2H，m)，2.94-3.00(3H，m)，3.32-3.38(2H，m)，5.44(1H，s)，7.24-7.36(3H，m)，7.56(1H，d，J＝7.3Hz)，8.52(1H，br)，9.24(1H，br)，9.79(1H，brs)，12.29(1H，brs)。
Embodiment 116
4-(2-bromophenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromophenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：397(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.56-1.63 (2H, m), 1.85-1.90 (2H, m), 2.01-2.06 (2H, m), 2.17 (3H, s), 2.62-2.65 (1H, m), 2.87-2.89 (2H, m), 5.34 (1H, s), 7.14-7.26 (3H, m), 7.36 (1H, dd, J=7.3Hz and 7.2Hz), 7.60 (1H, d, J=7.3Hz), 9.60 (1H, brs), 12.16 (1H, brs).
Embodiment 117
5-cyano group-4,7-dihydro-4-(2-p-methoxy-phenyl)-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-(2-p-methoxy-phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine prepares title compound.
MS(EI)：349(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.56-1.66 (2H, m), 1.86-1.92 (2H, m), 2.01-2.04 (2H, m), 2.17 (3H, s), 2.64-2.67 (1H, m), 2.86-2.88 (2H, m), 3.84 (3H, s), 5.20 (1H, s), (6.90 1H, dd, J=7.3Hz and 7.2Hz), 6.98 (1H, d, J=7.3Hz), 7.05 (1H, d, J=7.3Hz), 7.16-7.19 (2H, m), 9.41 (1H, brs), 12.01 (1H, brs).
Embodiment 118
5-cyano group-4-(2, the 3-dichlorophenyl)-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4-(2, the 3-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
MS(EI)：387(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.57-1.65 (2H, m), 1.85-1.90 (2H, m), 2.01-2.06 (2H, m), 2.17 (3H, s), 2.59-2.66 (1H, m), 2.86-2.89 (2H, m), 5.43 (1H, s), 7.23 (1H, d, J=7.3Hz), 7.29 (1H, s), 7.35 (1H, dd, J=7.3Hz and 7.2Hz), 7.51 (1H, d, J=7.3Hz), 9.65 (1H, brs), 12.18 (1H, brs).
Embodiment 119
5-cyano group-4,7-dihydro-4-(2-fluorophenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-fluorobenzaldehyde and 3-amino-pyrazol.
MS(EI)：323(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.85-1.89(2H，m)，2.12-2.20(2H，m)，2.90-2.98(3H，m)，3.33-3.39(2H，m)，5.20(1H，s)，7.14-7.28(5H，m)，8.37(1H，br)，9.09(1H，br)，9.66(1H，brs)，12.23(1H，brs)。
Embodiment 120
5-cyano group-4-(2, the 3-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 1 and embodiment 2, from nipecotic acid ethyl ester, 2,3-difluorobenzaldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：341(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.84-1.88 (2H, m), 2.14-2.19 (2H, m), 2.95-3.00 (3H, m), 3.33-3.38 (2H, m), 5.26 (1H, s), 7.03 (1H, d, J=7.3Hz), 7.18 (1H, dd, J=7.3Hz and 7.2Hz), 7.26-7.31 (2H, m), 8.80 (2H, br), 9.74 (1H, brs), 12.29 (1H, brs).
Embodiment 121
5-cyano group-4-(2, the 6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 1 and embodiment 2, from nipecotic acid ethyl ester, 2,6-difluorobenzaldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：341(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.76-1.84(2H，m)，2.13-2.18(2H，m)，2.91-2.95(3H，m)，3.28-3.30(2H，m)，5.35(1H，s)，7.02-7.07(2H，m)，7.31-7.38(2H，m)，8.77(2H，br)，9.68(1H，brs)，12.22(1H，brs)。
Embodiment 122
5-cyano group-4,7-dihydro-4-(2-methylthio group phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-methylthio phenyl formaldehyde and 3-amino-pyrazol.
MS(EI)：351(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.86-1.93(2H，m)，2.17-2.23(2H，m)，2.50(3H，s)，2.95-3.00(3H，m)，3.36-3.40(4H，m)，5.36(1H，s)，7.14-7.33(5H，m)，8.49(1H，br)，9.22(1H，br)，9.63(1H，brs)。
Embodiment 123
5-cyano group-4-(2, the 6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 1 and embodiment 2, from nipecotic acid ethyl ester, 2,6-dichlorobenzaldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：373(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.80-1.84 (2H, m), 2.12-2.20 (2H, m), 2.90-2.98 (3H, m), 3.30-3.33 (2H, m), 5.92 (1H, s), 7.19 (1H, s), 7.29 (1H, dd, J=7.3Hz and 7.2Hz), 7.38 (1H, d, J=7.3Hz), 7.51 (1H, d, J=7.3Hz), 8.41 (1H, br), 9.16 (1H, br), 9.73 (1H, brs), 12.18 (1H, brs).
Embodiment 124
5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethyl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-trifluoromethylated benzaldehyde and 3-amino-pyrazol.
MS(EI)：373(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.83-1.90(2H，m)，2.18-2.26(2H，m)，2.92-3.00(3H，m)，3.38-3.43(2H，m)，4.16(2H，br)，5.22(1H，s)，7.06(1H，s)，7.42-7.44(2H，m)，7.63-7.69(2H，m)，8.57(1H，br)，9.30(1H，br)，9.77(1H，br)。
Embodiment 125
5-cyano group-4,7-dihydro-4-(2-fluorophenyl)-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-(2-fluorophenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
MS(EI)：337(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.55-1.59(2H，m)，1.83-1.88(2H，m)，1.96-2.00(2H，m)，2.15(3H，s)，2.60-2.63(1H，m)，2.84-2.88(2H，m)，5.17(1H，s)，7.13-7.24(5H，m)，9.60(1H，brs)，12.18(1H，brs)。
Embodiment 126
5-cyano group-4-(2, the 3-difluorophenyl)-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4-(2, the 3-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
MS(EI)：355(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.55-1.59 (2H, m), 1.82-1.8 (2H, m), 1.99-2.02 (2H, m), 2.15 (3H, s), 2.57-2.60 (1H, m), 2.84-2.88 (2H, m), 5.23 (1H, s), (7.00 1H, dd, J=7.3Hz and 7.2Hz), 7.16 (1H, d, J=7.3Hz), 7.27-7.30 (2H, m), 9.66 (1H, brs), 12.24 (1H, brs).
Embodiment 127
5-cyano group-4-(2, the 6-difluorophenyl)-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4-(2, the 6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
MS(EI)：355(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.49-1.53(2H，m)，1.82-1.86(2H，m)，1.96-2.01(2H，m)，2.15(3H，s)，2.48-2.51(1H，m)，2.83-2.86(2H，m)，5.31(1H，s)，7.00-7.05(2H，m)，7.29-7.31(2H，m)，9.60(1H，brs)，12.15(1H，brs)。
Embodiment 128
5-cyano group-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-nitrobenzaldehyde and 3-amino-pyrazol.
MS(EI)：351(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.84-1.93 (2H, m), 2.17-2.23 (2H, m), 2.94-3.00 (3H, m), 3.35-3.38 (2H, m), 4.42 (2H, br), 5.40 (1H, s), 7.30 (1H, s), 7.46-7.51 (2H, m), 7.71 (1H, dd, J=7.3Hz and 7.2Hz), 7.90 (1H, d, J=7.3Hz), 8.61 (1H, br), 9.36 (1H, br), 9.87 (1H, brs).
Embodiment 129
5-cyano group-4,7-dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, phenyl aldehyde and 3-amino-pyrazol.
MS(EI)：305(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.81-1.89(2H，m)，2.14-2.20(2H，m)，2.90-2.96(3H，m)，3.32-3.35(2H，m)，4.20(2H，br)，4.89(1H，s)，7.17-7.22(4H，m)，7.28-7.31(2H，m)，8.58(1H，br)，9.32(1H，br)，9.65(1H，brs)。
Embodiment 130
5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-4-(2-methylthio group phenyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-(2-methylthio group phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：366(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.58-1.66(2H，m)，1.83-1.89(2H，m)，1.97-2.02(2H，m)，2.15(3H，s)，2.50(3H，s)，2.62-2.65(1H，m)，2.84-2.87(2H，m)，5.32(1H，s)，7.12-7.30(5H，m)，9.57(1H，brs)，12.18(1H，brs)。
Embodiment 131
5-cyano group-4-(2, the 6-dichlorophenyl)-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4-(2, the 6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine hydrochloride prepares title compound.
MS(EI)：387(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.52-1.56 (2H, m), 1.83-1.87 (2H, m), 1.99-2.06 (2H, m), 2.15 (3H, s), 2.52-2.55 (1H, s), 2.83-2.87 (2H, m), 5.90 (1H, s), 7.17 (1H, s), 7.28 (1H, dd, J=7.3Hz and 7.2Hz), 7.36 (1H, d, J=7.3Hz), 7.48 (1H, d, J=7.3Hz), 9.67 (1H, brs), 12.12 (1H, brs).
Embodiment 132
5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-4-(2-trifluoromethyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethyl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：387(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.57-1.62(2H，m)，1.83-1.86(2H，m)，1.97-2.03(2H，m)，2.16(3H，s)，2.60-2.63(1H，m)，2.84-2.87(2H，m)，5.18(1H，s)，7.05(1H，s)，7.40-7.42(2H，m)，7.62-7.68(2H，m)，9.69(1H，brs)，12.23(1H，brs)。
Embodiment 133
5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-4-(2-nitrophenyl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：365(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.58-1.67 (2H, m), 1.86-1.90 (2H, m), 1.99-2.06 (2H, m), 2.16 (3H, s), 2.58-2.61 (1H, m), 2.86-2.90 (2H, m), 5.36 (1H, s), 7.26 (1H, s), and 7.42-7.48 (2H, m), 7.69 (1H, dd, J=7.3Hz and 7.2Hz), 7.88 (1H, d, J=7.3Hz), 9.72 (1H, brs), 12.26 (1H, brs).
Embodiment 134
5-cyano group-4,7-dihydro-4-phenyl-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：319(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.54-1.57(2H，m)，1.81-1.87(2H，m)，1.97-2.03(2H，m)，2.15(3H，s)，2.58-2.60(1H，m)，2.84-2.86(2H，m)，4.87(1H，s)，7.17-7.20(4H，m)，7.27-7.32(2H，m)，9.52(1H，brs)，12.13(1H，brs)。
Embodiment 135
5-cyano group-4-(2,2-two fluoro-1,3-benzo dioxole-4-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from ethyl butyrate, 2,2-two fluoro-1,3-benzo dioxole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：322(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 0.93 (3H, t, J=7.3Hz), 1.63-1.68 (2H, m), 2.34-2.45 (2H, m), 5.16 (1H, s), 7.02 (1H, d, J=7.3Hz), 7.18 (1H, dd, J=7.3Hz and 7.2Hz), 7.28 (1H, d, J=7.2Hz), 9.88 (1H, brs), 12.22 (1H, brs).
Embodiment 136
4-(2,1,3-diazosulfide-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 1 and embodiment 2, from nipecotic acid ethyl ester, 2,1,3-diazosulfide-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：363(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.89-1.98 (2H, m), 2.22-2.29 (2H, m), 2.98-3.05 (3H, m), 3.37-3.43 (2H, m), 5.20 (2H, br), 5.72 (1H, s), 7.24 (1H, s), 7.48 (1H, d, J=6.6Hz), 7.72 (1H, dd, J=9.0Hz and 6.6Hz), 7.99 (1H, d, J=9.0Hz), 8.68 (1H, br), 9.43 (1H, br), 9.86 (1H, brs).
Embodiment 137
5-cyano group-4-(2,2-two fluoro-1,3-benzo dioxole-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
With the method identical with embodiment 1 and embodiment 2, from the nipecotic acid ethyl ester, 2,2-two fluoro-1,3-benzo dioxole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：385(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.82-1.85 (2H, m), 2.16-2.22 (2H, m), 2.95-3.00 (3H, m), 3.34-3.39 (2H, m), 5.17 (1H, s), 5.65 (2H, br), 7.05 (1H, d, J=7.3Hz), (7.19 1H, dd, J=7.3Hz and 7.2Hz), 7.29 (1H, d, J=7.3Hz), 7.33 (1H, s), 8.65 (1H, br), 9.43 (1H, br), 9.86 (1H, brs).
Embodiment 138
4-(2,1,3-diazosulfide-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2,1,3-diazosulfide-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：377(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.64-1.73 (2H, m), 1.91-1.97 (2H, m), 2.05-2.09 (2H, m), 2.419 (3H, s), 2.70-2.72 (1H, m), 2.90-2.93 (2H, m), 5.71 (1H, s), 7.22 (1H, s), 7.45 (1H, d, J=6.6Hz), 7.72 (1H, dd, J=9.0Hz and 6.6Hz), 7.98 (1H, d, J=9.0Hz), 9.71 (1H, brs), 12.13 (1H, brs).
Embodiment 139
5-cyano group-4-(2,2-two fluoro-1,3-benzo dioxole-4-yl)-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4-(2,2-two fluoro-1,3-benzo dioxole-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：399(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.5-1.58 (2H, m), 1.86-1.90 (2H, m), 1.99-2.03 (2H, m), 2.16 (3H, s), 2.59-2.62 (1H, m), 2.85-2.89 (2H, m), 5.15 (1H, s), 7.03 (1H, d, J=7.3Hz), 7.17 (1H, dd, J=7.3Hz and 7.2Hz), 7.26-7.31 (2H, m), 9.71 (1H, brs), 12.26 (1H, brs).
Embodiment 140
5-cyano group-4-(2-cyano-phenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, 2-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：330(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.86-1.90 (2H, m), 2.18-2.22 (2H, m), 2.92-2.98 (3H, m), 3.34-3.37 (2H, m), 5.10 (2H, br), 5.25 (1H, s), 7.27 (1H, s), 7.43-7.47 (2H, m), 7.68 (1H, dd, J=7.3Hz and 7.2Hz), 7.82 (1H, d, J=7.3Hz), 8.61 (1H, br), 9.41 (1H, br), 9.93 (1H, brs).
Embodiment 141
5-cyano group-4-(2-cyano-phenyl)-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4-(2-cyano-phenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：344(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.58-1.63 (2H, m), 1.82-1.87 (2H, m), 1.98-2.06 (2H, m), 2.16 (3H, s), 2.59-2.61 (1H, m), 2.84-2.88 (2H, m), 5.23 (1H, s), 7.25 (1H, s), and 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).
Embodiment 142
5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo [3,4-b] pyridine 3 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, pyridine-4-aldehyde and 3-amino-pyrazol.
MS(EI)：306(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.86-1.92(2H，m)，2.18-2.25(2H，m)，2.93-3.00(3H，m)，3.35-3.38(2H，m)，5.41(1H，s)，6.50(3H，br)，7.42(1H，s)，7.97(2H，d，J＝6.8Hz)，8.90(1H，br)，8.93(2H，d，J＝6.8Hz)，9.60(1H，br)，10.10(1H，brs)。
Embodiment 143
5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo [3,4-b] pyridine 3 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from nipecotic acid ethyl ester, pyridine-3-aldehyde and 3-amino-pyrazol.
MS(EI)：306(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.86-1.93 (2H, m), 2.19-2.25 (2H, m), 2.90-2.97 (3H, m), 3.35-3.38 (2H, m), 5.39 (1H, s), 6.50 (3H, br), 7.41 (1H, s), 8.09 (1H, dd, J=8.2Hz and 5.4Hz), 8.49 (1H, d, J=8.2Hz), 8.72 (1H, br), 8.88 (1H, d, J=5.4Hz), 8.92 (1H, s), 9.57 (1H, br), 10.02 (1H, brs).
Embodiment 144
5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo [3,4-b] pyridine 3 hydrochlorides prepare title compound.
MS(EI)：320(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.56-1.64(2H，m)，1.86-1.90(2H，m)，1.99-2.03(2H，m)，2.17(3H，s)，2.61-2.64(1H，m)，2.86-2.89(2H，m)，4.96(1H，s)，7.23(2H，d，J＝6.8Hz)，7.31(1H，s)，8.50(2H，d，J＝6.8Hz)，9.67(1H，brs)，12.25(1H，brs)。
Embodiment 145
5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo [3,4-b] pyridine 3 hydrochlorides prepare title compound.
MS(EI)：320(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.57-1.60 (2H, m), 1.84-1.89 (2H, m), 1.99-2.05 (2H, m), 2.17 (3H, s), 2.58-2.61 (1H, m), 2.85-2.8 (2H, m), 4.98 (1H, s), 7.29 (1H, s), 7.35 (1H, dd, J=8.2Hz and 5.4Hz), 7.55 (1H, d, J=8.2Hz), 8.42-8.45 (2H, m), 9.64 (1H, brs), 12.23 (1H, brs).
Embodiment 146
6-(external form-2-azabicyclo [2,2,2] octane-6-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from external form-2-azabicyclo [2,2,2] octane-6-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：435(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.52-1.54(1H，m)，1.74-2.18(6H，m)，3.06-3.09(2H，m)，3.50-3.52(2H，m)，3.87(2H，br)，5.51(1H，s)，7.33(1H，d，J＝7.3Hz)，7.55-7.60(2H，m)，7.84(1H，d，J＝7.3Hz)，8.97(1H，br)，9.73(1H，br)，9.78(1H，brs)。
Embodiment 147
6-(interior type-2-azabicyclo [2,2,2] octane-6-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 1 and embodiment 2 prepares title compound from interior type-2-azabicyclo [2,2,2] octane-6-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：435(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.67-1.69 (3H, m), 2.02-2.12 (4H, m), 3.02-3.05 (1H, m), and 3.31-3.35 (1H, m), 3.45-3.51 (2H, m), 4.04 (2H, br), 5.50 (1H, s), 7.34 (1H, s), 7.56 (1H, dd, J=7.3Hz and 7.2Hz), 7.82 (1H, d, J=7.3Hz), 8.16 (1H, br), 9.82 (1H, br), 9.93 (1H, brs).
Embodiment 148
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(external form-2-methyl-2-azabicyclo [2,2,2] octane-6-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 6-(external form-2-azabicyclo [2,2,2] octane-6-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：449(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.42-1.45 (1H, m), 1.72-1.88 (5H, m), 2.06-2.09 (1H, m), and 2.46-2.51 (4H, m), 3.04-3.07 (1H, m), and 3.45-3.48 (2H, m), 5.48 (1H, s), 7.34 (1H, s), 7.57-7.60 (2H, m), 7.83 (1H, dd, J=7.3Hz and 7.2Hz), 9.83 (1H, brs), 12.37 (1H, brs).
Embodiment 149
4-(2,2-two fluoro-1,3-benzo dioxole-4-yl)-4,7-dihydro-5-ethoxy carbonyl-6-propyl group-2H-pyrazolo [3,4-b] pyridine
With 2,2-two fluoro-1, acetate (20mL) solution of 3-benzo dioxole-4-aldehyde (2.0g), plum forests moral human relations acid (1.6g), 3-ketone-ethyl hexanoate (1.7g) and ammonium acetate (0.91g) stirred 12 hours under refluxing.With the reaction mixture cool to room temperature and remove solvent under reduced pressure, obtain clear crystal (2.4g).At chloroform (10mL) solution of the ice-cooled clear crystal (2.4g) that down in chloroform (10mL) solution of dimethyl formamide (1.9g), adds phosphoryl chloride (4.0g) and obtain, and stir the mixture and spend the night.Under ice-cooled, add sodium acetate (27g) aqueous solution, and stirred the mixture one hour.Use the chloroform extraction reaction mixture, and remove solvent under reduced pressure, obtain oily matter.(eluent: the oily matter that normal hexane-ethyl acetate (8: 2)) purifying obtains obtains clear crystal with silica gel column chromatography.In pyridine (20mL) solution of the clear crystal that obtains, add hydrazine (1.0g), and heated and stirred mixture 3 hours.With the reaction mixture cool to room temperature and remove solvent under reduced pressure, obtain oily matter.With silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying oily matter, obtain title compound (190mg), be clear crystal.
MS(EI)：391(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：0.90-0.97(6H，m)，1.58-1.64(2H，m)，2.60-2.64(1H，m)，2.83-2.86(1H，m)，3.83(2H，q，J＝7.3Hz)，5.32(1H，m)，6.86(1H，d，J＝7.3Hz)，7.03-7.11(2H，m)，7.24(1H，s)，9.61(1H，brs)，12.06(1H，brs)。
Embodiment 150
4-(2-bromo-3-cyano-phenyl)-4,7-dihydro-5-ethoxy carbonyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 110 prepares title compound from 2-bromo-3-cyanobenzaldehyde.
MS(EI)：455(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：0.84(3H，t，J＝7.3Hz)，1.78-1.81(1H，m)，1.98-2.14(3H，m)，2.87-2.90(2H，m)，3.40-3.42(2H，m)，3.78(2H，q，J＝7.3Hz)，3.80-4.25(3H，m)，5.64(1H，s)，7.35(1H，s)，7.40-7.47(2H，m)，7.70(1H，d，J＝7.3Hz)，8.10(1H，br)，8.73(1H，br)，9.37(1H，brs)。
Embodiment 151
4-(2-bromo-3-cyano-phenyl)-4,7-dihydro-5-ethoxy carbonyl-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 3, from 4-(2-bromo-3-cyano-phenyl)-4,7-dihydro-5-ethoxy carbonyl-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides prepare title compound.
MS(EI)：469(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：0.85(3H，t，J＝7.3Hz)，1.53-1.55(1H，m)，1.70-1.72(1H，m)，1.87-2.06(4H，m)，2.16(3H，s)，2.84-2.88(2H，m)，3.78(2H，q，J＝7.3Hz)，3.94-3.96(1H，m)，5.63(1H，s)，7.34-7.48(3H，m)，7.68(1H，d，J＝7.3Hz)，9.34(1H，brs)，12.16(1H，brs)。
Embodiment 152
4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl-2-oxo-piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 1, from 1-methyl-2-oxo-piperidine-4-ethyl formate, 2,1,3-Ben Bing oxadiazole-4-aldehyde and 3-amino-pyrazol prepare title compound.
MS(EI)：375(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.88-1.91 (1H, m), 2.26-2.33 (2H, m), 2.65-2.70 (1H, m), 2.82 (3H, m), 3.17-3.20 (1H, m), 3.31-3.36 (2H, m), 5.40 (1H, s), 7.29 (1H, s), 7.44 (1H, d, J=6.6Hz), 7.58 (1H, dd, J=9.0Hz and 6.6Hz), 7.92 (1H, d, J=9.0Hz), 9.88 (1H, brs), 12.22 (1H, brs).
Embodiment 153
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl-2-oxo-piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 1 prepares title compound from 1-methyl-2-oxo-piperidine-4-ethyl formate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：437(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.88-1.92(1H，m)，2.25-2.36(2H，m)，2.69-2.74(1H，m)，2.84(3H，s)，3.18-3.36(3H，m)，5.50(1H，s)，7.37(1H，s)，7.59-7.62(2H，m)，7.85(1H，d，J＝7.3Hz)，9.90(1H，brs)，12.33(1H，brs)。
Embodiment 154
4-(2-chloro-phenyl-)-4,7-dihydro-5-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-6-propyl group-2H-pyrazolo [3,4-b] pyridine
Acetate (150mL) vlil of 2-chlorobenzaldehyde (21g), plum forests moral human relations acid (21g), 3-ketone-caproic acid-2-cyano ethyl ester (27g) and ammonium acetate (13g) is spent the night.With the reaction mixture cool to room temperature and remove solvent under reduced pressure, obtain clear crystal (16g).Add 1N NaOH solution (100mL), and heated and stirred mixture 3 hours.With the reaction mixture cool to room temperature, and acidified solvent.Use the ethyl acetate extraction reaction mixture, and remove solvent under reduced pressure, obtain clear crystal (9.6g).In the DMF of the clear crystal that obtains (1.0g) (5mL) solution, add hydrazine (0.22g) and CDI (0.66g), and stirred the mixture 3 hours.Filter the crystal of collecting precipitation, obtain clear crystal (0.7g).In the DMF of the clear crystal that obtains (1.0g) (5mL) solution, added triethly orthoacetate (3.7g) and heated mixt 3 hours.Filter the crystal of collecting precipitation, obtain clear crystal (0.6g).At chloroform (6mL) solution of the ice-cooled clear crystal that down in chloroform (3mL) solution of dimethyl formamide (0.55g), adds phosphoryl chloride (1.2g) and obtain and stir the mixture and spend the night.Add sodium acetate (7.7g) aqueous solution down ice-cooled, and stirred the mixture one hour.Use the chloroform extraction reaction mixture, and remove solvent under reduced pressure, obtain oily matter.(eluent: the oily matter that normal hexane-ethyl acetate (8: 2)) purifying obtains obtains clear crystal with silica gel column chromatography.In pyridine (10mL) solution of the clear crystal that obtains, add hydrazine (0.15g), heated and stirred mixture 3 hours.With the reaction mixture cool to room temperature and remove solvent under reduced pressure, obtain oily matter.With silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying oily matter, obtain title compound (170mg), be clear crystal.
MS(EI)：356(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：1.00(3H，t，J＝7.3Hz)，1.67-1.74(2H，m)，2.31(3H，s)，2.70-2.83(2H，m)，5.71(1H，s)，7.07-7.12(3H，m)，7.33-7.40(2H，m)，9.49(1H，brs)，12.04(1H，brs)。
Embodiment 155
4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-(methylamino) ethyl)-2H-pyrazolo [3,4-b] pyridine 2 hydrochlorides
Method with identical with embodiment 15 and embodiment 2 prepares title compound from 2-methylglycine ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazol.
MS(EI)：384(M +)。
1H-NMR(400MHz，DMSO-d 6)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)。
Embodiment 156
4-(2-chloro-phenyl-)-4,7-dihydro-5-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-6-propyl group-2H-pyrazolo [3,4-b] pyridine
Acetate (150mL) solution heated overnight under refluxing with 2-chlorobenzaldehyde (21g), plum forests moral human relations acid (21g), 3-ketone-caproic acid-2-cyano group ethyl ester (27g) and ammonium acetate (13g).With the reaction mixture cool to room temperature, remove solvent under reduced pressure, obtain clear crystal (16g).Added 1NNaOH solution (100mL) and heated and stirred mixture 3 hours.With reaction mixture cool to room temperature, acidified solvent.With the ethyl acetate extraction reaction mixture and remove solvent under reduced pressure, obtain clear crystal (9.6g).In the DMF of the clear crystal that obtains (4.2g) (20mL) solution, add ammonia solution (3.0g) and CDI (2.8g), and stir and spend the night.Use the ethyl acetate extraction reaction mixture, and remove solvent under reduced pressure, obtain oily matter.N,N-dimethylacetamide dimethylacetal (30mL) solution that adds thermal residue reaches 2 hours, and removes solvent under reduced pressure.In resistates, add azanol (hydroxyammonium) (1.4g), 1N NaOH (20mL), dioxane (20mL) and acetate (28mL), and heated mixt one hour.Use the ethyl acetate extraction reaction mixture, and remove solvent under reduced pressure, obtain oily matter.(eluent: normal hexane-ethyl acetate (1: 1)) purifying oily matter obtains clear crystal (1.3g) with silica gel column chromatography.At chloroform (20mL) solution of the ice-cooled clear crystal that down in chloroform (10mL) solution of dimethyl formamide (1.7g), adds phosphoryl chloride (3.5g) and obtain and stir the mixture and spend the night.Add sodium acetate (23g) aqueous solution down ice-cooled, and stirred the mixture one hour.Use the chloroform extraction reaction mixture, and remove solvent under reduced pressure, obtain oily matter.(eluent: the oily matter that normal hexane-ethyl acetate (8: 2)) purifying obtains obtains clear crystal with silica gel column chromatography.In pyridine (15mL) solution of the clear crystal that obtains, add hydrazine (0.6g), heated and stirred mixture 3 hours.With the reaction mixture cool to room temperature and remove solvent under reduced pressure, obtain oily matter.With silica gel column chromatography (eluent: normal hexane-ethyl acetate (1: 1)) purifying oily matter, obtain title compound (500mg), be clear crystal.
MS(EI)：356(M +)。
1H-NMR(400MHz，DMSO-d 6)δ(ppm)：0.99(3H，s)，1.62(3H，t，J＝7.3Hz)，1.66-1.73(2H，m)，2.13(3H，s)，2.35-2.38(2H，m)，2.84-3.05(2H，m)，5.73(1H，s)，7.06-7.17(3H，m)，9.90(1H，brs)，12.11(1H，brs)。
Embodiment 157
4-(2,1,3-Ben Bing oxadiazole-4-yl)-4,7-dihydro-5-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-6-propyl group-2H-pyrazolo [3,4-b] pyridine
With the method identical with embodiment 154, from 2,1,3-Ben Bing oxadiazole-4-aldehyde prepares title compound.
MS(EI)：364(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.01 (3H, t, J=7.3Hz), 1.69-1.76 (2H, m), 2.31 (3H, s), 2.72-2.86 (2H, m), 5.82 (1H, s), 7.18 (1H, d, J=6.6Hz), 7.32 (1H, s), 7.48 (1H, dd, J=9.0Hz and 6.6Hz), 7.80 (1H, d, J=9.0Hz), 9.65 (1H, brs), 12.07 (1H, brs).
Embodiment 158
4-(2-bromo-3-cyano-phenyl)-4,7-dihydro-5-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-6-propyl group-2H-pyrazolo [3,4-b] pyridine
Method with identical with embodiment 154 prepares title compound from 2-bromo-3-cyanobenzaldehyde.
MS(EI)：425(M +)。
1H-NMR (400MHz, DMSO-d 6) δ (ppm): 1.00 (3H, t, J=7.3Hz), 1.66-1.73 (2H, m), 2.33 (3H, s), 2.74-2.78 (2H, m), 5.78 (1H, s), 7.40-7.47 (3H, m), 7.69 (1H, dd, J=7.3Hz and 7.2Hz), 9.63 (1H, brs), 12.14 (1H, brs).
Embodiment 159
6-(1-amino-1-methylethyl)-4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine hydrochloride
With the method identical with embodiment 15 and embodiment 2, from 2,2-N-methylsarcosine ethyl ester, 2-chlorobenzaldehyde and 3-amino-pyrazol prepare title compound.
Embodiment 1 embodiment 2 embodiment 3 embodiment 4
Embodiment 5 embodiment 6 embodiment 7 embodiment 8
Figure A0381903601003
Embodiment 9 embodiment 10 embodiment 11 embodiment 12
Embodiment 13 embodiment 14 embodiment 15 embodiment 16
Figure A0381903601005
Embodiment 17 embodiment 18 embodiment 19 embodiment 20
Embodiment 21 embodiment 22 embodiment 23 embodiment 24
Figure A0381903601012
Embodiment 25 embodiment 26 embodiment 27 embodiment 28
Embodiment 29 embodiment 30 embodiment 31 embodiment 32
Figure A0381903601014
Embodiment 33 embodiment 34 embodiment 35 embodiment 36
Embodiment 37 embodiment 38 embodiment 39 embodiment 40
Figure A0381903601021
Embodiment 41 embodiment 42 embodiment 43 example examples 44
Embodiment 45 embodiment 46 example examples 47 embodiment 48
Figure A0381903601023
Embodiment 49 embodiment 50 embodiment 51 embodiment 52
Embodiment 53 embodiment 54 embodiment 55 embodiment 56
Embodiment 57 embodiment 58 embodiment 59 embodiment 60
Figure A0381903601031
Embodiment 61 embodiment 62 embodiment 63 embodiment 64
Figure A0381903601032
Embodiment 65 embodiment 66 embodiment 67 embodiment 68
Embodiment 69 embodiment 70 embodiment 7l embodiment 72
Embodiment 73 embodiment 74 embodiment 75 embodiment 76
Figure A0381903601037
Embodiment 77 embodiment 78 embodiment 79 embodiment 80
Figure A0381903601041
Embodiment 81 embodiment 82 embodiment 83 embodiment 84
Figure A0381903601042
Embodiment 85 embodiment 86 embodiment 87 embodiment 88
Embodiment 89 embodiment 90 embodiment 91 embodiment 92
Figure A0381903601044
Embodiment 93 embodiment 94 embodiment 95
Embodiment 96 embodiment 97 embodiment 98 embodiment 99
Figure A0381903601052
Embodiment 100 embodiment 101 embodiment 102 embodiment 103
Figure A0381903601053
Embodiment 104 embodiment 105 embodiment 106 embodiment 107
Embodiment 108 embodiment 109 embodiment 110 embodiment 111
Embodiment 112 embodiment 113 embodiment 114 embodiment 115
Figure A0381903601061
Embodiment 116 embodiment 117 embodiment 118 embodiment 119
Embodiment 120 embodiment 121 embodiment 122 embodiment 123
Figure A0381903601063
Embodiment 124 embodiment 125 embodiment 126 embodiment 127
Figure A0381903601064
Embodiment 128 embodiment 129 embodiment 130 embodiment 131
Figure A0381903601065
Embodiment 132 embodiment 133 embodiment 134 embodiment 135
Embodiment 136 embodiment 137 embodiment 138 embodiment 139
Embodiment 140 embodiment 141 embodiment 142 embodiment 143
Embodiment 144 embodiment 145 embodiment 146 embodiment 147
Embodiment 148 embodiment 149 embodiment 150 embodiment 151
Embodiment 152 embodiment 153 embodiment 154 embodiment 155
Embodiment 156 embodiment 157 embodiment 158 embodiment 159
Example of formulations 1
With compound (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and W-Gum (3 parts) thorough mixing of embodiment 1 and use the tackiness agent of making by W-Gum (2 parts) to knead.Make the product of kneading through 16 mesh sieves, dry also by 24 mesh sieves in 50 ℃ baking oven.The powder of kneading, W-Gum (8 parts), crystalline cellulose (11 parts) and the talcum (9 parts) that so obtains mixed up hill and dale and compress punching press, obtain every tablet of tablet that comprises the 0.5mg activeconstituents.
Example of formulations 2
Compound (1.0mg) and the sodium-chlor (9.0mg) of embodiment 1 are dissolved in the water for injection, and filtering solution is to remove pyrogen.Under aseptic condition, filtrate is transferred in the ampoule.Melting welding sealed ampoule in sterilization back obtains comprising the injection liquid of 1.0mg activeconstituents.
Following evaluation and proof The compounds of this invention are to the effect of glycogen synthase kinase-3 β (GSK-3 β).
Test routine 1:GSK-3 β and suppress active
Make CREB phospho-peptide (4.6nmol), rabbit GSK-3 β (0.5 unit), ATP (5nmol), [γ- 32P] reaction 20 minutes in 30 ℃ the GSK-3 β damping fluid that comprises 1% methyl-sulphoxide (25 μ L) (20mmol/L Tris-HCl (pH 7.5), 10mmol/L magnesium chloride, 5mmol/L dithiothreitol (DTT)) of ATP (12.3kBq) and test compounds.(10 μ L) is adsorbed onto on the P81 ion exchange paper with reaction product, washes ion exchange paper and measure cpm on scintillometer with phosphoric acid (100mmol/L).The result is that compound of the present invention shows the IC of 1nmol/L to 1000nmol/L 50For example, the IC of compound 50Value as shown in the following Table 1.
The CREB phospho-peptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser-Arg-Arg-Pro-Ser (P)-Tyr-Arg.
Table 1
The embodiment numbering ????IC 50????(nmol/L)
????2 ????10
????3 ????2.5
????8 ????3.7
????11 ????14
????23 ????4.1
????58 ????1.8
????63 ????3.0
????146 ????0.61
????148 ????3.2
????155 ????2.2
????158 ????0.65
Test example 2: the GSK-3 β in the hippocampus of rats of artificial culture suppresses active
After gestation, obtained hippocampal neuron from rat embryo in the 18 day.Cultivating hippocampal neuron after 7 days, handling neurone, and continuing to cultivate 3 hours, thereby inducing the proteic phosphorylation of Tau with amyloid beta (25-35) (20 μ mol/L) and test compounds (GSK-3 beta inhibitor).After finishing cultivation, use phosphorylation Tau identification antibody (by the position of GSK-3 β phosphorylation) to measure the proteic phosphorylation level of Tau, and estimate the GSK-3 beta inhibitor neuronic restraining effect by the EIA method.
The test example 3: in the hippocampus of rats of artificial culture to the Cytotoxic effect of amyloid beta inductive
After gestation, obtained hippocampal neuron from rat embryo in the 18 day.Cultivating hippocampal neuron after 7 days, handling neurone, and continuing to cultivate 24 hours with amyloid beta (25-35) (20 μ mol/L) and test compounds (GSK-3 beta inhibitor), thus inducing cytotoxic (dehydrogenase activity reduces in the cell).After finishing cultivation, measure dehydrogenase activity in the cell, and estimate the GSK-3 beta inhibitor the Cytotoxic effect of amyloid beta inductive.
Test example 4: the GSK-3 β restraining effect in gerbil jird cerebral ischaemia model
Give gerbil jird with test compounds (GSK-3 beta inhibitor) peritoneal injection, after 30 minutes, produce local asphyxia, thereby induce the Tau protein phosphorylation in the brain by closeall carotid artery (4 minutes).After cerebral ischaemia three hours, from the gerbil jird brain, obtain hippocampus, and use phosphorylation Tau to discern antibody (by the position of GSK-3 β phosphorylation) by Western blotting and measure the proteic phosphorylation level of Tau, estimate the GSK-3 β restraining effect of GSK-3 beta inhibitor in the gerbil jird brain based on this.
Industrial applicibility
Compound of the present invention shows optionally active with strong inhibition to glycogen synthase kinase-3β (GSK-3 β), and useful as drug, be used for preventing and/or treating the tumour of diabetes, diabetic complication, nerve degeneration sick (Parkinson's neurological dysfunction, boxer's encephalopathic, Guam type op parkinson's chronic brain syndrome, thunder dimension corpusculum disease, pik disease, cortico-basal degeneration, volume temporal lobe type dementia, AIDS encephalopathic, Huntington's disease and manic-depressive psychosis etc. after the cerebral ischemia that Alzheimer's, ischemic cerebral vascular disorder, Down's syndrome, Cerebral amyloid angiopathy cause, stein-leventhal syndrome, subacute sclerosing panencephalitis Parkinson neurological dysfunction, the encephalitis), alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T cell or B cell leukemia or virus induction, or will be as immunopotentiator.
The application is based on the patent application No.2002-230581 that submits in Japan, and its content is incorporated this paper into way of reference.

Claims (17)

1. the dihydro-pyrazolo pyridine compounds of formula (I) expression, or its optical activity form, or its pharmacologically acceptable salt:
Wherein
R 0Be hydrogen; alkyl; aralkyl; acyl group; cycloalkyl; formyl radical; haloalkyl; aminoalkyl group; alkoxyalkyl; phenoxyalkyl; hydroxyalkyl; aminocarboxyl; the alkylthio carbonyl; carboxyalkyl; the cycloalkyloxy alkyl; alkyl sulphinyl; alkyl sulphonyl; phenyl sulfonyl; the phenyl sulfinyl; mercaptoalkyl; alkylthio alkyl; the acyloxy ethanoyl; the acyloxy alkyl; randomly has substituent phenyl; randomly has substituent aromatic heterocycle group; randomly has substituent phenylalkyl; or formula-COOR 8Shown group (R wherein 8For hydrogen, alkyl, randomly have substituent aryl or randomly have substituent aralkyl);
R 1Be hydrogen;
R 2Be hydrogen, alkyl, aralkyl, acyl group, cycloalkyl, hydroxyl, thiol, halogen, amino, formyl radical, carboxyl, cyano group, nitro, alkylthio, haloalkyl, aminoalkyl group, amido, alkoxyl group, cycloalkyloxy, phenoxy group, the phenyl alkoxyl group, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxy carbonyl, aminocarboxyl, the alkylthio carbonyl, carboxyalkyl, the cycloalkyloxy alkyl, thiophenyl, alkyl sulphinyl, alkyl sulphonyl, phenyl sulfonyl, mercaptoalkyl, alkylthio alkyl, randomly has substituent phenyl, aromatic heterocycle group or phenylalkyl;
R 3For
(1) alkyl or haloalkyl,
(2) cycloalkyl,
(3) randomly have substituent phenyl,
(4) aromatic heterocycle group,
(5) derived from the group of phenyl ring, described phenyl ring and saturated or undersaturated 5 or 6 yuan carbocyclic fused,
(6) derived from the group of phenyl ring, described phenyl ring condenses with comprising 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, or
(7) derived from the group that comprises 1 to 3 heteroatomic 5 to 7 yuan of saturated or unsaturated carbocyclic, described carbocyclic ring and phenyl ring condense,
Wherein (2) to (7) listed group can have one or more substituting groups; Or
The group that is selected from following formula (II) and (III) represents:
Figure A038190360003C1
R wherein 6And R 7Respectively doing for oneself randomly has substituent phenyl or aromatic heterocycle group,
Perhaps, R 2And R 3Randomly comprise heteroatomic ring in conjunction with forming, wherein said ring can with randomly have substituent phenyl ring and condense;
R 4For
Alkoxy carbonyl,
Alkyl-carbonyl,
Alkyl sulphonyl,
Alkyl sulphinyl,
The phenyl sulfinyl,
Phenyl sulfonyl,
The dialkyl group phosphinyl,
The dialkyl phosphine acyl group,
Randomly have substituent phenyl,
Randomly have substituent aromatic heterocycle group,
Cyano group, or
Nitro; And
R 5For
Alkyl,
The phenyl amino alkyl,
Acyl group,
The acyl group alkyl,
Aminocarboxyl,
Aromatic yl aminocarbonyl,
Randomly have substituent 4 to 7 yuan of saturated or unsaturated heterocycles,
Have substituent 3 to 7 yuan of saturated carbon rings,
Saturated or unsaturated 4 to 7 yuan of cyclosubstituted alkyl of involved 1 or 2 nitrogen-atoms, described 4 to 7 yuan of rings can randomly have substituting group, or
Suc as formula-(CR aR b) nNR 11R 12Shown group, wherein n is 1 to 4 integer, R aBe hydrogen or alkyl, R bBe hydrogen or alkyl, R 11Be hydrogen, alkyl, alkyl sulphonyl, phenyl sulfonyl, phenylalkyl alkylsulfonyl, alkyl sulphinyl, phenyl sulfinyl, phenylalkyl sulfinyl, alkoxy carbonyl, phenyloxycarbonyl, phenyl alkoxy carbonyl, alkyl-carbonyl, phenylcarbonyl group or phenylalkyl carbonyl, and R 12Be hydrogen or alkyl,
Condition is to work as R 0, R 1And R 2Hydrogen, R respectively do for oneself 4Be methoxycarbonyl and R 5During for methyl, R then 3Be not phenyl, 2-chloro-phenyl-, 3-nitrophenyl, 4-carboxyl phenyl or 4-methoxycarbonyl phenyl, and work as R 5During for alkyl, R then 4Be not alkoxy carbonyl, alkyl sulphonyl, alkyl sulphinyl, phenyl sulfinyl, phenyl sulfonyl, dialkyl group phosphinyl, dialkyl phosphine acyl group, cyano group or nitro.
2. the dihydro-pyrazolo pyridine compounds of claim 1, or its optical activity form, or its pharmacologically acceptable salt, wherein
R 4Be alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl, alkyl sulphinyl, phenyl sulfinyl, phenyl sulfonyl, dialkyl group phosphinyl; the dialkyl phosphine acyl group, randomly have substituent phenyl, have substituent aromatic heterocycle group, cyano group or nitro, and
R 5For alkyl, phenyl amino alkyl, acyl group, acyl group alkyl, aminocarboxyl, aromatic yl aminocarbonyl, randomly have substituent saturated or unsaturated 4 to 7 yuan of heterocycles, have substituent saturated 3 to 7 yuan of carbocyclic rings, involved 1 or 2 nitrogen-atoms and randomly have substituent saturated or unsaturated 4 to 7 yuan of cyclosubstituted alkyl, or suc as formula-(CH 2) nNR 11R 12Shown group, wherein n is 1 to 4 integer, R 11Be hydrogen, alkyl, alkyl sulphonyl, phenyl sulfonyl, phenylalkyl alkylsulfonyl, alkyl sulphinyl, phenyl sulfinyl, phenylalkyl sulfinyl, alkoxy carbonyl, phenyloxycarbonyl, phenyl alkoxy carbonyl, alkyl-carbonyl, phenylcarbonyl group or phenylalkyl carbonyl, and
R 12Be hydrogen or alkyl.
3. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R 2Be hydrogen or alkyl.
4. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R 3For randomly having 1 to 3 substituent phenyl, naphthyl, 2,1,3-Ben Bing oxadiazole-4-base or 3,4-dihydro-2H-chromene-8-base.
5. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R 4For alkoxy carbonyl, alkyl-carbonyl with 2 to 5 carbon atoms with 2 to 5 carbon atoms, have the alkyl sulphonyl of 1 to 4 carbon atom or have the alkyl sulphinyl of 1 to 4 carbon atom.
6. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R 5For suc as formula-(CH 2) nNR 11R 12Shown group, wherein n is 1 to 4 integer, R 11Be hydrogen, alkyl or alkoxy carbonyl, and R 12Be hydrogen or alkyl.
7. claim 1 or 2 dihydro-pyrazolo pyridine compounds, or its optical activity form, or its pharmacologically acceptable salt, wherein R 0For hydrogen or suc as formula-COOR 8Shown group, wherein R 8For alkyl, randomly have a substituent aryl or randomly have substituent aralkyl.
8. claim 1 or 2 dihydro-pyrazolo pyridine compounds, its tautomer, its optical activity form or its pharmacologically acceptable salt, described compound is selected from:
(2) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(3) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(11) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine,
(14) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(23) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-(N, N-dimethylamino) cyclohexyl)-2H-pyrazolo [3,4-b] pyridine,
(27) 6-(1-ethanoyl-1,2,3,6-tetrahydropyridine-4-yl)-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(33) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(1-ethyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(37) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(38) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(41) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl piperidine-3-yl)-2H-pyrazolo [3,4-b] pyridine,
(46) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(4-methylmorpholine-2-yl)-2H-pyrazolo [3,4-b] pyridine,
(48) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(51) 6-(1-ethanoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(52) 6-(1-benzoyl piperidin-4-yl)-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(53) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(1-methylsulfonyl piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(59) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-6-(4-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine,
(62) 4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-6-(2-oxo hexanaphthene-1-yl)-2H-pyrazolo [3,4-b] pyridine,
(63) 6-ethanoyl methyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(73) 5-cyano group-4,7-dihydro-4-(2,3-(methylene-dioxy) phenyl)-6-(piperidin-4-yl)-2H-pyrazolo [3,4-b] pyridine,
(75) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-6-phenyl amino carbonyl-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(78) 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(4-phenylpiperazine-1-yl) methyl-2H-pyrazolo [3,4-b] pyridine,
(81) 6-ethanoyl-4-(2-bromo-3-cyano-phenyl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(82) 6-ethanoyl-4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-cyano group-4,7-dihydro-2H-pyrazolo [3,4-b] pyridine,
(84) 4-(2-bromo-3-cyano-phenyl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine,
(86) 4-(2-chloro-phenyl-)-5-cyano group-4,7-dihydro-6-(tetramethyleneimine-3-yl)-2H-pyrazolo [3,4-b] pyridine and
(87) 4-(2,1,3-Ben Bing oxadiazole-4-yl)-5-(pyridine-2-yl)-4,7-dihydro-6-propyl group-2H-pyrazolo [3,4-b] pyridine.
9. medicine, it comprises dihydro-pyrazolo pyridine compounds, its optical activity form or its pharmacologically acceptable salt of claim 1 or 2.
10. pharmaceutical composition, it comprises dihydro-pyrazolo pyridine compounds, its optical activity form or its pharmacologically acceptable salt of claim 1 or 2, and pharmaceutically acceptable additive.
11. a glycogen synthase kinase-3 beta inhibitor, it comprises the compound of the dihydro-pyrazolo pyridine compounds, its optical activity form and the pharmacologically acceptable salt thereof that are selected from claim 1.
12. the medicine of claim 9, it is used to prevent and/or treat by the too high disease that causes of glycogen synthase kinase-3 'beta ' activity.
13. the medicine of claim 9, it is used to prevent and/or treat the nerve degeneration disease.
14. the medicine of claim 13, wherein said disease are selected from Parkinson's neurological dysfunction after cerebral ischemia that Alzheimer, ischemic cerebral vascular disorder, Down's syndrome, brain amyloid blood vessel disease cause, stein-leventhal syndrome, subacute sclerosing panencephalitis Parkinson neurological dysfunction, the encephalitis, boxer's encephalopathic, Guam type Parkinson chronic brain syndrome, thunder dimension corpusculum disease, Pick's disease, the sex change of cortex Basal ganglia, volume temporal lobe type dementia, AIDS encephalopathic, Huntington's disease and manic depressive psychosis.
15. the medicine of claim 9, it is used to prevent and/or treat diabetes and diabetic complication.
16. the medicine of claim 9, it is as immunostimulant.
17. the medicine of claim 9, it is used to prevent and/or treat the tumour of alopecia, mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T cell or B cell leukemia or virus induction.
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